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Ebrahimi M, Ahmadieh H, Rezaei Kanavi M, Safi S, Alipour-Parsa S, Advani S, Sorenson CM, Sheibani N. Shared signaling pathways and comprehensive therapeutic approaches among diabetes complications. Front Med (Lausanne) 2025; 11:1497750. [PMID: 39845838 PMCID: PMC11750824 DOI: 10.3389/fmed.2024.1497750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 12/23/2024] [Indexed: 01/24/2025] Open
Abstract
The growing global prevalence of diabetes mellitus (DM), along with its associated complications, continues to rise. When clinically detected most DM complications are irreversible. It is therefore crucial to detect and address these complications early and systematically in order to improve patient care and outcomes. The current clinical practice often prioritizes DM complications by addressing one complication while overlooking others that could occur. It is proposed that the commonly targeted cell types including vascular cells, immune cells, glial cells, and fibroblasts that mediate DM complications, might share early responses to diabetes. In addition, the impact of one complication could be influenced by other complications. Recognizing and focusing on the shared early responses among DM complications, and the impacted cellular constituents, will allow to simultaneously address all DM-related complications and limit adverse treatment impacts. This review explores the current understanding of shared pathological signaling mechanisms among DM complications and recognizes new concepts that will benefit from further investigation in both basic and clinical settings. The ultimate goal is to develop more comprehensive treatment strategies, which effectively impact DM complications in multiple organs and improve patient care and outcomes.
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Affiliation(s)
- Moein Ebrahimi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Ahmadieh
- Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mozhgan Rezaei Kanavi
- Ocular Tissue Engineering Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sare Safi
- Ophthalmic Epidemiology Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Alipour-Parsa
- Cardiovascular Research Center, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soroor Advani
- Neurology Department, Shohada Tajrish Hospital, Shahid-Beheshti University of Medical Sciences, Tehran, Iran
| | - Christine M. Sorenson
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Nader Sheibani
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
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Yao Z, Lu Y, Wang P, Chen Z, Zhou L, Sang X, Yang Q, Wang K, Hao M, Cao G. The role of JNK signaling pathway in organ fibrosis. J Adv Res 2024:S2090-1232(24)00431-4. [PMID: 39366483 DOI: 10.1016/j.jare.2024.09.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/28/2024] [Accepted: 09/29/2024] [Indexed: 10/06/2024] Open
Abstract
BACKGROUND Fibrosis is a tissue damage repair response caused by multiple pathogenic factors which could occur in almost every apparatus and leading to the tissue structure damage, physiological abnormality, and even organ failure until death. Up to now, there is still no specific drugs or strategies can effectively block or changeover tissue fibrosis. JNKs, a subset of mitogen-activated protein kinases (MAPK), have been reported that participates in various biological processes, such as genetic expression, DNA damage, and cell activation/proliferation/death pathways. Increasing studies indicated that abnormal regulation of JNK signal pathway has strongly associated with tissue fibrosis. AIM OF REVIEW This review designed to sum up the molecular mechanism progresses in the role of JNK signal pathway in organ fibrosis, hoping to provide a novel therapy strategy to tackle tissue fibrosis. KEY SCIENTIFIC CONCEPTS OF REVIEW Recent evidence shows that JNK signaling pathway could modulates inflammation, immunoreaction, oxidative stress and Multiple cell biological functions in organ fibrosis. Therefore, targeting the JNK pathway may be a useful strategy in cure fibrosis.
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Affiliation(s)
- Zhouhui Yao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Yandan Lu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Pingping Wang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Ziyan Chen
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Licheng Zhou
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Xianan Sang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Qiao Yang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Kuilong Wang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Min Hao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; Songyang Research Institute of Zhejiang Chinese Medical University, Songyang, 323400, China.
| | - Gang Cao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
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Miyamoto S. Untangling the role of RhoA in the heart: protective effect and mechanism. Cell Death Dis 2024; 15:579. [PMID: 39122698 PMCID: PMC11315981 DOI: 10.1038/s41419-024-06928-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 07/17/2024] [Accepted: 07/19/2024] [Indexed: 08/12/2024]
Abstract
RhoA (ras homolog family member A) is a small G-protein that transduces intracellular signaling to regulate a broad range of cellular functions such as cell growth, proliferation, migration, and survival. RhoA serves as a proximal downstream effector of numerous G protein-coupled receptors (GPCRs) and is also responsive to various stresses in the heart. Upon its activation, RhoA engages multiple downstream signaling pathways. Rho-associated coiled-coil-containing protein kinase (ROCK) is the first discovered and best characterized effector or RhoA, playing a major role in cytoskeletal arrangement. Many other RhoA effectors have been identified, including myocardin-related transcription factor A (MRTF-A), Yes-associated Protein (YAP) and phospholipase Cε (PLCε) to regulate transcriptional and post-transcriptional processes. The role of RhoA signaling in the heart has been increasingly studied in last decades. It was initially suggested that RhoA signaling pathway is maladaptive in the heart, but more recent studies using cardiac-specific expression or deletion of RhoA have revealed that RhoA activation provides cardioprotection against stress through various mechanisms including the novel role of RhoA in mitochondrial quality control. This review summarizes recent advances in understanding the role of RhoA in the heart and its signaling pathways to prevent progression of heart disease.
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Affiliation(s)
- Shigeki Miyamoto
- Department of Pharmacology, University of California, San Diego, La Jolla, CA, 92093-0636, USA.
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Yuan L, Wang T, Duan J, Zhou J, Li N, Li G, Zhou H. Expression Profiles and Bioinformatic Analysis of Circular RNAs in Db/Db Mice with Cardiac Fibrosis. Diabetes Metab Syndr Obes 2024; 17:2107-2120. [PMID: 38799279 PMCID: PMC11128257 DOI: 10.2147/dmso.s465588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 05/15/2024] [Indexed: 05/29/2024] Open
Abstract
Introduction Cardiac fibrosis is one of the important causes of heart failure and death in diabetic cardiomyopathy (DCM) patients. Circular RNAs (circRNAs) are covalently closed RNA molecules in eukaryotes and have high stability. Their role in myocardial fibrosis with diabetic cardiomyopathy (DCM) remain to be fully elucidated. This study aimed to understand the expression profiles of circRNAs in myocardial fibrosis with DCM, exploring the possible biomarkers and therapeutic targets for DCM. Methods At 21 weeks of age, db/db mice established the type 2 DCM model measured by echocardiography, and the cardiac tissue was extracted for Hematoxylin-eosin, Masson's trichrome staining, and transmission electron microscopy. Subsequently, the expression profile of circRNAs in myocardial fibrosis of db/db mice was constructed using microarray hybridization and verified by real-time quantitative polymerase chain reaction. A circRNA-microRNA-messenger RNA coexpression network was constructed, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were done. Results Compared with normal control mice, db/db mice had 77 upregulated circRNAs and 135 downregulated circRNAs in their chromosomes (fold change ≥1.5, P ≤ 0.05). Moreover, the enrichment analysis of circRNA host genes showed that these differentially expressed circRNAs were mainly involved in mitogen-activated protein kinase signaling pathways. CircPHF20L1, circCLASP1, and circSLC8A1 were the key circRNAs. Moreover, circCLASP1/miR-182-5p/Wnt7a, circSLC8A1/miR-29b-1-5p/Col12a1, and most especially circPHF20L1/miR-29a-3p/Col6a2 might be three novel axes in the development of myocardial fibrosis in DCM. Conclusion The findings will provide some novel circRNAs and molecular pathways for the prevention or clinical treatment of DCM through intervention with specific circRNAs.
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Affiliation(s)
- Lingling Yuan
- Department of Endocrinology, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050004, People’s Republic of China
| | - Ting Wang
- Department of Endocrinology, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050004, People’s Republic of China
| | - Jinsheng Duan
- Department of Cardiology, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050004, People’s Republic of China
| | - Jing Zhou
- Department of Endocrinology, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050004, People’s Republic of China
| | - Na Li
- Department of Endocrinology, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050004, People’s Republic of China
| | - Guizhi Li
- Department of Endocrinology, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050004, People’s Republic of China
| | - Hong Zhou
- Department of Endocrinology, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050004, People’s Republic of China
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Bargavi P, Balakumar S, Raghunandhakumar S. Multi-functional bandage - bioactive glass/metal oxides/alginate composites based regenerative membrane facilitating re-epithelialization in diabetic wounds with sustained drug delivery and anti-bactericidal efficacy. Int J Biol Macromol 2024; 262:130054. [PMID: 38342258 DOI: 10.1016/j.ijbiomac.2024.130054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 02/05/2024] [Accepted: 02/06/2024] [Indexed: 02/13/2024]
Abstract
Chronic wounds, especially diabetic, foot and pressure ulcers are a major health problem affecting >10 % of the world's populace. Calcium phosphate materials, particularly, bioactive glasses (BG), used as a potential material for hard and soft tissue repair. This study combines nanostructured 45S5 BG with titania (TiO2) and alumina (Al2O3) into a composite via simple sol-gel method. Prepared composites with alginate (Alg) formed a bioactive nanocomposite hydrogel membrane via freezing method. X-ray diffraction revealed formation of two phases such as Na1.8Ca1.1Si6O14 and β-Na2Ca4(PO4)2SiO4 in the silica network. Fourier transformed InfraRed spectroscopy confirmed the network formation and cross-linking between composite and alginate. <2 % hemolysis, optimal in vitro degradation and porosity was systematically evaluated up to 7 days, resulting in increasing membrane bioactivity. Significant cytocompatibility, cell migration and proliferation and a 3-4-fold increase in Collagen (Col) and Vascular Endothelial Growth Factor (VEGF) expression were obtained. Sustained delivery of 80 % Dox in 24 h and effective growth reduction of S. aureus and destruction of biofilm development against E. coli and S. aureus within 24 h. Anatomical fin regeneration, rapid re-epithelialization and wound closure were achieved within 14 days in both zebrafish and in streptozotocin (STZ) induced rat in vivo animal models with optimal blood glucose levels. Hence, the fabricated bioactive membrane can act as effective wound dressing material, for diabetic chronic infectious wounds.
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Affiliation(s)
- P Bargavi
- National Centre for Nanoscience and Nanotechnology, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu, India; Department of Oral Pathology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai 600077, India
| | - S Balakumar
- National Centre for Nanoscience and Nanotechnology, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu, India.
| | - S Raghunandhakumar
- Department of Pharmacology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai 600077, India
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Song XM, Zhao MN, Li GZ, Li N, Wang T, Zhou H. Atorvastatin ameliorated myocardial fibrosis in db/db mice by inhibiting oxidative stress and modulating macrophage polarization. World J Diabetes 2023; 14:1849-1861. [PMID: 38222782 PMCID: PMC10784803 DOI: 10.4239/wjd.v14.i12.1849] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 09/29/2023] [Accepted: 10/23/2023] [Indexed: 12/14/2023] Open
Abstract
BACKGROUND People with diabetes mellitus (DM) suffer from multiple chronic complications due to sustained hyperglycemia, especially diabetic cardiomyopathy (DCM). Oxidative stress and inflammatory cells play crucial roles in the occurrence and progression of myocardial remodeling. Macrophages polarize to two distinct phenotypes: M1 and M2, and such plasticity in phenotypes provide macrophages various biological functions. AIM To investigate the effect of atorvastatin on cardiac function of DCM in db/db mice and its underlying mechanisms. METHODS DCM mouse models were established and randomly divided into DM, atorvastatin, and metformin groups. C57BL/6 mice were used as the control. Cardiac function was evaluated by echocardiography. Hematoxylin and eosin and Masson staining was used to examine the morphology and collagen fibers in myocardial tissues. The expression of transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β),M1 macrophages (iNOS+), and M2 macrophages (CD206+) were demonstrated by immunohistochemistry and immunofluorescence staining. The levels of TGF-β1, IL-1β, and TNF-α were detected by ELISA and real-time quantitative polymerase chain reaction. Malondialdehyde (MDA) concentrations and superoxide dismutase (SOD) ac-tivities were also measured. RESULTS Treatment with atorvastatin alleviated cardiac dysfunction and decreased db/db mice. The broken myocardial fibers and deposition of collagen in the myocardial interstitium were relieved especially by atorvastatin treatment. Atorvastatin also reduced the levels of serum lactate dehydrogenase, creatine kinase isoenzyme, and troponin; lowered the levels of TGF-β1, TNF-α and IL-1β in serum and myocardium; decreased the concentration of MDA and increased SOD activity in myocardium of db/db mice; inhibited M1 macrophages; and promoted M2 macrophages. CONCLUSION Administration of atorvastatin attenuates myocardial fibrosis in db/db mice, which may be associated with the antioxidative stress and anti-inflammatory effects of atorvastatin on diabetic myocardium through modulating macrophage polarization.
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Affiliation(s)
- Xian-Min Song
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
- Department of Geriatrics, Handan Central Hospital, Handan 056001, Hebei Province, China
| | - Meng-Nan Zhao
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Gui-Zhi Li
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Na Li
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Ting Wang
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Hong Zhou
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
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Li N, Zhu QX, Li GZ, Wang T, Zhou H. Empagliflozin ameliorates diabetic cardiomyopathy probably via activating AMPK/PGC-1α and inhibiting the RhoA/ROCK pathway. World J Diabetes 2023; 14:1862-1876. [PMID: 38222788 PMCID: PMC10784799 DOI: 10.4239/wjd.v14.i12.1862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/20/2023] [Accepted: 11/17/2023] [Indexed: 12/14/2023] Open
Abstract
BACKGROUND Diabetic cardiomyopathy (DCM) increases the risk of hospitalization for heart failure (HF) and mortality in patients with diabetes mellitus. However, no specific therapy to delay the progression of DCM has been identified. Mitochondrial dysfunction, oxidative stress, inflammation, and calcium handling imbalance play a crucial role in the pathological processes of DCM, ultimately leading to cardiomyocyte apoptosis and cardiac dysfunctions. Empagliflozin, a novel glucose-lowering agent, has been confirmed to reduce the risk of hospitalization for HF in diabetic patients. Nevertheless, the molecular mechanisms by which this agent provides cardioprotection remain unclear. AIM To investigate the effects of empagliflozin on high glucose (HG)-induced oxidative stress and cardiomyocyte apoptosis and the underlying molecular mechanism. METHODS Twelve-week-old db/db mice and primary cardiomyocytes from neonatal rats stimulated with HG (30 mmol/L) were separately employed as in vivo and in vitro models. Echocardiography was used to evaluate cardiac function. Flow cytometry and TdT-mediated dUTP-biotin nick end labeling staining were used to assess apoptosis in myocardial cells. Mitochondrial function was assessed by cellular ATP levels and changes in mitochondrial membrane potential. Furthermore, intracellular reactive oxygen species production and superoxide dismutase activity were analyzed. Real-time quantitative PCR was used to analyze Bax and Bcl-2 mRNA expression. Western blot analysis was used to measure the phosphorylation of AMP-activated protein kinase (AMPK) and myosin phosphatase target subunit 1 (MYPT1), as well as the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and active caspase-3 protein levels. RESULTS In the in vivo experiment, db/db mice developed DCM. However, the treatment of db/db mice with empagliflozin (10 mg/kg/d) for 8 wk substantially enhanced cardiac function and significantly reduced myocardial apoptosis, accompanied by an increase in the phosphorylation of AMPK and PGC-1α protein levels, as well as a decrease in the phosphorylation of MYPT1 in the heart. In the in vitro experiment, the findings indicate that treatment of cardiomyocytes with empagliflozin (10 μM) or fasudil (FA) (a ROCK inhibitor, 100 μM) or overexpression of PGC-1α significantly attenuated HG-induced mitochondrial injury, oxidative stress, and cardiomyocyte apoptosis. However, the above effects were partly reversed by the addition of compound C (CC). In cells exposed to HG, empagliflozin treatment increased the protein levels of p-AMPK and PGC-1α protein while decreasing phosphorylated MYPT1 levels, and these changes were mitigated by the addition of CC. Adding FA and overexpressing PGC-1α in cells exposed to HG substantially increased PGC-1α protein levels. In addition, no sodium-glucose cotransporter (SGLT)2 protein expression was detected in cardiomyocytes. CONCLUSION Empagliflozin partially achieves anti-oxidative stress and anti-apoptotic effects on cardiomyocytes under HG conditions by activating AMPK/PGC-1α and suppressing of the RhoA/ROCK pathway independent of SGLT2.
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Affiliation(s)
- Na Li
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Qiu-Xiao Zhu
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Gui-Zhi Li
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Ting Wang
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Hong Zhou
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
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Zhang LH, Wang J, Tan BH, Yin YB, Kang YM. Roux-en-Y Gastric Bypass Improves Insulin Sensitivity in Obese Rats with Type 2 Diabetes Mellitus by Regulating the Grin3a/AMPK Signal Axis in Hypothalamic Arcuate Nucleus. Diabetes Metab Syndr Obes 2023; 16:3617-3629. [PMID: 38028990 PMCID: PMC10644885 DOI: 10.2147/dmso.s430445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 10/21/2023] [Indexed: 12/01/2023] Open
Abstract
Objective The objective of this study was to explore the effects and related mechanisms of Roux-en-Y gastric bypass (RYGB) on insulin sensitivity in obese rats with type 2 diabetes mellitus (T2DM). Methods The obese T2DM rat model was constructed by feeding a high-fat diet and injecting streptozotocin (STZ), and treated with RYGB. Grin3a shRNA was injected into the bilateral hypothalamic arcuate nucleus (ARC) to knockdown the Grin3a expression on T2DM rats. Eight weeks after operation, the body weight, fasting blood glucose (FBG), fasting serum insulin (FSI), homeostatic model assessment of insulin resistance (HOMA-IR), and plasma triglyceride (TG) levels were assessed. Hematoxylin & eosin (H&E) staining was adopted to observe the white adipose tissue (WAT) of rats. Western blot and qRT-PCR were used to detect the expression of Grin3a, adenosine 5' monophosphate-activated protein kinase (AMPK) and p-AMPK in ARC of rats. Later, the plasmid over-expressing or knocking down Grin3a was transfected into differentiated 3T3-L1 adipocytes, and the TG level and the formation of lipid droplets in adipocyte were assessed by TG kit and oil red O staining. The expression of lipogenic transcription factors in cells was detected by qRT-PCR. Results RYGB reduced FBG, FSI, HOMA-IR and plasma TG levels in T2DM rats while increasing Grin3a expression and p-AMPK/AMPK ratio in ARC. Knockdown of Grin3a not only reversed the decrease of FBG, FSI, HOMA-IR and plasma TG levels in T2DM rats induced by RYGB, but also reversed the up-regulation of p-AMPK/AMPK ratio in ARC affected by RYGB. Moreover, knocking down Grin3a significantly increased the TG level, promoted the formation of lipid droplets and up-regulated the expressions of lipogenic transcription factors in adipocytes. Conclusion RYGB improved the insulin sensitivity, reduced the plasma TG level and lessens the fat accumulation in obese T2DM rats by regulating the Grin3a/AMPK signal in ARC.
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Affiliation(s)
- Li-Hai Zhang
- Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Basic Medical Sciences, Xi’an, People’s Republic of China
- Six Wards of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi, People’s Republic of China
| | - Jiao Wang
- Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Basic Medical Sciences, Xi’an, People’s Republic of China
- Six Wards of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi, People’s Republic of China
| | - Bai-Hong Tan
- Six Wards of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi, People’s Republic of China
| | - Yan-Bin Yin
- Six Wards of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi, People’s Republic of China
| | - Yu-Ming Kang
- Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Basic Medical Sciences, Xi’an, People’s Republic of China
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Wang T, Li N, Yuan L, Zhao M, Li G, Chen Y, Zhou H. MALAT1/miR-185-5p mediated high glucose-induced oxidative stress, mitochondrial injury and cardiomyocyte apoptosis via the RhoA/ROCK pathway. J Cell Mol Med 2023; 27:2495-2506. [PMID: 37395157 PMCID: PMC10468660 DOI: 10.1111/jcmm.17835] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 06/20/2023] [Accepted: 06/24/2023] [Indexed: 07/04/2023] Open
Abstract
To explore the underlying mechanism of lncRNA MALAT1 in the pathogenesis of diabetic cardiomyopathy (DCM). DCM models were confirmed in db/db mice. MiRNAs in myocardium were detected by miRNA sequencing. The interactions of miR-185-5p with MALAT1 and RhoA were validated by dual-luciferase reporter assays. Primary neonatal cardiomyocytes were cultured with 5.5 or 30 mmol/L D-glucose (HG) in the presence or absence of MALAT1-shRNA and fasudil, a ROCK inhibitor. MALAT1 and miR-185-5p expression were determined by real-time quantitative PCR. The apoptotic cardiomyocytes were evaluated using flow cytometry and TUNEL staining. SOD activity and MDA contents were measured. The ROCK activity, phosphorylation of Drp1S616 , mitofusin 2 and apoptosis-related proteins were analysed by Western blotting. Mitochondrial membrane potential was examined by JC-1. MALAT1 was significantly up-regulated while miR-185-5p was down-regulated in myocardium of db/db mice and HG-induced cardiomyocytes. MALAT1 regulated RhoA/ROCK pathway via sponging miR-185-5p in cardiomyocytes in HG. Knockdown of MALAT1 and fasudil all inhibited HG-induced oxidative stress, and alleviated imbalance of mitochondrial dynamics and mitochondrial dysfunction, accompanied by reduced cardiomyocyte apoptosis. MALAT1 activated the RhoA/ROCK pathway via sponging miR-185-5p and mediated HG-induced oxidative stress, mitochondrial damage and apoptosis of cardiomyocytes in mice.
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Affiliation(s)
- Ting Wang
- Department of EndocrinologyThe Second Hospital of Hebei Medical UniversityShijiazhuangPeople's Republic of China
| | - Na Li
- Department of EndocrinologyThe Second Hospital of Hebei Medical UniversityShijiazhuangPeople's Republic of China
| | - Lingling Yuan
- Department of EndocrinologyThe Second Hospital of Hebei Medical UniversityShijiazhuangPeople's Republic of China
| | - Mengnan Zhao
- Department of EndocrinologyThe Second Hospital of Hebei Medical UniversityShijiazhuangPeople's Republic of China
| | - Guizhi Li
- Department of EndocrinologyThe Second Hospital of Hebei Medical UniversityShijiazhuangPeople's Republic of China
| | - Yanxia Chen
- Department of EndocrinologyThe Second Hospital of Hebei Medical UniversityShijiazhuangPeople's Republic of China
| | - Hong Zhou
- Department of EndocrinologyThe Second Hospital of Hebei Medical UniversityShijiazhuangPeople's Republic of China
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Wang T, Yuan L, Chen Y, Wang J, Li N, Zhou H. Expression profiles and bioinformatic analysis of microRNAs in myocardium of diabetic cardiomyopathy mice. Genes Genomics 2023; 45:1003-1011. [PMID: 37253907 DOI: 10.1007/s13258-023-01403-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 05/15/2023] [Indexed: 06/01/2023]
Abstract
BACKGROUND MicroRNAs (miRNAs) can regulate expression of target genes at post transcriptional level, and mediate the pathophysiological process of many diseases. OBJECTIVE The study will illuminate the miRNA expression profiles of diabetic cardiomyopathy (DCM), seeking probable biomarkers of DCM at early stage and determining a target for the treatment of DCM. METHODS Db/db mice were used as an animal model of type 2 diabetes mellitus. At 22 weeks of age, cardiac function was evaluated by echocardiography, and the structural changes in myocardium were evaluated by HE staining and TEM. The miRNA expression profiles were detected using miRNA sequencing and differentially expressed miRNAs were validated by real-time PCR. Bioinformatic analysis was used to analyze target genes of these miRNAs and relevant pathways in DCM. RESULTS The results showed that 40 miRNAs were differentially expressed, including 28 upregulated miRNAs and 12 downregulated miRNAs. GO and KEGG pathway analysis showed that the target genes of up-regulated miRNAs were involved in 66 pathways, including Wnt, p53 and calcium signaling pathways, as well as FOXO and apoptosis signaling pathways, etc. The target genes of down-regulated miRNAs were involved in 68 pathways, including mitophagy, Ras and MAPK signaling pathways, etc. Moreover, some differentially expressed miRNAs were found in myocardium of DCM for the first time, such as miR-7225-5p, miR-696, miR-3470a, miR-3470b, miR-6240, miR-6538, miR-5128, miR-1195, miR-203-3p and miR-330-5p. CONCLUSIONS It is hoped that a few novel molecular pathways or targets of treatment for DCM would be found through understanding the expression features of miRNAs in diabetic myocardium.
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Affiliation(s)
- Ting Wang
- Department of Endocrinology, The second Hospital of Hebei Medical University, NO.215 Heping West Road, Xinhua District, 050051, Shijiazhuang, Hebei, PR China
| | - Lingling Yuan
- Department of Endocrinology, The second Hospital of Hebei Medical University, NO.215 Heping West Road, Xinhua District, 050051, Shijiazhuang, Hebei, PR China
| | - Yanxia Chen
- Department of Endocrinology, The second Hospital of Hebei Medical University, NO.215 Heping West Road, Xinhua District, 050051, Shijiazhuang, Hebei, PR China
| | - Jing Wang
- Department of Endocrinology, The second Hospital of Hebei Medical University, NO.215 Heping West Road, Xinhua District, 050051, Shijiazhuang, Hebei, PR China
| | - Na Li
- Department of Endocrinology, The second Hospital of Hebei Medical University, NO.215 Heping West Road, Xinhua District, 050051, Shijiazhuang, Hebei, PR China
| | - Hong Zhou
- Department of Endocrinology, The second Hospital of Hebei Medical University, NO.215 Heping West Road, Xinhua District, 050051, Shijiazhuang, Hebei, PR China.
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11
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Di X, Gao X, Peng L, Ai J, Jin X, Qi S, Li H, Wang K, Luo D. Cellular mechanotransduction in health and diseases: from molecular mechanism to therapeutic targets. Signal Transduct Target Ther 2023; 8:282. [PMID: 37518181 PMCID: PMC10387486 DOI: 10.1038/s41392-023-01501-9] [Citation(s) in RCA: 134] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 05/10/2023] [Accepted: 05/11/2023] [Indexed: 08/01/2023] Open
Abstract
Cellular mechanotransduction, a critical regulator of numerous biological processes, is the conversion from mechanical signals to biochemical signals regarding cell activities and metabolism. Typical mechanical cues in organisms include hydrostatic pressure, fluid shear stress, tensile force, extracellular matrix stiffness or tissue elasticity, and extracellular fluid viscosity. Mechanotransduction has been expected to trigger multiple biological processes, such as embryonic development, tissue repair and regeneration. However, prolonged excessive mechanical stimulation can result in pathological processes, such as multi-organ fibrosis, tumorigenesis, and cancer immunotherapy resistance. Although the associations between mechanical cues and normal tissue homeostasis or diseases have been identified, the regulatory mechanisms among different mechanical cues are not yet comprehensively illustrated, and no effective therapies are currently available targeting mechanical cue-related signaling. This review systematically summarizes the characteristics and regulatory mechanisms of typical mechanical cues in normal conditions and diseases with the updated evidence. The key effectors responding to mechanical stimulations are listed, such as Piezo channels, integrins, Yes-associated protein (YAP) /transcriptional coactivator with PDZ-binding motif (TAZ), and transient receptor potential vanilloid 4 (TRPV4). We also reviewed the key signaling pathways, therapeutic targets and cutting-edge clinical applications of diseases related to mechanical cues.
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Affiliation(s)
- Xingpeng Di
- Department of Urology and Institute of Urology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Xiaoshuai Gao
- Department of Urology and Institute of Urology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Liao Peng
- Department of Urology and Institute of Urology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Jianzhong Ai
- Department of Urology and Institute of Urology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Xi Jin
- Department of Urology and Institute of Urology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Shiqian Qi
- Department of Urology and Institute of Urology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, P.R. China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Hong Li
- Department of Urology and Institute of Urology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Kunjie Wang
- Department of Urology and Institute of Urology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, P.R. China.
| | - Deyi Luo
- Department of Urology and Institute of Urology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, P.R. China.
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Xiao C, Chen MY, Han YP, Liu LJ, Yan JL, Qian LB. The protection of luteolin against diabetic cardiomyopathy in rats is related to reversing JNK-suppressed autophagy. Food Funct 2023; 14:2740-2749. [PMID: 36852907 DOI: 10.1039/d2fo03871d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Increasing evidence has shown that impaired autophagy dramatically causes myocardial hypertrophy and fibrosis in the diabetic heart, ultimately leading to diabetic cardiomyopathy (DCM). Luteolin has been reported to effectively attenuate diabetic cardiovascular injury by inhibiting oxidative stress and alleviate sepsis-induced myocardial injury by enhancing autophagy. However, whether luteolin can reduce DCM through activating autophagy and the underlying mechanism remain unclear. Here, reversing the c-Jun N-terminal kinase (JNK)-suppressed autophagy pathway by which luteolin attenuates DCM was explored. Male Sprague-Dawley rats were injected with streptozotocin to induce diabetes. After 6 weeks of diabetes, rats were treated with luteolin (50, 100 and 200 mg kg-1, i.g.) for 4 weeks. Histological and functional alterations in the diabetic heart were determined using HE staining, Masson staining and echocardiography. The expressions of myocardial miR-221, JNK, and c-Jun and autophagic vesicles in diabetes were evaluated by quantitative PCR, Western blotting and electron microscopy. Luteolin significantly improved cardiac function and attenuated myocardial disorganization and fibrosis in the diabetic rat accompanying the dose-dependent down-regulation of JNK, c-Jun, miR-221 and p62, increase of LC3-II/I and autophagic vesicles, and decrease of mitochondrial swelling in the diabetic heart. These data suggest that the protection of luteolin against DCM, at least, is related to suppressing JNK/c-Jun-regulated miR-221 and the subsequent blockage of autophagy.
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Affiliation(s)
- Chi Xiao
- School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China.
| | - Meng-Yuan Chen
- School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China.
| | - Yu-Peng Han
- School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China.
| | - Li-Juan Liu
- School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China.
| | - Jia-Lin Yan
- School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China.
| | - Ling-Bo Qian
- School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, China.
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Proietti R, Giordani AS, Lorenzo CA. ROCK (RhoA/Rho Kinase) Activation in Atrial Fibrillation: Molecular Pathways and Clinical Implications. Curr Cardiol Rev 2023; 19:e171122210986. [PMID: 36625201 PMCID: PMC10280999 DOI: 10.2174/1573403x19666221117092951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 11/07/2022] [Accepted: 11/07/2022] [Indexed: 12/15/2022] Open
Abstract
Among the complex mechanisms of AF pathogenesis, intracellular calcium overload and oxidative stress play a major role, both triggered by inflammatory processes. The additional basic event taking place in AF is atrial fibrotic remodeling, again triggered by oxidative stress, which is determined by connexins rearrangement and differentiation of fibroblasts into active collagensecreting myofibroblasts. RhoA/ROCK system is the final pathway of a wide spectrum of molecular effectors such as Angiotensin II, platelet-derived growth factor, connective tissue growth factor and transforming growth factor β, that overall determine calcium dysregulation and pro-fibrotic remodeling. Both in experimental and clinical studies, RhoA/ROCK activation has been linked to superoxide ion production, fibrotic remodeling and connexins rearrangement, with important consequences for AF pathogenesis. ROCK pathway inhibition may therefore be a therapeutic or preventive target for special AF subgroups of patients.
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Affiliation(s)
- Riccardo Proietti
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom
| | - Andrea S. Giordani
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
| | - Calò A. Lorenzo
- Department of Medicine (DIMED), Nephrology, Dialysis and Transplantation Unit, University of Padua and Azienda Ospedale Università di Padova, Padua, Italy
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Impact of Glyphosate on the Development of Insulin Resistance in Experimental Diabetic Rats: Role of NFκB Signalling Pathways. Antioxidants (Basel) 2022; 11:antiox11122436. [PMID: 36552644 PMCID: PMC9774325 DOI: 10.3390/antiox11122436] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 11/23/2022] [Accepted: 11/24/2022] [Indexed: 12/14/2022] Open
Abstract
Glyphosate, an endocrine disruptor, has an adverse impact on human health through food and also has the potential to produce reactive oxygen species (ROS), which can lead to metabolic diseases. Glyphosate consumption from food has been shown to have a substantial part in insulin resistance, making it a severe concern to those with type 2 diabetes (T2DM). However, minimal evidence exists on how glyphosate impacts insulin-mediated glucose oxidation in the liver. Hence the current study was performed to explore the potential of glyphosate toxicity on insulin signaling in the liver of experimental animals. For 16 weeks, male albino Wistar rats were given 50 mg, 100 mg and 250 mg/kg b. wt. of glyphosate orally. In the current study, glyphosate exposure group was linked to a rise in fasting sugar and insulin as well as a drop in serum testosterone. At the same time, in a dose dependent fashion, glyphosate exposure showed alternations in glucose metabolic enzymes. Glyphosate exposure resulted in a raise in H2O2 formation, LPO and a reduction in antioxidant levels those results in impact on membrane integrity and insulin receptor efficacy in the liver. It also registered a reduced levels of mRNA and protein expression of insulin receptor (IR), glucose transporter-2 (GLUT2) with concomitant increase in the production of proinflammatory factors such as JNK, IKKβ, NFkB, IL-6, IL-1β, and TNF-α as well as transcriptional factors like SREBP1c and PPAR-γ leading to pro-inflammation and cirrhosis in the liver which results in the development of insulin resistance and type 2 diabetes. Our present findings for the first time providing an evidence that exposure of glyphosate develops insulin resistance and type 2 diabetes by aggravating NFkB signaling pathway in liver.
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Liu Q, Li HY, Wang SJ, Huang SQ, Yue Y, Maihemuti A, Zhang Y, Huang L, Luo L, Feng KN, Wu ZK. Belumosudil, ROCK2-Specific Inhibitor, alleviates cardiac fibrosis by inhibiting cardiac fibroblasts activation. Am J Physiol Heart Circ Physiol 2022; 323:H235-H247. [PMID: 35657612 DOI: 10.1152/ajpheart.00014.2022] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cardiac fibrosis is thought to be the hallmark of pathological hypertrophic remodeling, of which the myofibroblasts transdifferentiation is the key cell biological event. However, there is still no specific and effective therapeutic agent approved for cardiac fibrosis. To investigate the effects of Belumosudil, the first ROCK2-specific inhibitor, on cardiac hypertrophy, fibrosis and dysfunction induced by pressure overload, the transverse aortic constriction (TAC) or sham operation was carried out on wild-type C57BL/6 mice (male, 6-8 week old) under pentobarbital anesthesia. After that, mice were randomly divided into three groups: sham operation + vehicle, TAC + vehicle, TAC + 50 mg·kg-1·d-1 Belumosudil. We found that Belumosudil effectively ameliorated cardiac hypertrophy, fibrosis and dysfunction in TAC mice. To elucidate the underlying mechanism, we inhibited the expression of ROCK2 in vitro by either Belumosudil or siRNA. We showed that the inhibition of ROCK2 by either Belumosudil or knockdown suppressed cardiac fibroblasts activation and proliferation significantly induced by Transforming Growth Factor-β1 (TGF-β1). Furthermore, our study confirmed ROCK2 mediates cardiac fibrosis by interacting with Transforming Growth Factor-β1 (TGF-β1)/mothers against decapentaplegic homolog (Smad2) pathway. Taken together, we demonstrated that Belumosudil ameliorates cardiac hypertrophy and fibrosis induced by TAC via inhibiting cardiac fibroblasts activation. In conclusion, Belumosudil may be a promising therapeutic drug for cardiac hypertrophy and fibrosis induced by myocardial pressure overload.
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Affiliation(s)
- Quan Liu
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Hua-Yang Li
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Shun-Jun Wang
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Sui-Qing Huang
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Yuan Yue
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Adilai Maihemuti
- Department of Operating Room, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Yi Zhang
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Lin Huang
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Li Luo
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Kang-Ni Feng
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Zhong-Kai Wu
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
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Xie L, Wang T, Lin S, Lu Z, Wang Y, Shen Z, Cheng Y, Shen A, Peng J, Chu J. Uncaria Rhynchophylla attenuates angiotensin Ⅱ-induced myocardial fibrosis via suppression of the RhoA/ROCK1 pathway. Biomed Pharmacother 2022; 146:112607. [PMID: 35062072 DOI: 10.1016/j.biopha.2021.112607] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/26/2021] [Accepted: 12/26/2021] [Indexed: 11/15/2022] Open
Abstract
Uncaria rhynchophylla (UR), a traditional Chinese medicine, has been proven effective in treating hypertensive patients in China. However, the mechanisms of action of UR in reducing hypertension and myocardial fibrosis are still unclear. The purpose of this study was to explore the role of UR in an angiotensin Ⅱ (Ang Ⅱ) induced mouse model. The mice were randomly divided into 5 groups and infused with Ang Ⅱ (500 ng/kg/min) or saline, then administered UR (0.78, 1.56 or 3.12 g/kg/d) or saline for 4 weeks. UR treatment significantly attenuated the elevation of blood pressure caused by Ang Ⅱ. It enhanced myocardial function and attenuated the increase in the heart weight index and the pathological changes in the Ang Ⅱ-induced hypertensive mice. Furthermore, UR treatment inhibited cardiac fibrosis and significantly down-regulated collagen I, collagen Ⅲ, and α-SMA protein expression in cardiac tissues. UR also attenuated the expression of RhoA, ROCK1, CTGF, and TGF-β1. In cultured cardiac fibroblasts stimulated with Ang Ⅱ, UR significantly down-regulated the expression of Collagen I, Collagen III, RhoA, ROCK1, and α-SMA. In summary, UR can significantly attenuate Ang Ⅱ-induced hypertension and cardiac fibrosis, partly via suppression of the RhoA/ROCK1 signaling pathway.
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Affiliation(s)
- Lingling Xie
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Tianyi Wang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Shan Lin
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Zhuqing Lu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Yilian Wang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Zhiqing Shen
- The People's Hospital of Fujian Traditional Medical University, No. 602, 817 Middle Road, Taijiang District, Fuzhou, Fujian 350004, China.
| | - Ying Cheng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Aling Shen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Jun Peng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Jianfeng Chu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
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17
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Peng ML, Fu Y, Wu CW, Zhang Y, Ren H, Zhou SS. Signaling Pathways Related to Oxidative Stress in Diabetic Cardiomyopathy. Front Endocrinol (Lausanne) 2022; 13:907757. [PMID: 35784531 PMCID: PMC9240190 DOI: 10.3389/fendo.2022.907757] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/09/2022] [Indexed: 12/19/2022] Open
Abstract
Diabetes is a chronic metabolic disease that is increasing in prevalence and causes many complications. Diabetic cardiomyopathy (DCM) is a complication of diabetes that is associated with high mortality, but it is not well defined. Nevertheless, it is generally accepted that DCM refers to a clinical disease that occurs in patients with diabetes and involves ventricular dysfunction, in the absence of other cardiovascular diseases, such as coronary atherosclerotic heart disease, hypertension, or valvular heart disease. However, it is currently uncertain whether the pathogenesis of DCM is directly attributable to metabolic dysfunction or secondary to diabetic microangiopathy. Oxidative stress (OS) is considered to be a key component of its pathogenesis. The production of reactive oxygen species (ROS) in cardiomyocytes is a vicious circle, resulting in further production of ROS, mitochondrial DNA damage, lipid peroxidation, and the post-translational modification of proteins, as well as inflammation, cardiac hypertrophy and fibrosis, ultimately leading to cell death and cardiac dysfunction. ROS have been shown to affect various signaling pathways involved in the development of DCM. For instance, OS causes metabolic disorders by affecting the regulation of PPARα, AMPK/mTOR, and SIRT3/FOXO3a. Furthermore, OS participates in inflammation mediated by the NF-κB pathway, NLRP3 inflammasome, and the TLR4 pathway. OS also promotes TGF-β-, Rho-ROCK-, and Notch-mediated cardiac remodeling, and is involved in the regulation of calcium homeostasis, which impairs ATP production and causes ROS overproduction. In this review, we summarize the signaling pathways that link OS to DCM, with the intention of identifying appropriate targets and new antioxidant therapies for DCM.
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Affiliation(s)
- Meng-ling Peng
- Department of Cardiology, The First Hospital of Jilin University, Changchun, China
| | - Yu Fu
- Department of Cardiology, The First Hospital of Jilin University, Changchun, China
| | - Chu-wen Wu
- Department of Cardiology, The First Hospital of Jilin University, Changchun, China
| | - Ying Zhang
- Department of Cardiology, The First Hospital of Jilin University, Changchun, China
| | - Hang Ren
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, China
| | - Shan-shan Zhou
- Department of Cardiology, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Shan-shan Zhou,
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Tolomeu HV, Fraga CAM. The Outcomes of Small-Molecule Kinase Inhibitors and the Role of ROCK2 as a Molecular Target for the Treatment of Alzheimer's Disease. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2022; 21:188-205. [PMID: 34414875 DOI: 10.2174/1871527320666210820092220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 02/17/2021] [Accepted: 03/13/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Alzheimer's disease is rapidly becoming a major threat to public health, with an increasing number of individuals affected as the world's population ages. In this sense, studies have been carried out aiming at the identification of new small-molecule kinase inhibitors useful for the treatment of Alzheimer's disease. OBJECTIVE In the present study, we investigated the compounds developed as inhibitors of different protein kinases associated with the pathogenesis of Alzheimer's disease. METHODS The applied methodology was the use of the Clarivate Analytics Integrity and ClinicalTrials. com databases. Moreover, we highlight ROCK2 as a promising target despite being little studied for this purpose. A careful structure-activity relationship analysis of the ROCK2 inhibitors was performed to identify important structural features and fragments for the interaction with the kinase active site, aiming to rationally design novel potent and selective inhibitors. RESULTS We were able to notice some structural characteristics that could serve as the basis to better guide the rational design of new ROCK2 inhibitors as well as some more in-depth characteristics regarding the topology of the active site of both isoforms of these enzymes, thereby identifying differences that could lead to planning more selective compounds. CONCLUSION We hope that this work can be useful to update researchers working in this area, enabling the emergence of new ideas and a greater direction of efforts for designing new ROCK2 inhibitors to identify new therapeutic alternatives for Alzheimer's disease.
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Affiliation(s)
- Heber Victor Tolomeu
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil | Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941- 902 Rio de Janeiro, RJ, Brazil
| | - Carlos Alberto Manssour Fraga
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil | Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941- 902 Rio de Janeiro, RJ, Brazil
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Tuleta I, Frangogiannis NG. Fibrosis of the diabetic heart: Clinical significance, molecular mechanisms, and therapeutic opportunities. Adv Drug Deliv Rev 2021; 176:113904. [PMID: 34331987 PMCID: PMC8444077 DOI: 10.1016/j.addr.2021.113904] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 07/19/2021] [Accepted: 07/24/2021] [Indexed: 01/02/2023]
Abstract
In patients with diabetes, myocardial fibrosis may contribute to the pathogenesis of heart failure and arrhythmogenesis, increasing ventricular stiffness and delaying conduction. Diabetic myocardial fibrosis involves effects of hyperglycemia, lipotoxicity and insulin resistance on cardiac fibroblasts, directly resulting in increased matrix secretion, and activation of paracrine signaling in cardiomyocytes, immune and vascular cells, that release fibroblast-activating mediators. Neurohumoral pathways, cytokines, growth factors, oxidative stress, advanced glycation end-products (AGEs), and matricellular proteins have been implicated in diabetic fibrosis; however, the molecular links between the metabolic perturbations and activation of a fibrogenic program remain poorly understood. Although existing therapies using glucose- and lipid-lowering agents and neurohumoral inhibition may act in part by attenuating myocardial collagen deposition, specific therapies targeting the fibrotic response are lacking. This review manuscript discusses the clinical significance, molecular mechanisms and cell biology of diabetic cardiac fibrosis and proposes therapeutic targets that may attenuate the fibrotic response, preventing heart failure progression.
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Affiliation(s)
- Izabela Tuleta
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx NY, USA
| | - Nikolaos G Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx NY, USA.
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Jayaraman S, Devarajan N, Rajagopal P, Babu S, Ganesan SK, Veeraraghavan VP, Palanisamy CP, Cui B, Periyasamy V, Chandrasekar K. β-Sitosterol Circumvents Obesity Induced Inflammation and Insulin Resistance by down-Regulating IKKβ/NF-κB and JNK Signaling Pathway in Adipocytes of Type 2 Diabetic Rats. Molecules 2021; 26:molecules26072101. [PMID: 33917607 PMCID: PMC8038823 DOI: 10.3390/molecules26072101] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/19/2021] [Accepted: 03/19/2021] [Indexed: 01/23/2023] Open
Abstract
β-sitosterol (SIT), the most abundant bioactive component of vegetable oil and other plants, is a highly potent antidiabetic drug. Our previous studies show that SIT controls hyperglycemia and insulin resistance by activating insulin receptor and glucose transporter 4 (GLUT-4) in the adipocytes of obesity induced type 2 diabetic rats. The current research was undertaken to investigate if SIT could also exert its antidiabetic effects by circumventing adipocyte induced inflammation, a key driving factor for insulin resistance in obese individuals. Effective dose of SIT (20 mg/kg b.wt) was administered orally for 30 days to high fat diet and sucrose induced type-2 diabetic rats. Metformin, the conventionally used antidiabetic drug was used as a positive control. Interestingly, SIT treatment restores the elevated serum levels of proinflammatory cytokines including leptin, resistin, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) to normalcy and increases anti-inflammatory adipocytokines including adiponectin in type 2 diabetic rats. Furthermore, SIT decreases sterol regulatory element binding protein-1c (SREBP-1c) and enhances Peroxisome Proliferator–activated receptor-γ (PPAR-γ) gene expression in adipocytes of diabetic rats. The gene and protein expression of c-Jun-N-terminal kinase-1 (JNK1), inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) and nuclear factor kappa B (NF-κB) were also significantly attenuated in SIT treated groups. More importantly, SIT acts very effectively as metformin to circumvent inflammation and insulin resistance in diabetic rats. Our results clearly show that SIT inhibits obesity induced insulin resistance by ameliorating the inflammatory events in the adipose tissue through the downregulation of IKKβ/NF-κB and c-Jun-N-terminal kinase (JNK) signaling pathway.
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Affiliation(s)
- Selvaraj Jayaraman
- Department of Biochemistry, Saveetha Institute of Medical and Technical Sciences, Saveetha Dental College and Hospitals, Saveetha University, Chennai, Tamil Nadu 600077, India; (S.B.); (V.P.V.)
- Correspondence: (S.J.); (K.C.)
| | - Nalini Devarajan
- Central Research Laboratory, Meenakshi Ammal Dental College, Meenakshi Academy of Higher Education and Research, Maduravoyal, Chennai, Tamil Nadu 600095, India;
| | - Ponnulakshmi Rajagopal
- Central Research Laboratory, Meenakshi Academy of Higher Education and Research, Chennai, Tamil Nadu 600078, India;
| | - Shyamaladevi Babu
- Department of Biochemistry, Saveetha Institute of Medical and Technical Sciences, Saveetha Dental College and Hospitals, Saveetha University, Chennai, Tamil Nadu 600077, India; (S.B.); (V.P.V.)
| | - Senthil Kumar Ganesan
- Structural Biology & Bioinformatics Division, TRUE Campus, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India;
| | - Vishnu Priya Veeraraghavan
- Department of Biochemistry, Saveetha Institute of Medical and Technical Sciences, Saveetha Dental College and Hospitals, Saveetha University, Chennai, Tamil Nadu 600077, India; (S.B.); (V.P.V.)
| | - Chella Perumal Palanisamy
- State Key Laboratory of Biobased Materials and Green Papermaking, College of Food Science and Engineering, Qilu University of Technology, Shandong Academy of Science, Jinan 250353, China; (C.P.P.); (B.C.)
| | - Bo Cui
- State Key Laboratory of Biobased Materials and Green Papermaking, College of Food Science and Engineering, Qilu University of Technology, Shandong Academy of Science, Jinan 250353, China; (C.P.P.); (B.C.)
| | - Vijayalakshmi Periyasamy
- Department of Biotechnology and Bioinformatics, Holy Cross College, Trichy, Tamil Nadu 620002, India;
| | - Kirubhanand Chandrasekar
- Department of Anatomy, All India Institute of Medical Sciences, Nagpur, Maharashtra 440025, India
- Correspondence: (S.J.); (K.C.)
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Bai Y, Du Q, Zhang L, Li L, Tang L, Zhang W, Du R, Li P, Li L. Fasudil alleviated insulin resistance through promotion of proliferation, attenuation of cell apoptosis and inflammation and regulation of RhoA/Rho kinase/insulin/nuclear factor-κB signalling pathway in HTR-8/SVneo cells. J Pharm Pharmacol 2021; 73:1118-1127. [PMID: 33779714 DOI: 10.1093/jpp/rgab033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 02/10/2021] [Indexed: 01/12/2023]
Abstract
OBJECTIVES The aim of this study was to evaluate the effects of fasudil on insulin resistance (IR) in HTR-8/SVneo cells. METHODS HTR-8/SVneo cells were treated with insulin or/and fasudil. Cell proliferation, apoptosis, inflammation and related signalling pathways were assessed. KEY FINDINGS Insulin treatment significantly enhanced the protein expressions of RhoA and Rho kinase (ROCK1 and ROCK2), but decreased glucose consumption. Administration of fasudil effectively promoted glucose uptake. Moreover, fasudil enhanced cell viability and the level of proliferating cell nuclear antigen (PCNA). Insulin-mediated cell apoptosis was inhibited by fasudil via the down-regulation of bax and cleaved-caspase-3, and the up-regulation of bcl-2. At the same time, fasudil led to the reduction of IL-1β, TNF-α, IL-6 and IL-8 mRNA levels in insulin-treated cells. In addition, RhoA, ROCK2 and phosphorylated myosin phosphatase target subunit-1 (p-MYPT-1) expressions were down-regulated by fasudil. Importantly, fasudil activated insulin receptor substrate-1 (IRS-1) through increasing p-IRS-1 (Tyr612) and p-Akt expressions. The nuclear NF-κB p65 and p-IκB-α levels were reduced via the administration of fasudil in insulin-treated cells. CONCLUSIONS Fasudil mitigated IR by the promotion of cell proliferation, inhibition of apoptosis and inflammation and regulation of RhoA/ROCK/insulin/NF-κB signalling pathway through in vitro studies.
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Affiliation(s)
- Yu Bai
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Qiang Du
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Le Zhang
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Ling Li
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Lei Tang
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Wei Zhang
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Runyu Du
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Ping Li
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Ling Li
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
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22
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Sharma P, Roy K. ROCK-2-selective targeting and its therapeutic outcomes. Drug Discov Today 2020; 25:446-455. [DOI: 10.1016/j.drudis.2019.11.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 11/08/2019] [Accepted: 11/30/2019] [Indexed: 01/21/2023]
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You P, Cheng Z, He X, Deng J, Diao J, Chen H, Cheng G. Lin28a protects against diabetic cardiomyopathy through Mst1 inhibition. J Cell Physiol 2019; 235:4455-4465. [PMID: 31637712 DOI: 10.1002/jcp.29321] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 09/30/2019] [Indexed: 11/06/2022]
Abstract
Lin28a has been found to enhance glucose uptake and insulin sensitivity. Lin28a alleviates cardiac dysfunction under various pathological conditions. However, the effects and underlying mechanisms of Lin28a on diabetic cardiomyopathy (DCM) are not well-understood. The aim of this study was to determine whether Lin28a protects against DCM and the potential mechanisms. Two to three days old mouse neonatal primary cardiomyocytes were randomized for treatment with adenoviruses harboring Lin28a and mammalian sterile 20-like kinase 1 (Mst1) short hairpin RNA, 48 hr before culturing in normal or high glucose medium. Cardiomyocyte apoptosis, autophagy, mitochondrial morphology, adenosine triphosphate content, and cytokine levels in the high glucose or normal conditions were observed between all groups. Either Lin28a overexpression or Mst1 knockdown alleviated mitochondrial ultrastructure impairment, decreased cytokine levels, inhibited apoptosis, and enhanced autophagy in primary neonatal mouse cardiomyocytes treated with high glucose. Importantly, the protective effects of Lin28a and Mst1 disappeared after treatment with 3-methyladenine, an autophagy inhibitor. Interestingly, in Mst1 knockdown cardiomyocytes, Lin28a overexpression failed to further enhance autophagy and alleviate high glucose-induced cardiomyocyte injury, which implies the protective roles of Lin28a counteracting high glucose-induced cardiomyocyte injury are dependent on Mst1 inhibition. Furthermore, co-immunoprecipitation and immunofluorescence double staining suggested that there were no direct interactions between Mst1 and Lin28a. Lin28a increased the expression of Akt, which inhibited the activation of Mst1-mediated apoptotic pathways.
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Affiliation(s)
- Penghua You
- Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.,Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Zheng Cheng
- Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Xiaomin He
- Department of Internal Medicine, The Hospital of Xi'an University of Technology, Xi'an, China
| | - Jizhao Deng
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Jiayu Diao
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Haichao Chen
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Gong Cheng
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
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Anaruma CP, Pereira RM, Cristina da Cruz Rodrigues K, Ramos da Silva AS, Cintra DE, Ropelle ER, Pauli JR, Pereira de Moura L. Rock protein as cardiac hypertrophy modulator in obesity and physical exercise. Life Sci 2019; 254:116955. [PMID: 31626788 DOI: 10.1016/j.lfs.2019.116955] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 10/02/2019] [Accepted: 10/10/2019] [Indexed: 01/03/2023]
Abstract
Obesity and cardiovascular diseases are worldwide public health issues. In this review, we discussed the participation of ROCK protein in cardiac hypertrophy, mainly through the modulation of leptin and insulin signaling pathways. Leptin plays a role in cardiovascular disease development and, through the Rho-associated protein kinase (ROCK), promotes cardiac hypertrophy. ROCK protein, is regulated by small Rho-GTPases and has two isoforms with high homology. ROCK is able to activate the MAP kinase (MAPK) pathway and modulate insulin signaling in the heart, participating in cardiac hypertrophy development of concentric and eccentric left ventricle growth. Although different types of stimulus can lead to morphologically antagonistic heart growth, physical exercise promotes improvements in hemodynamic function, emerging as a promising non-pharmacological tool to improve overall health. Leptin can activate ROCK in a pathological way, increasing MAPK activity and decreasing insulin signaling via insulin receptor substrate 1 (IRS1) serine 307 residue phosphorylation, phosphatase and tensin homolog, and protein kinase Cβ2. In turn, physical exercise decreases leptin levels and positively modulates insulin signaling as well as increases ROCK-dependent IRS1 (Ser632/635) phosphorylation, improving phosphatidylinositol 3-kinase/protein kinase B axis and promoting physiologic heart growth. Currently, there is a lack of studies about differences in ROCK isoforms, especially during exercise and/or obesity. However, the understanding of its biological function and the complex mechanism underlying the distinct types of cardiac hypertrophy development can be a useful tool in the improvement and treatment of cardiovascular outcomes.
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Affiliation(s)
- Chadi Pellegrini Anaruma
- Department of Physical Education, Institute of Biosciences - São Paulo State University (UNESP), Rio Claro, SP, Brazil; Exercise Cell Biology Lab (ECEBIL), School of Applied Science - University of Campinas, Limeira, SP, Brazil
| | - Rodrigo Martins Pereira
- Exercise Cell Biology Lab (ECEBIL), School of Applied Science - University of Campinas, Limeira, SP, Brazil; CEPECE - Center of Research in Sport Sciences, School of Applied Sciences - University of Campinas (UNICAMP), Limeira, SP, Brazil
| | - Kellen Cristina da Cruz Rodrigues
- Exercise Cell Biology Lab (ECEBIL), School of Applied Science - University of Campinas, Limeira, SP, Brazil; CEPECE - Center of Research in Sport Sciences, School of Applied Sciences - University of Campinas (UNICAMP), Limeira, SP, Brazil
| | | | - Dennys Esper Cintra
- CEPECE - Center of Research in Sport Sciences, School of Applied Sciences - University of Campinas (UNICAMP), Limeira, SP, Brazil; Laboratory of Nutritional Genomics (LabGeN), School of Applied Science - University of Campinas, Limeira, SP, Brazil
| | - Eduardo Rochete Ropelle
- CEPECE - Center of Research in Sport Sciences, School of Applied Sciences - University of Campinas (UNICAMP), Limeira, SP, Brazil; Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Science - University of Campinas, Limeira, SP, Brazil
| | - José Rodrigo Pauli
- CEPECE - Center of Research in Sport Sciences, School of Applied Sciences - University of Campinas (UNICAMP), Limeira, SP, Brazil; Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Science - University of Campinas, Limeira, SP, Brazil
| | - Leandro Pereira de Moura
- Department of Physical Education, Institute of Biosciences - São Paulo State University (UNESP), Rio Claro, SP, Brazil; Exercise Cell Biology Lab (ECEBIL), School of Applied Science - University of Campinas, Limeira, SP, Brazil; CEPECE - Center of Research in Sport Sciences, School of Applied Sciences - University of Campinas (UNICAMP), Limeira, SP, Brazil.
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Zhao L, Zhang Q, Liang J, Li J, Tan X, Tang N. Astrocyte elevated gene-1 induces autophagy in diabetic cardiomyopathy through upregulation of KLF4. J Cell Biochem 2018; 120:9709-9715. [PMID: 30520133 DOI: 10.1002/jcb.28249] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 10/22/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Astrocyte elevated gene-1 (AEG-1), also known as metadherin, 3D3, and lysine-rich carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) coisolated, has emerged as an important oncogene that is overexpressed in a variety of cancers. Previous studies revealed that AEG-1 is also involved in multiple physiological and pathological processes, such as development, inflammation, neurodegeneration, migraine, and Huntington's disease. However, the function of AEG-1 in diabetic cardiomyopathy (DCM) has not been reported yet. Therefore, we conducted this study to characterize the potential role and mechanism of AEG-1 in DCM rats. METHODS DCM was induced by injections of streptozocin (STZ) in Wistar rats. Rats were randomized to be injected with lentivirus carrying AEG-1 small interfering RNA. Haemodynamic changes of Wistar rats, assessment of cardiac weight index, and the expression of AEG-1 and KLF4 were detected and compared among these three groups. RESULTS The expressions of AEG-1 and KLF4 in the STZ group were significantly elevated in cardiac tissues compared with the control group. Knockdown of AEG-1 significantly increased the values of left ventricular ejection fraction, ±dp/dt max , repressed autophagy, as well as upregulated the expression of KLF4. CONCLUSIONS Knockdown of AEG-1 suppresses autophagy in DCM by downregulating the expression of KLF4. This study provide first-notion evidence for the potential value of AEG-1 as a therapeutic target for the treatment of the patients with DCM.
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Affiliation(s)
- Lichun Zhao
- Department of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
| | - Qianhua Zhang
- Department of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
| | - Jie Liang
- Department of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
| | - Junxiu Li
- Department of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
| | - Xiaoming Tan
- Department of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
| | - Nong Tang
- Department of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
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26
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Zheng W, Li D, Gao X, Zhang W, Robinson BO. Carvedilol alleviates diabetic cardiomyopathy in diabetic rats. Exp Ther Med 2018; 17:479-487. [PMID: 30651825 DOI: 10.3892/etm.2018.6954] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 09/27/2018] [Indexed: 01/06/2023] Open
Abstract
Diabetic cardiomyopathy (DCM) is characterized by structural and functional changes in the myocardium. Several studies have revealed that myocardial apoptosis and fibrosis occur during DCM. Studies have also indicated that oxidative stress may be a major factor associated with the development of DCM. Protein kinase C (PKC)β2 has been demonstrated to be activated in diabetic rats, and overexpression of PKCβ2 in the myocardium may result in cardiac hypertrophy and fibrosis. The P66shc adaptor protein, which is mediated by PKCβ, serves an important role in apoptosis during oxidative stress. The aim of the present study was to investigate whether the PKCβ2/P66shc oxidative stress pathway is associated with DCM, and to investigate the role and mechanisms of carvedilol in preserving cardiac function. Experimental diabetic rat models were induced by streptozotocin treatment accompanied by high energy intake. Carvedilol was orally administrated at a dose of 1 or 10 mg/kg/day. Cardiac function was evaluated by serum N-terminal pro-B-type natriuretic peptide level and cardiac ultrasound. Myocardial inflammation, oxidative stress, apoptosis and fibrosis were assessed by histopathological and echocardiographic analyses and tests for oxidative markers. Associated proteins and factors were examined by immunohistochemical and western blot analyses. Rats in the diabetes mellitus group exhibited significantly decreased systolic cardiac function along with elevated expression levels of phosphorylated (p)-PKCβ2, phos-P66shc, caspase-3, malondialdehyde, collagen type I, tumor necrosis factor-α and interleukin-1β, which were accompanied by disorder in metabolic processes. Treatment with carvedilol reversed these changes. Thus, the present results suggest that the PKCβ2/P66shc signaling pathway may be associated with diabetic cardiomyopathy; furthermore, carvedilol, as a novel β-receptor blocker, may protect the myocardium from injury by suppressing the myocardial inflammatory response, fibrosis, P66shc-mediated oxidative stress and subsequent apoptosis in myocardial tissue. Consequently, carvedilol may have potential as a therapy for the treatment of DCM.
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Affiliation(s)
- Wencheng Zheng
- Fourth Department of Cardiology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Ding Li
- Department of Cardiac Electrophysiology, Peking University People's Hospital, Peking University, Beijing 100044, P.R. China
| | - Xiang Gao
- First Department of Cardiology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Wenqian Zhang
- Department of Neurosurgery, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Barry O Robinson
- Department of Non-Invasive Cardiovascular Services, Brookwood Health Hospital, Birmingham, AL 35211, USA
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Zhou H, Sun Y, Zhang L, Kang W, Li N, Li Y. The RhoA/ROCK pathway mediates high glucose-induced cardiomyocyte apoptosis via oxidative stress, JNK, and p38MAPK pathways. Diabetes Metab Res Rev 2018; 34:e3022. [PMID: 29745021 DOI: 10.1002/dmrr.3022] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Revised: 04/09/2018] [Accepted: 04/20/2018] [Indexed: 12/21/2022]
Abstract
AIMS To understand the roles of the RhoA/ROCK and mitogen-activated protein kinase (MAPK) pathways in high glucose (HG)-induced apoptosis and oxidative stress in cardiomyocytes. MATERIALS AND METHODS Neonatal rat cardiomyocytes were cultured in Dulbecco's modified Eagle's medium, supplemented with 5.5 or 30 mmol/L D-glucose, in the presence or absence of fasudil (50 or 100 μM), SB203580, SP600125, or PD98059 (10 μM, respectively). The percentage of early apoptotic cardiomyocytes was evaluated using flow cytometry. The superoxide dismutase activity and malondialdehyde contents in the cellular supernatants were measured. The Bax and Bcl-2 mRNA levels were determined by quantitative real-time PCR. Phosphorylation of myosin phosphatase target subunit 1 (MYPT1), p38MAPK, JNK, and ERK as well as the protein levels of Bax, Bcl-2, and cleaved caspase-3 was analysed by Western blot. RESULTS Fasudil, SB203580, and SP600125 effectively inhibited the HG-induced early apoptosis increase and decreased Bax mRNA expression, the Bax/Bcl-2 protein expression ratio, and cleaved caspase-3 protein levels in the cardiomyocytes; this was accompanied by upregulation of the Bcl-2 mRNA. Moreover, fasudil markedly increased the superoxide dismutase activity level and suppressed the elevation in HG-induced malondialdehyde content and the phosphorylation of MYPT1, p38MAPK and JNK. CONCLUSIONS The RhoA/ROCK pathway mediates HG-induced cardiomyocyte apoptosis via oxidative stress and activation of p38MAPK and JNK in neonatal rats in vitro. Fasudil effectively ameliorates HG-induced cardiomyocyte apoptosis by suppressing oxidative stress and the p38MAPK and JNK pathways.
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Affiliation(s)
- Hong Zhou
- Department of Endocrinology, the Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yonghong Sun
- Nutriology, the Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lihui Zhang
- Department of Endocrinology, the Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Wenyuan Kang
- Department of Endocrinology, the Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Na Li
- Department of Endocrinology, the Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yongjun Li
- Cardiology, the Second Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Institute of Cardiovascular and Cerebrovascular Diseases, Shijiazhuang, China
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Yan Q, Wang X, Zha M, Yu M, Sheng M, Yu J. The RhoA/ROCK signaling pathway affects the development of diabetic nephropathy resulting from the epithelial to mesenchymal transition. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:4296-4304. [PMID: 31949826 PMCID: PMC6962964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 04/28/2018] [Indexed: 06/10/2023]
Abstract
Diabetic nephropathy is a common complication of type 2 diabetes and is related to the epithelial to mesenchymal transition. In this study, we aimed to find whether the RhoA/ROCK pathway affects the development of diabetic nephropathy caused by the epithelial to mesenchymal transition both in vivo and in vitro. The results show that inhibition of the RhoA/ROCK signaling pathway improved the pathology and degree of fibrosis in diabetic nephropathy as determined by hematoxylin and eosin staining and Masson staining. We also found, using immunohistochemistry and quantitative reverse transcription polymerase chain reaction, that a RhoA/Rock inhibitor regulated relative protein and gene expression levels in a dose-dependent manner. Furthermore, the inhibitor improved fibrosis induced by high levels of glucose in HK-2 cells by suppressing E-cadherin, α-SMA, and FSP-1 expression. In conclusion, the RhoA/ROCK signaling pathway plays an important role in the development of diabetic nephropathy and could be a potential therapeutic target for type 2 diabetes.
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Affiliation(s)
- Qianhua Yan
- Department of Endocrinology, Jiangsu Province Hospital of Traditional Chinese Medicine, The Affiliated Hospital of Nanjing University of Traditional Chinese MedicineNanjing, China
| | - Xin Wang
- Department of Endocrinology, Jiangsu Province Hospital of Traditional Chinese Medicine, The Affiliated Hospital of Nanjing University of Traditional Chinese MedicineNanjing, China
| | - Min Zha
- Department of Endocrinology, Jiangsu Province Hospital of Traditional Chinese Medicine, The Affiliated Hospital of Nanjing University of Traditional Chinese MedicineNanjing, China
| | - Manshu Yu
- Nanjing University of Chinese MedicineNanjing, China
| | - Meixiao Sheng
- Department of Nephropathy, Jiangsu Province Hospital of Traditional Chinese Medicine, The Affiliated Hospital of Nanjing University of Traditional Chinese MedicineNanjing, China
| | - Jiangyi Yu
- Department of Endocrinology, Jiangsu Province Hospital of Traditional Chinese Medicine, The Affiliated Hospital of Nanjing University of Traditional Chinese MedicineNanjing, China
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MicroRNA-410-5p exacerbates high-fat diet-induced cardiac remodeling in mice in an endocrine fashion. Sci Rep 2018; 8:8780. [PMID: 29884823 PMCID: PMC5993721 DOI: 10.1038/s41598-018-26646-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 04/30/2018] [Indexed: 12/15/2022] Open
Abstract
Metabolic disorders, such as obesity and type 2 diabetes, are associated with an increased risk of cardiomyopathy. To date, microRNA (miRNAs) functions in cardiac remodeling induced by obesity remain to be elucidated. We found that rats fed a high fat diet (HFD) manifested cardiac fibrosis and LV dysfunction. In the heart of rats fed HFD, the phosphorylation levels of Smad 2 and the expression of fibrotic genes, such as connective tissue growth factor, collagen-1α1 (Col1α1), Col3α1, and Col4α1, were up-regulated, which accompanied by an increase in Smad 7 protein levels, but not its mRNA levels. Using miRNA microarray analysis, we showed that the miRNA miR-410-5p inhibited the protein expression of Smad 7, thus increasing the phosphorylation levels of Smad 2. Overexpression of miR-410-5p promoted cardiac fibrosis in rats fed normal diet, whereas inhibition of miR-410-5p by way of miR-410-5p antimiR suppressed cardiac fibrosis in rats fed HFD. Finally, our data revealed that miR-410-5p from the kidney and adipose tissues was probably transferred to heart to induce cardiac fibrosis. Taken together, our study characterizes an endocrine mechanism in which adipose- or kidney-derived circulating miR-410-5p regulates metabolic disorders-mediated cardiac remodeling by activating the TGFβ/Smad signaling in heart.
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30
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Katare R, Pearson JT, Lew JKS, Wei M, Tsuchimouchi H, Du CK, Zhan DY, Umetani K, Shirai M, Schwenke DO. Progressive Decrease in Coronary Vascular Function Associated With Type 2 Diabetic Heart Disease. Front Physiol 2018; 9:696. [PMID: 29928236 PMCID: PMC5997806 DOI: 10.3389/fphys.2018.00696] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 05/18/2018] [Indexed: 12/18/2022] Open
Abstract
Background: The causal factors underpinning the onset and progression of diabetic heart disease (DHD) remain to be fully elucidated. Myocardial function is critically dependent on optimal coronary blood flow. Considering vascular disease occurs early in diabetes due to endothelial dysfunction, this study aimed to determine whether impaired coronary perfusion contributes to the origins of myocardial dysfunction in DHD, or whether coronary and cardiac dysfunction are independent pathologies associated with diabetes. Methods: Synchrotron radiation microangiography was used to image the coronary circulation of type-2 diabetic db/db and non-diabetic db/+ mice in vivo at 8, 16, and 24 weeks of age. We further assessed vascular function based on the vasodilatory responses to acetylcholine (ACh, 3 μg/kg/min), sodium nitroprusside (SNP, 5 μg/kg/min) and the Rho-kinase inhibitor, fasudil (20 mg/kg, i.v.). Cardiac function was assessed using echocardiography, and cardiac eNOS and ROCK expression were measured using immunohistochemistry. Results: Coronary and cardiac function were normal in 8-week-old diabetic mice. However, by 16 weeks of age, diabetic mice had advanced cardiac dysfunction. In comparison, normal coronary perfusion was preserved in diabetes until 24 weeks of age. Moreover, only the 24-week-old diabetic mice showed clear evidence of advanced coronary vascular dysfunction, based on (i) the absence of a vasodilatory response to ACh, and (ii) an exaggerated vasodilatory response to fasudil. Interestingly, fasudil also restored normal coronary perfusion in the 24-week-old diabetic heart by restoring blood flow to previously constricted vessels (diameter < 100 μm). Importantly, there was a ubiquitous decrease, and increase, in the cardiac expression of eNOS and ROCK, respectively. Conclusion: These results suggest that both cardiac and coronary dysfunction appear to have independent origins associated with diabetes and Rho-kinase pathway may be playing a role in the onset and progression of DHD.
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Affiliation(s)
- Rajesh Katare
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - James T Pearson
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan.,Bioscience Discovery Institute and Department of Physiology, Monash University, Melbourne, VIC, Australia
| | - Jason Kar-Sheng Lew
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Melanie Wei
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Hirotsugu Tsuchimouchi
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
| | - Cheng-Kun Du
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
| | - Dong-Yun Zhan
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
| | - Keiji Umetani
- Japan Synchrotron Radiation Research Institute, Hyōgo, Japan
| | - Mikiyasu Shirai
- Department of Advanced Medical Research for Pulmonary Hypertension, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
| | - Daryl O Schwenke
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
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Inhibition of Rho-kinase Attenuates Left Ventricular Remodeling Caused by Chronic Intermittent Hypoxia in Rats via Suppressing Myocardial Inflammation and Apoptosis. J Cardiovasc Pharmacol 2018; 70:102-109. [PMID: 28437280 DOI: 10.1097/fjc.0000000000000496] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Chronic intermittent hypoxia (CIH), the hallmark of obstructive sleep apnea syndrome (OSAS), has been reported to play a key role in the development of OSAS-associated cardiovascular diseases including cardiac remodeling. RhoA/Rho-kinase (ROCK) pathway has also been implicated in myocardial remodeling, but the exact mechanisms are not fully elucidated. This study's purpose is to investigate the influence of fasudil, a selective ROCK inhibitor, on CIH-induced left ventricular remodeling in rats and its possible mechanisms. Adult male Sprague-Dawley rats suffered from CIH or normoxia stimulus and were intervened with vehicle or fasudil (10 mg·kg·d, intraperitoneal injection) for 6 weeks. In this study, treatment with fasudil significantly reversed intermittent hypoxia-induced histopathological transformations and ultrastructural changes in rat myocardium. Moreover, fasudil downregulated the protein levels of RhoA and phosphorylation of myosin phosphatase targeting subunit-1 (MYPT1), thus effectively inhibited the activation of RhoA/ROCK signaling pathway. Simultaneously, activity of nuclear factor (NF)-kB was suppressed by fasudil, which was accompanied by reduced NF-kB downstream inflammatory genes including interleukin-6, tumor necrosis factor-a and monocyte chemotactic protein-1, and apoptosis. These results suggest that fasudil attenuates myocardial remodeling in CIH rats, at least partly by suppressing activation of NF-kB. Inhibition of the RhoA/ROCK pathway could become an important therapeutic target in the prevention of OSAS-related cardiomyopathy.
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32
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Elrashidy RA, Zhang J, Liu G. Long-term consumption of Western diet contributes to endothelial dysfunction and aortic remodeling in rats: Implication of Rho-kinase signaling. Clin Exp Hypertens 2018; 41:174-180. [DOI: 10.1080/10641963.2018.1462375] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- Rania A. Elrashidy
- Department of Surgery, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Jing Zhang
- Department of Hyperbaric Oxygen, Capital Medical University Beijing Chao-Yang Hospital, Beijing, China
| | - Guiming Liu
- Department of Surgery, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA
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33
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Tong F, Chai R, Jiang H, Dong B. In vitro/vivo drug release and anti-diabetic cardiomyopathy properties of curcumin/PBLG-PEG-PBLG nanoparticles. Int J Nanomedicine 2018; 13:1945-1962. [PMID: 29662310 PMCID: PMC5892954 DOI: 10.2147/ijn.s153763] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Background The objective of this study was to survey the therapeutic function of curcumin-encapsulated poly(gamma-benzyl l-glutamate)-poly(ethylene glycol)-poly(gammabenzyl l-glutamate) (PBLG-PEG-PBLG) (P) on diabetic cardiomyopathy (DCM) via cross regulation effect of calcium-sensing receptor (CaSR) and endogenous cystathionine-γ-lyase (CSE)/hydrogen sulfide (H2S). Methods Diabetic rats were preconditioned with 20 mg/kg curcumin or curcumin/P complex continuously for 8 weeks. The blood and myocardiums were collected, the level of serum H2S was observed, and the [Ca2+]i content was measured in myocardial cells, and hematoxylin-eosin, CaSR, CSE, and calmodulin (CaM) expression were detected. Results Both curcumin and curcumin/P pretreatment alleviated pathological morphological damage of myocardium, increased H2S and [Ca2+]i levels, and upregulated the expression of CaSR, CSE, and CaM as compared to DCM group, while curcumin/P remarkably augmented this effect. Conclusion PBLG-PEG-PBLG could improve water-solubility and bioactivity of curcumin and curcumin/PBLG-PEG-PBLG significantly alleviated diabetic cardiomyopathy.
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Affiliation(s)
- Fei Tong
- Department of Pathology and Pathophysiology, Provincial Key Discipline of Pharmacology, Jiaxing University Medical College, Jiaxing, Zhejiang, People's Republic of China
| | - Rongkui Chai
- Department of Pathology and Pathophysiology, Provincial Key Discipline of Pharmacology, Jiaxing University Medical College, Jiaxing, Zhejiang, People's Republic of China
| | - Haiying Jiang
- Department of Pathology and Pathophysiology, Provincial Key Discipline of Pharmacology, Jiaxing University Medical College, Jiaxing, Zhejiang, People's Republic of China
| | - Bo Dong
- Department of Pathology and Pathophysiology, Provincial Key Discipline of Pharmacology, Jiaxing University Medical College, Jiaxing, Zhejiang, People's Republic of China
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34
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Zafirovic S, Sudar-Milovanovic E, Obradovic M, Djordjevic J, Jasnic N, Borovic ML, Isenovic ER. Involvement of PI3K, Akt and RhoA in Oestradiol Regulation of Cardiac iNOS Expression. Curr Vasc Pharmacol 2018; 17:307-318. [PMID: 29437011 DOI: 10.2174/1570161116666180212142414] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 02/06/2018] [Accepted: 02/07/2018] [Indexed: 01/12/2023]
Abstract
BACKGROUND Oestradiol is an important regulatory factor with several positive effects on the cardiovascular (CV) system. We evaluated the molecular mechanism of the in vivo effects of oestradiol on the regulation of cardiac inducible nitric oxide (NO) synthase (iNOS) expression and activity. METHODS Male Wistar rats were treated with oestradiol (40 mg/kg, intraperitoneally) and after 24 h the animals were sacrificed. The concentrations of NO and L-Arginine (L-Arg) were determined spectrophotometrically. For protein expressions of iNOS, p65 subunit of nuclear factor-κB (NFκB-p65), Ras homolog gene family-member A (RhoA), angiotensin II receptor type 1 (AT1R), insulin receptor substrate 1 (IRS-1), p85, p110 and protein kinase B (Akt), Western blot method was used. Coimmunoprecipitation was used for measuring the association of IRS-1 with the p85 subunit of phosphatidylinositol- 3-kinase (PI3K). The expression of iNOS messenger ribonucleic acid (mRNA) was measured with the quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of the tissue was used to detect localization and expression of iNOS in heart tissue. RESULTS Oestradiol treatment reduced L-Arg concentration (p<0.01), iNOS mRNA (p<0.01) and protein (p<0.001) expression, level of RhoA (p<0.05) and AT1R (p<0.001) protein. In contrast, plasma NO (p<0.05), Akt phosphorylation at Thr308 (p<0.05) and protein level of p85 (p<0.001) increased after oestradiol treatment. CONCLUSION Our results suggest that oestradiol in vivo regulates cardiac iNOS expression via the PI3K/Akt signaling pathway, through attenuation of RhoA and AT1R.
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Affiliation(s)
- Sonja Zafirovic
- Institute of Nuclear Sciences "Vinca", Department of Radiobiology and Molecular Genetics, University of Belgrade, Belgrade, Serbia
| | - Emina Sudar-Milovanovic
- Institute of Nuclear Sciences "Vinca", Department of Radiobiology and Molecular Genetics, University of Belgrade, Belgrade, Serbia
| | - Milan Obradovic
- Institute of Nuclear Sciences "Vinca", Department of Radiobiology and Molecular Genetics, University of Belgrade, Belgrade, Serbia
| | - Jelena Djordjevic
- Institute of Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Nebojsa Jasnic
- Institute of Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Milica Labudovic Borovic
- Institute of Histology and Embryology "Aleksandar D. Kostic", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Esma R Isenovic
- Institute of Nuclear Sciences "Vinca", Department of Radiobiology and Molecular Genetics, University of Belgrade, Belgrade, Serbia.,Faculty of Stomatology, Pancevo, University Business Academy, Novi Sad, Serbia
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35
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Mu X, Tang Y, Takayama K, Chen W, Lu A, Wang B, Weiss K, Huard J. RhoA/ROCK inhibition improves the beneficial effects of glucocorticoid treatment in dystrophic muscle: implications for stem cell depletion. Hum Mol Genet 2018; 26:2813-2824. [PMID: 28549178 DOI: 10.1093/hmg/ddx117] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 03/10/2017] [Indexed: 12/31/2022] Open
Abstract
Glucocorticoid treatment represents a standard palliative treatment for Duchenne muscular dystrophy (DMD) patients, but various adverse effects have limited this treatment. In an effort to understand the mechanism(s) by which glucocorticoids impart their effects on the dystrophic muscle, and potentially reduce the adverse effects, we have studied the effect of prednisolone treatment in dystrophin/utrophin double knockout (dKO) mice, which exhibit a severe dystrophic phenotype due to rapid muscle stem cell depletion. Our results indicate that muscle stem cell depletion in dKO muscle is related to upregulation of mTOR, and that prednisolone treatment reduces the expression of mTOR and other pro-inflammatory mediators, consequently slowing down muscle stem cell depletion. However, prednisolone treatment was unable to improve the myogenesis of stem cells and reduce fibrosis in dKO muscle. We then studied whether glucocorticoid treatment can be improved by co-administration of an inhibitor of RhoA/ROCK signaling, which can be activated by glucocorticoids and was found in our previous work to be over-activated in dystrophic muscle. Our results indicate that the combination of RhoA/ROCK inhibition and glucocorticoid treatment in dystrophic muscle have a synergistic effect in alleviating the dystrophic phenotype. Taken together, our study not only shed light on the mechanism by which glucocorticoid imparts its beneficial effect on dystrophic muscle, but also revealed the synergistic effect of RhoA/ROCK inhibition and glucocorticoid treatment, which could lead to the development of more efficient therapeutic approaches for treating DMD patients.
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Affiliation(s)
- Xiaodong Mu
- Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, TX 77054, USA.,Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA
| | - Ying Tang
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Koji Takayama
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Wanqun Chen
- Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, TX 77054, USA.,Department of Biochemistry and Molecular Biology, Jinan University, Guangdong, China
| | - Aiping Lu
- Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, TX 77054, USA.,Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA
| | - Bing Wang
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Kurt Weiss
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Johnny Huard
- Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, TX 77054, USA.,Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA
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36
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Valero-Muñoz M, Backman W, Sam F. Murine Models of Heart Failure with Preserved Ejection Fraction: a "Fishing Expedition". JACC Basic Transl Sci 2017; 2:770-789. [PMID: 29333506 PMCID: PMC5764178 DOI: 10.1016/j.jacbts.2017.07.013] [Citation(s) in RCA: 155] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 07/25/2017] [Accepted: 07/27/2017] [Indexed: 12/28/2022]
Abstract
Heart failure with preserved ejection fraction (HFpEF) is characterized by signs and symptoms of HF in the presence of a normal left ventricular (LV) ejection fraction (EF). Despite accounting for up to 50% of all clinical presentations of HF, the mechanisms implicated in HFpEF are poorly understood, thus precluding effective therapy. The pathophysiological heterogeneity in the HFpEF phenotype also contributes to this disease and likely to the absence of evidence-based therapies. Limited access to human samples and imperfect animal models that completely recapitulate the human HFpEF phenotype have impeded our understanding of the mechanistic underpinnings that exist in this disease. Aging and comorbidities such as atrial fibrillation, hypertension, diabetes and obesity, pulmonary hypertension and renal dysfunction are highly associated with HFpEF. Yet, the relationship and contribution between them remains ill-defined. This review discusses some of the distinctive clinical features of HFpEF in association with these comorbidities and highlights the advantages and disadvantage of commonly used murine models, used to study the HFpEF phenotype.
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Affiliation(s)
- Maria Valero-Muñoz
- Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
| | - Warren Backman
- Evans Department of Internal Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Flora Sam
- Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
- Evans Department of Internal Medicine, Boston University School of Medicine, Boston, Massachusetts
- Cardiovascular Section, Boston University School of Medicine, Boston, Massachusetts
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37
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Karam BS, Chavez-Moreno A, Koh W, Akar JG, Akar FG. Oxidative stress and inflammation as central mediators of atrial fibrillation in obesity and diabetes. Cardiovasc Diabetol 2017; 16:120. [PMID: 28962617 PMCID: PMC5622555 DOI: 10.1186/s12933-017-0604-9] [Citation(s) in RCA: 329] [Impact Index Per Article: 41.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 09/22/2017] [Indexed: 02/07/2023] Open
Abstract
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans. Several risk factors promote AF, among which diabetes mellitus has emerged as one of the most important. The growing recognition that obesity, diabetes and AF are closely intertwined disorders has spurred major interest in uncovering their mechanistic links. In this article we provide an update on the growing evidence linking oxidative stress and inflammation to adverse atrial structural and electrical remodeling that leads to the onset and maintenance of AF in the diabetic heart. We then discuss several therapeutic strategies to improve atrial excitability by targeting pathways that control oxidative stress and inflammation.
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Affiliation(s)
- Basil S Karam
- Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Wonjoon Koh
- Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Joseph G Akar
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Fadi G Akar
- Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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38
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Yang D, Liu W, Ma L, Wang Y, Ma J, Jiang M, Deng X, Huang F, Yang T, Chen M. Profilin‑1 contributes to cardiac injury induced by advanced glycation end‑products in rats. Mol Med Rep 2017; 16:6634-6641. [PMID: 28901418 PMCID: PMC5865800 DOI: 10.3892/mmr.2017.7446] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 07/20/2017] [Indexed: 12/21/2022] Open
Abstract
Cardiac injury, including hypertrophy and fibrosis, induced by advanced glycation end products (AGEs) has an important function in the onset and development of diabetic cardiomyopathy. Profilin-1, a ubiquitously expressed and multifunctional actin-binding protein, has been reported to be an important mediator in cardiac hypertrophy and fibrosis. However, whether profilin-1 is involved in AGE-induced cardiac hypertrophy and fibrosis remains to be determined. Therefore, the present study aimed to investigate the function of profilin-1 in cardiac injury induced by AGEs. The model of cardiac injury was established by chronic tail vein injection of AGEs (50 mg/kg/day for 8 weeks) in Sprague-Dawley rats. Rats were randomly assigned to control, AGEs, AGEs + profilin-1 shRNA adenovirus vectors (AGEs + S)or AGEs + control adenovirus vectors (AGEs + V) groups. Profilin-1 shRNA adenovirus vectors were injected via the tail vein to knockdown profilin-1 expression at a dose of 3×109 plaque forming units every 4 weeks. Echocardiography was performed to measure cardiac contractile function. Cardiac tissues were stained with Masson's trichrome stain to evaluate ventricular remodeling. The serum levels of procollagen type III N-terminal peptide were detected by ELISA. The expression of profilin-1, receptor for AGEs (RAGE), Rho, p65, atrial natriuretic peptide, β-myosin heavy chain, matrix metalloproteinase (MMP)-2 and MMP-9 were determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and/or western blot analysis and immunohistochemistry staining. The results demonstrated that chronic injection of exogenous AGEs led to cardiac dysfunction, hypertrophy and fibrosis, as determined by echocardiography, Masson trichrome staining and the expression of associated genes. The expression of profilin-1 was markedly increased in heart tissue at the mRNA and protein level following AGE administration, as determined by RT-qPCR and western blotting, which was further confirmed by immunohistochemistry staining. Furthermore, the expression of RAGE, Rho and p65 was also increased at the protein level. Notably, knockdown of profilin-1 expression ameliorated AGE-induced cardiac injury and reduced the expression of RAGE, Rho and p65. These results indicate an important role for profilin-1 in AGE-induced cardiac injury, which may provide a novel therapeutic target for patients with diabetic heart failure.
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Affiliation(s)
- Dafeng Yang
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Weiwei Liu
- Department of Cardiology, The First Hospital of Changsha, Changsha, Hunan 410005, P.R. China
| | - Liping Ma
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Ya Wang
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Jing Ma
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Minna Jiang
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Xu Deng
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410006, P.R. China
| | - Fang Huang
- Department of Cardiology, The First Hospital of Changsha, Changsha, Hunan 410005, P.R. China
| | - Tianlun Yang
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Meifang Chen
- Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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Hofni A, Shehata Messiha BA, Mangoura SA. Fasudil ameliorates endothelial dysfunction in streptozotocin-induced diabetic rats: a possible role of Rho kinase. Naunyn Schmiedebergs Arch Pharmacol 2017; 390:801-811. [PMID: 28493050 DOI: 10.1007/s00210-017-1379-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 04/20/2017] [Indexed: 02/07/2023]
Abstract
Endothelial dysfunction is a major contributor to the pathogenesis of vascular disease in diabetes mellitus and RhoA/Rho-kinase (ROCK) system appears to play a crucial role in this setting. The present study was conducted to investigate the effect of the selective ROCK inhibitor, fasudil, on diabetes-related endothelial dysfunction and elucidated its underlying mechanism(s). Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg), and fasudil (5 mg/kg per day) was orally administered for 8 weeks. Our results showed that fasudil administration attenuated the increased activity/expression of ROCK (627.5 ± 27 vs. 247.8 ± 19.1) and the NADPH oxidase subunits, NOX2 and p47phox, in diabetic rat aorta. Fasudil could reduce the elevated tumor necrosis factor (TNF)-α (70.2 ± 14.1 vs. 25.3 ± 5.2) and transforming growth factor (TGF-β) levels and restored the deficit in antioxidant level of the diabetic aorta. Additionally, fasudil markedly improved the endothelial dysfunction in the diabetic aorta (73.8 ± 8.1 vs. 47.42 ± 8.69) and corrected the dysregulated endothelial nitric oxide (eNOS) expression. In conclusion, the present study demonstrates that fasudil effectively ameliorates the endothelial dysfunction in STZ-induced diabetic rats through inhibition of the Rho/ROCK pathway and thereby reducing the TNF-α-mediated NADPH oxidase activation.
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Affiliation(s)
- Amal Hofni
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
| | - Basim A Shehata Messiha
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Safwat A Mangoura
- Department of Pharmacology, Faculty of Medicine, Assuit University, Assuit, Egypt
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40
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Zheng W, Shang X, Zhang C, Gao X, Robinson B, Liu J. The Effects of Carvedilol on Cardiac Function and the AKT/XIAP Signaling Pathway in Diabetic Cardiomyopathy Rats. Cardiology 2016; 136:204-211. [PMID: 27780169 DOI: 10.1159/000450825] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 09/07/2016] [Indexed: 11/19/2022]
Abstract
OBJECTIVES Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction, myocardial inflammation, interstitial fibrosis and cardiomyocytes apoptosis. The present study aimed to investigate the effects of carvedilol on cardiac function and the AKT/XIAP signaling pathway in DCM rats. METHODS Male Wistar rats were randomly divided into 3 groups: the control group, diabetic mellitus (DM) group and DM with carvedilol treatment group. DM rats were induced by streptozotocin accompanied by high energy intake. Carvedilol was orally administered at a dose of 10 mg/kg/day. After 16 weeks, the interrelated blood data were detected by biochemical analysis. Cardiac function was evaluated by echocardiography and the serum NT-proBNP level. The changes of myocardium ultrastructural and fibrosis were determined by electron microscopy and Masson's staining. Apoptotic cells were examined by TUNEL staining and interrelated proteins were measured by immunohistochemical and Western blots. RESULTS Rats in the DM group showed significant serum elevation of glucose, cholesterol, triglyceride, NT-proBNP, IL-1β and TNF-α, along with decreased cardiac function. Moreover, in the DM group, the levels of myocardial apoptosis and fibrosis were all increased accompanied by upregulation of caspase-3 and downregulation of phos-AKT and phos-XIAP, whereas carvedilol treatment prevented or reversed all the changes without influencing plasma levels of glucose, cholesterol and triglyceride. CONCLUSIONS The AKT/XIAP signaling pathway may be involved in DCM. Carvedilol can improve cardiac function, possibly not only by upregulating the AKT/XIAP antiapoptotic signaling pathway and subsequently attenuating myocardial fibrosis, but also through suppressing the myocardial inflammation response.
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Affiliation(s)
- Wencheng Zheng
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, China
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Cossette SM, Bhute VJ, Bao X, Harmann LM, Horswill MA, Sinha I, Gastonguay A, Pooya S, Bordas M, Kumar SN, Mirza SP, Palecek SP, Strande JL, Ramchandran R. Sucrose Nonfermenting-Related Kinase Enzyme-Mediated Rho-Associated Kinase Signaling is Responsible for Cardiac Function. ACTA ACUST UNITED AC 2016; 9:474-486. [PMID: 27780848 DOI: 10.1161/circgenetics.116.001515] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 09/28/2016] [Indexed: 11/16/2022]
Abstract
BACKGROUND Cardiac metabolism is critical for the functioning of the heart, and disturbance in this homeostasis is likely to influence cardiac disorders or cardiomyopathy. Our laboratory has previously shown that SNRK (sucrose nonfermenting related kinase) enzyme, which belongs to the AMPK (adenosine monophosphate-activated kinase) family, was essential for cardiac metabolism in mammals. Snrk global homozygous knockout (KO) mice die at postnatal day 0, and conditional deletion of Snrk in cardiomyocytes (Snrk cmcKO) leads to cardiac failure and death by 8 to 10 months. METHODS AND RESULTS We performed additional cardiac functional studies using echocardiography and identified further cardiac functional deficits in Snrk cmcKO mice. Nuclear magnetic resonance-based metabolomics analysis identified key metabolic pathway deficits in SNRK knockdown cardiomyocytes in vitro. Specifically, metabolites involved in lipid metabolism and oxidative phosphorylation are altered, and perturbations in these pathways can result in cardiac function deficits and heart failure. A phosphopeptide-based proteomic screen identified ROCK (Rho-associated kinase) as a putative substrate for SNRK, and mass spec-based fragment analysis confirmed key amino acid residues on ROCK that are phosphorylated by SNRK. Western blot analysis on heart lysates from Snrk cmcKO adult mice and SNRK knockdown cardiomyocytes showed increased ROCK activity. In addition, in vivo inhibition of ROCK partially rescued the in vivo Snrk cmcKO cardiac function deficits. CONCLUSIONS Collectively, our data suggest that SNRK in cardiomyocytes is responsible for maintaining cardiac metabolic homeostasis, which is mediated in part by ROCK, and alteration of this homeostasis influences cardiac function in the adult heart.
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Affiliation(s)
- Stephanie M Cossette
- From the Department of Pediatrics (S.M.C., A.G., S. Pooya, M.B., R.R.), OBGYN, Developmental Vascular Biology Program, Children's Research Institute (R.R.), Division of Cardiovascular Medicine, Cardiovascular Center, Clinical and Translational Science Institute (L.M.H.), Division of Cardiovascular Medicine, Department of Cell Biology, Neurobiology and Anatomy, Cardiovascular Center, Clinical and Translational Science Institute (J.L.S.), and Division of Pediatric Pathology, Department of Pathology (S.N.K.), Medical College of Wisconsin, Milwaukee; Department of Chemical and Biological Engineering (V.J.B., X.B., S. Palecek), Morgridge Institute for Research (M.A.H.), University of Wisconsin-Madison; Marginalen Bank, Stockholm, Sweden (I.S.); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee (S.P.M.)
| | - Vijesh J Bhute
- From the Department of Pediatrics (S.M.C., A.G., S. Pooya, M.B., R.R.), OBGYN, Developmental Vascular Biology Program, Children's Research Institute (R.R.), Division of Cardiovascular Medicine, Cardiovascular Center, Clinical and Translational Science Institute (L.M.H.), Division of Cardiovascular Medicine, Department of Cell Biology, Neurobiology and Anatomy, Cardiovascular Center, Clinical and Translational Science Institute (J.L.S.), and Division of Pediatric Pathology, Department of Pathology (S.N.K.), Medical College of Wisconsin, Milwaukee; Department of Chemical and Biological Engineering (V.J.B., X.B., S. Palecek), Morgridge Institute for Research (M.A.H.), University of Wisconsin-Madison; Marginalen Bank, Stockholm, Sweden (I.S.); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee (S.P.M.)
| | - Xiaoping Bao
- From the Department of Pediatrics (S.M.C., A.G., S. Pooya, M.B., R.R.), OBGYN, Developmental Vascular Biology Program, Children's Research Institute (R.R.), Division of Cardiovascular Medicine, Cardiovascular Center, Clinical and Translational Science Institute (L.M.H.), Division of Cardiovascular Medicine, Department of Cell Biology, Neurobiology and Anatomy, Cardiovascular Center, Clinical and Translational Science Institute (J.L.S.), and Division of Pediatric Pathology, Department of Pathology (S.N.K.), Medical College of Wisconsin, Milwaukee; Department of Chemical and Biological Engineering (V.J.B., X.B., S. Palecek), Morgridge Institute for Research (M.A.H.), University of Wisconsin-Madison; Marginalen Bank, Stockholm, Sweden (I.S.); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee (S.P.M.)
| | - Leanne M Harmann
- From the Department of Pediatrics (S.M.C., A.G., S. Pooya, M.B., R.R.), OBGYN, Developmental Vascular Biology Program, Children's Research Institute (R.R.), Division of Cardiovascular Medicine, Cardiovascular Center, Clinical and Translational Science Institute (L.M.H.), Division of Cardiovascular Medicine, Department of Cell Biology, Neurobiology and Anatomy, Cardiovascular Center, Clinical and Translational Science Institute (J.L.S.), and Division of Pediatric Pathology, Department of Pathology (S.N.K.), Medical College of Wisconsin, Milwaukee; Department of Chemical and Biological Engineering (V.J.B., X.B., S. Palecek), Morgridge Institute for Research (M.A.H.), University of Wisconsin-Madison; Marginalen Bank, Stockholm, Sweden (I.S.); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee (S.P.M.)
| | - Mark A Horswill
- From the Department of Pediatrics (S.M.C., A.G., S. Pooya, M.B., R.R.), OBGYN, Developmental Vascular Biology Program, Children's Research Institute (R.R.), Division of Cardiovascular Medicine, Cardiovascular Center, Clinical and Translational Science Institute (L.M.H.), Division of Cardiovascular Medicine, Department of Cell Biology, Neurobiology and Anatomy, Cardiovascular Center, Clinical and Translational Science Institute (J.L.S.), and Division of Pediatric Pathology, Department of Pathology (S.N.K.), Medical College of Wisconsin, Milwaukee; Department of Chemical and Biological Engineering (V.J.B., X.B., S. Palecek), Morgridge Institute for Research (M.A.H.), University of Wisconsin-Madison; Marginalen Bank, Stockholm, Sweden (I.S.); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee (S.P.M.)
| | - Indranil Sinha
- From the Department of Pediatrics (S.M.C., A.G., S. Pooya, M.B., R.R.), OBGYN, Developmental Vascular Biology Program, Children's Research Institute (R.R.), Division of Cardiovascular Medicine, Cardiovascular Center, Clinical and Translational Science Institute (L.M.H.), Division of Cardiovascular Medicine, Department of Cell Biology, Neurobiology and Anatomy, Cardiovascular Center, Clinical and Translational Science Institute (J.L.S.), and Division of Pediatric Pathology, Department of Pathology (S.N.K.), Medical College of Wisconsin, Milwaukee; Department of Chemical and Biological Engineering (V.J.B., X.B., S. Palecek), Morgridge Institute for Research (M.A.H.), University of Wisconsin-Madison; Marginalen Bank, Stockholm, Sweden (I.S.); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee (S.P.M.)
| | - Adam Gastonguay
- From the Department of Pediatrics (S.M.C., A.G., S. Pooya, M.B., R.R.), OBGYN, Developmental Vascular Biology Program, Children's Research Institute (R.R.), Division of Cardiovascular Medicine, Cardiovascular Center, Clinical and Translational Science Institute (L.M.H.), Division of Cardiovascular Medicine, Department of Cell Biology, Neurobiology and Anatomy, Cardiovascular Center, Clinical and Translational Science Institute (J.L.S.), and Division of Pediatric Pathology, Department of Pathology (S.N.K.), Medical College of Wisconsin, Milwaukee; Department of Chemical and Biological Engineering (V.J.B., X.B., S. Palecek), Morgridge Institute for Research (M.A.H.), University of Wisconsin-Madison; Marginalen Bank, Stockholm, Sweden (I.S.); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee (S.P.M.)
| | - Shabnam Pooya
- From the Department of Pediatrics (S.M.C., A.G., S. Pooya, M.B., R.R.), OBGYN, Developmental Vascular Biology Program, Children's Research Institute (R.R.), Division of Cardiovascular Medicine, Cardiovascular Center, Clinical and Translational Science Institute (L.M.H.), Division of Cardiovascular Medicine, Department of Cell Biology, Neurobiology and Anatomy, Cardiovascular Center, Clinical and Translational Science Institute (J.L.S.), and Division of Pediatric Pathology, Department of Pathology (S.N.K.), Medical College of Wisconsin, Milwaukee; Department of Chemical and Biological Engineering (V.J.B., X.B., S. Palecek), Morgridge Institute for Research (M.A.H.), University of Wisconsin-Madison; Marginalen Bank, Stockholm, Sweden (I.S.); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee (S.P.M.)
| | - Michelle Bordas
- From the Department of Pediatrics (S.M.C., A.G., S. Pooya, M.B., R.R.), OBGYN, Developmental Vascular Biology Program, Children's Research Institute (R.R.), Division of Cardiovascular Medicine, Cardiovascular Center, Clinical and Translational Science Institute (L.M.H.), Division of Cardiovascular Medicine, Department of Cell Biology, Neurobiology and Anatomy, Cardiovascular Center, Clinical and Translational Science Institute (J.L.S.), and Division of Pediatric Pathology, Department of Pathology (S.N.K.), Medical College of Wisconsin, Milwaukee; Department of Chemical and Biological Engineering (V.J.B., X.B., S. Palecek), Morgridge Institute for Research (M.A.H.), University of Wisconsin-Madison; Marginalen Bank, Stockholm, Sweden (I.S.); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee (S.P.M.)
| | - Suresh N Kumar
- From the Department of Pediatrics (S.M.C., A.G., S. Pooya, M.B., R.R.), OBGYN, Developmental Vascular Biology Program, Children's Research Institute (R.R.), Division of Cardiovascular Medicine, Cardiovascular Center, Clinical and Translational Science Institute (L.M.H.), Division of Cardiovascular Medicine, Department of Cell Biology, Neurobiology and Anatomy, Cardiovascular Center, Clinical and Translational Science Institute (J.L.S.), and Division of Pediatric Pathology, Department of Pathology (S.N.K.), Medical College of Wisconsin, Milwaukee; Department of Chemical and Biological Engineering (V.J.B., X.B., S. Palecek), Morgridge Institute for Research (M.A.H.), University of Wisconsin-Madison; Marginalen Bank, Stockholm, Sweden (I.S.); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee (S.P.M.)
| | - Shama P Mirza
- From the Department of Pediatrics (S.M.C., A.G., S. Pooya, M.B., R.R.), OBGYN, Developmental Vascular Biology Program, Children's Research Institute (R.R.), Division of Cardiovascular Medicine, Cardiovascular Center, Clinical and Translational Science Institute (L.M.H.), Division of Cardiovascular Medicine, Department of Cell Biology, Neurobiology and Anatomy, Cardiovascular Center, Clinical and Translational Science Institute (J.L.S.), and Division of Pediatric Pathology, Department of Pathology (S.N.K.), Medical College of Wisconsin, Milwaukee; Department of Chemical and Biological Engineering (V.J.B., X.B., S. Palecek), Morgridge Institute for Research (M.A.H.), University of Wisconsin-Madison; Marginalen Bank, Stockholm, Sweden (I.S.); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee (S.P.M.)
| | - Sean P Palecek
- From the Department of Pediatrics (S.M.C., A.G., S. Pooya, M.B., R.R.), OBGYN, Developmental Vascular Biology Program, Children's Research Institute (R.R.), Division of Cardiovascular Medicine, Cardiovascular Center, Clinical and Translational Science Institute (L.M.H.), Division of Cardiovascular Medicine, Department of Cell Biology, Neurobiology and Anatomy, Cardiovascular Center, Clinical and Translational Science Institute (J.L.S.), and Division of Pediatric Pathology, Department of Pathology (S.N.K.), Medical College of Wisconsin, Milwaukee; Department of Chemical and Biological Engineering (V.J.B., X.B., S. Palecek), Morgridge Institute for Research (M.A.H.), University of Wisconsin-Madison; Marginalen Bank, Stockholm, Sweden (I.S.); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee (S.P.M.)
| | - Jennifer L Strande
- From the Department of Pediatrics (S.M.C., A.G., S. Pooya, M.B., R.R.), OBGYN, Developmental Vascular Biology Program, Children's Research Institute (R.R.), Division of Cardiovascular Medicine, Cardiovascular Center, Clinical and Translational Science Institute (L.M.H.), Division of Cardiovascular Medicine, Department of Cell Biology, Neurobiology and Anatomy, Cardiovascular Center, Clinical and Translational Science Institute (J.L.S.), and Division of Pediatric Pathology, Department of Pathology (S.N.K.), Medical College of Wisconsin, Milwaukee; Department of Chemical and Biological Engineering (V.J.B., X.B., S. Palecek), Morgridge Institute for Research (M.A.H.), University of Wisconsin-Madison; Marginalen Bank, Stockholm, Sweden (I.S.); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee (S.P.M.)
| | - Ramani Ramchandran
- From the Department of Pediatrics (S.M.C., A.G., S. Pooya, M.B., R.R.), OBGYN, Developmental Vascular Biology Program, Children's Research Institute (R.R.), Division of Cardiovascular Medicine, Cardiovascular Center, Clinical and Translational Science Institute (L.M.H.), Division of Cardiovascular Medicine, Department of Cell Biology, Neurobiology and Anatomy, Cardiovascular Center, Clinical and Translational Science Institute (J.L.S.), and Division of Pediatric Pathology, Department of Pathology (S.N.K.), Medical College of Wisconsin, Milwaukee; Department of Chemical and Biological Engineering (V.J.B., X.B., S. Palecek), Morgridge Institute for Research (M.A.H.), University of Wisconsin-Madison; Marginalen Bank, Stockholm, Sweden (I.S.); Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee (S.P.M.).
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Sun Z, Wu X, Li W, Peng H, Shen X, Ma L, Liu H, Li H. RhoA/rock signaling mediates peroxynitrite-induced functional impairment of Rat coronary vessels. BMC Cardiovasc Disord 2016; 16:193. [PMID: 27724862 PMCID: PMC5057502 DOI: 10.1186/s12872-016-0372-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 09/28/2016] [Indexed: 01/03/2023] Open
Abstract
Background Diabetes-induced vascular dysfunction may arise from reduced nitric oxide (NO) availability, following interaction with superoxide to form peroxynitrite. Peroxynitrite can induce formation of 3-nitrotyrosine-modified proteins. RhoA/ROCK signaling is also involved in diabetes-induced vascular dysfunction. The study aimed to investigate possible links between Rho/ROCK signaling, hyperglycemia, and peroxynitrite in small coronary arteries. Methods Rat small coronary arteries were exposed to normal (NG; 5.5 mM) or high (HG; 23 mM) D-glucose. Vascular ring constriction to 3 mM 4-aminopyridine and dilation to 1 μM forskolin were measured. Protein expression (immunohistochemistry and western blot), mRNA expression (real-time PCR), and protein activity (luminescence-based G-LISA and kinase activity spectroscopy assays) of RhoA, ROCK1, and ROCK2 were determined. Results Vascular ring constriction and dilation were smaller in the HG group than in the NG group (P < 0.05); inhibition of RhoA or ROCK partially reversed the effects of HG. Peroxynitrite impaired vascular ring constriction/dilation; this was partially reversed by inhibition of RhoA or ROCK. Protein and mRNA expressions of RhoA, ROCK1, and ROCK2 were higher under HG than NG (P < 0.05). This HG-induced upregulation was attenuated by inhibition of RhoA or ROCK (P < 0.05). HG increased RhoA, ROCK1, and ROCK2 activity (P < 0.05). Peroxynitrite also enhanced RhoA, ROCK1, and ROCK2 activity; these actions were partially inhibited by 100 μM urate (peroxynitrite scavenger). Exogenous peroxynitrite had no effect on the expression of the voltage-dependent K+ channels 1.2 and 1.5. Conclusions Peroxynitrite-induced coronary vascular dysfunction may be mediated, at least in part, through increased expressions and activities of RhoA, ROCK1, and ROCK2.
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Affiliation(s)
- Zhijun Sun
- Department of Heart Center, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, China
| | - Xing Wu
- Department of Heart Center, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, China
| | - Weiping Li
- Department of Heart Center, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, China
| | - Hui Peng
- Department of Heart Center, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, China
| | - Xuhua Shen
- Department of Heart Center, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, China
| | - Lu Ma
- Beijing Key Laboratory of Metabolic Disturbance Related Cardiovascular Disease, Beijing, People's Republic of China
| | - Huirong Liu
- Beijing Key Laboratory of Metabolic Disturbance Related Cardiovascular Disease, Beijing, People's Republic of China
| | - Hongwei Li
- Department of Heart Center, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, China.
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Liu LJ, Yao FJ, Lu GH, Xu CG, Xu Z, Tang K, Cheng YJ, Gao XR, Wu SH. The Role of the Rho/ROCK Pathway in Ang II and TGF-β1-Induced Atrial Remodeling. PLoS One 2016; 11:e0161625. [PMID: 27611832 PMCID: PMC5017578 DOI: 10.1371/journal.pone.0161625] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 08/09/2016] [Indexed: 02/05/2023] Open
Abstract
Objectives To study the role of the Rho/ROCK pathway in Ang II and TGF-β1-induced atrial remodeling. Methods and Results A canine atrial fibrillation (AF) model was established by rapid atrial pacing (RAP) of the left atrium. The roles of TGF-β1, the RhoA/ROCK signaling pathway and connective tissue growth factor (CTGF) in atrial remodeling were studied via both in vitro and in vivo experiments. Each of the dogs that received RAP developed persistent AF within 4 weeks. The mRNA expression levels of TGF-β1 (1.32±0.38), Collagen-I(1.33±0.91), CTGF(5.83±3.71), RhoA(1.23±0.57) and ROCK-1 (1.02±0.27) in the left atrium were significantly increased following 4 weeks of RAP. Angiotensin II (Ang II) induced the proliferation of atrial fibroblasts and up-regulated the expression of both CTGF and ROCK-1 in a dose-dependent manner. Simvastatin and Y27632 reversed Ang II-induced CFs proliferation, as well as ROCK-1(0.89±0.05 and 1.27±0.03, respectively) and CTGF (0.87±0.04 and 0.91±0.02, respectively) expression. The expression mRNA of ROCK-1(1.74±0.13) and CTGF (2.28±0.11) can upregulated by TGF-β1, and down-regulated by Simvastatin (1.22±0.03 vs 2.27±0.11), Y27632 (1.01±0.04 vs 1.64±0.03), Los (1.04±0.11 vs 1.26±0.05), respectively. Losartan and Simvastatin attenuated the effects of TGF-β1, inhibited RhoA activity as opposed to RhoA protein expression. Y27632 had no effect on either the expression or the activity of RhoA. Conclusions The increased expression of profibrotic factors (CTGF, ROCK1 and Smad2/3) played an important role in our RAP-induced AF model. Increased atrial profibrotic factors involve the activation of either the TGF-β1/RhoA/ROCK-1 or the TGF-β1/Smad2/3 signaling pathway.
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Affiliation(s)
- Li-Juan Liu
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Feng-Juan Yao
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Gui-Hua Lu
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Cheng-Gui Xu
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhe Xu
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Kai Tang
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yun-Jiu Cheng
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiu-Ren Gao
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- * E-mail: (SW); (XG)
| | - Su-Hua Wu
- Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- * E-mail: (SW); (XG)
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Li S, Hong Y, Jin X, Zhang G, Hu Z, Nie L. A new Agkistrodon halys venom-purified protein C activator prevents myocardial fibrosis in diabetic rats. Croat Med J 2016; 56:439-46. [PMID: 26526881 PMCID: PMC4655929 DOI: 10.3325/cmj.2015.56.439] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Aim To assess the effects of protein C activator (PCA) from Agkistrodon halys snake venom on cardiac fibrosis in streptozotocin (STZ) induced diabetic rat model, and investigate the mechanisms of its action. Methods PCA was identified by one-dimensional reversed phase liquid chromatography – mass spectrometry/mass spectrometry. Male Sprague-Dawley rats (120-140 g) were randomly assigned to negative control (NC) and diabetic group. Diabetes was induced by STZ in high-fat diet fed rats. Diabetic group was subdivided into three groups: diabetic group (DM), diabetic group treated with PCA (0.5, 2, and 8 mg/kg), and diabetic group treated with metformin (5 mg/kg, positive control). NC and DM groups received the same volume of distilled water. Left ventricular mass index (LVWI) and collagen volume fraction were measured by hematoxylin and eosin and Masson staining. Transforming growth factor beta-1 (TGF-β1) and interleukin 1 beta (IL-1β) levels were determined by enzyme-linked immunosorbent assay. Results The diabetic rat model was successfully established by STZ induction and high-fat diet. Glucose level, LVWI, TGF-β1 and IL-1β level, and collagen volume fraction were significantly reduced in diabetic rats treated by PCA in a dose-dependent manner (P < 0.050), especially in the high dose (8 mg/kg) group (P < 0.010), compared to diabetes group. The high dose PCA had the same effect as metformin positive control in reducing the level of fasting blood glucose. PCA decreased the expression of MMP-2 and reduced that of TIMP-2. Conclusion Our results indicate that PCA has anti-fibrotic effects and that it may be used to treat myocardial fibrosis.
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Affiliation(s)
| | | | | | | | | | - Liuwang Nie
- Liuwang Nie, The Provincial Key Lab of the Conservation and Exploitation Research of Biological Resources in Anhui Life Science College, Anhui Normal University, Beijing East Road 1#, Wuhu 241000, People's Republic of China,
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Yu Y, Jia XJ, Zhang WP, Fang TT, Hu J, Ma SF, Gao Q. The Protective Effect of Low-Dose Ethanol on Myocardial Fibrosis through Downregulating the JNK Signaling Pathway in Diabetic Rats. J Diabetes Res 2016; 2016:3834283. [PMID: 27547765 PMCID: PMC4983369 DOI: 10.1155/2016/3834283] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 06/30/2016] [Accepted: 07/03/2016] [Indexed: 11/27/2022] Open
Abstract
Objective. To investigate the effects of low dose ethanol feeding in diabetic rats and analyze its underlying mechanisms. Methods. Male Sprague-Dawley rats were divided into 4 groups: control (Con), diabetes at 4 weeks (DM4W), diabetes at 8 weeks (DM8W), and EtOH + DM8W. After 8 weeks, hemodynamic parameters were recorded and heart weight/body weight (H/B) and hydroxyproline (Hp) content in myocardium were measured. Morphology of collagen in myocardial tissue was observed with Masson's trichrome staining method and collagen volume fraction (CVF) was analysed. The mRNA expression of ALDH2 was assessed with Real-Time PCR. The protein expressions of p-JNK and JNK were evaluated using western blot. Results. In contrast to Con group, there was no difference in hemodynamic parameters in DM4W group, but mean arterial pressure and heart rate were decreased in DM8W group, and the ratios of H/B, Hp, and CVF were markedly increased. ALDH2 mRNA expression was decreased, while the ratio of p-JNK/JNK were increased. Compared with DM8W group, the above indexes were improved in EtOH + DM8W group. Conclusion. With low dose ethanol intervention, enhanced ALDH2 expression can antagonize the happening of myocardial fibrosis in diabetic rats, which may be relevant with downregulating the JNK pathway.
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Affiliation(s)
- Ying Yu
- Department of Physiology, Bengbu Medical College, 2600 Dong Hai Avenue, Bengbu 233030, China
| | - Xian-Jie Jia
- Department of Epidemiology and Statistics, Bengbu Medical College, 2600 Dong Hai Avenue, Bengbu 233030, China
| | - Wei-ping Zhang
- Department of Physiology, Bengbu Medical College, 2600 Dong Hai Avenue, Bengbu 233030, China
| | - Ting-ting Fang
- Department of Physiology, Bengbu Medical College, 2600 Dong Hai Avenue, Bengbu 233030, China
| | - Jie Hu
- Department of Physiology, Bengbu Medical College, 2600 Dong Hai Avenue, Bengbu 233030, China
| | - Shan-Feng Ma
- Department of Physiology, Bengbu Medical College, 2600 Dong Hai Avenue, Bengbu 233030, China
| | - Qin Gao
- Department of Physiology, Bengbu Medical College, 2600 Dong Hai Avenue, Bengbu 233030, China
- *Qin Gao:
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Sun S, Zhang M, Lin J, Hu J, Zhang R, Li C, Wei T, Sun D, Wei J, Wang H. Lin28a protects against diabetic cardiomyopathy via the PKA/ROCK2 pathway. Biochem Biophys Res Commun 2015; 469:29-36. [PMID: 26626075 DOI: 10.1016/j.bbrc.2015.11.065] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 11/16/2015] [Indexed: 10/22/2022]
Abstract
BACKGROUND Lin28a enhances glucose uptake and insulin-sensitivity. However, the role of Lin28a on experimental diabetic cardiomyopathy (DCM) is not well understood. We investigated the potential role and mechanism ofLin28a in diabetes-induced myocardial dysfunction in mice. METHODS Diabetes was induced by intraperitoneal (i.p.) injections of Streptozocin (STZ) in mice. Animals were randomized to be treated with lentivirus carrying Lin28a siRNA or Lin28a cDNA. Cardiac function, cardiomyocyte autophagy, apoptosis and mitochondria morphology in diabetic mice were compared between groups. The target proteins of Lin28a were examined by western blot analysis. RESULTS Lin28a levels were markedly reduced in the cardiac tissue compared to the control mice. Lin28a overexpression significantly improved left ventricular ejection fraction (LVEF), promoted autophagy, decreased myocardial apoptotic index and alleviated mitochondria cristae destruction in diabetic mice. Lin28a knockdown exacerbated diabetic injury as evidenced by decreased LVEF, increased apoptotic index and aggravated mitochondria cristae destruction. Interestingly, pretreatment with a PKA inhibitor, N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide], di-HCl Salt (H89) abolished the beneficial effects of Lin28a overexpression. RhoA-expression and ROCK2-expression were decreased in vivo after Lin28a overexpression, while Lin28a knockdown increased the expression of RhoA and ROCK2 in diabetic mice. CONCLUSIONS Lin28a protects against DCM through PKA/ROCK2 dependent pathway. Lin28a might serve as a potential therapeutic target for the treatment of the patients with DCM.
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Affiliation(s)
- Shuhong Sun
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Department of Cardiology, Shaanxi Provincial Crops Hospital, Chinese People's Armed Police Forces, Xi' an, 710054, China
| | - Mingming Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jie Lin
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jianqiang Hu
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Rongqing Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Congye Li
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Tianlu Wei
- Department of Medicine, the First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, 530023, China
| | - Dongdong Sun
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jianqin Wei
- Department of Medicine, Division of Cardiology, Miller's School of Medicine, University of Miami, USA.
| | - Haichang Wang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
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Baba I, Egi Y, Suzuki K. Partial deletion of the ROCK2 protein fails to reduce renal fibrosis in a unilateral ureteral obstruction model in mice. Mol Med Rep 2015; 13:231-6. [PMID: 26572751 DOI: 10.3892/mmr.2015.4569] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 09/29/2015] [Indexed: 11/06/2022] Open
Abstract
Renal fibrosis is a well‑known cause for the progression of chronic kidney disease. Rho/Rho‑associated coiled‑coil kinase (ROCK) signaling is involved in renal fibrotic processes. Non‑selective ROCK1/2 inhibitors have been reported to reduce renal interstitial fibrosis in a rodent unilateral ureteral obstruction (UUO) model. To clarify the role and contribution of ROCK2 in renal fibrosis, the present study used ROCK2 heterozygous knockout (HKO) mice to assess collagen deposition and fibrosis‑associated gene expression in the kidney of the UUO model. In the ROCK2 HKO mice, the expression level of ROCK2 in the normal kidney was half of that in the kidney of wild‑type (WT) mice. The expression levels of ROCK1 in the ROCK2 HKO mice and WT mice were equivalent. Furthermore, in the ROCK2 HKO and the WT mice, the hydroxyproline content and the gene expression levels of collagen I and transforming growth factor‑β1 in the obstructed kidneys were augmented following UUO. By contrast, the mRNA expression of α‑smooth muscle actin decreased in the ROCK2 HKO mice, compared with that in the WT mice. The activity of ROCK in the obstructed kidneys, indicated by the phosphorylation of myosin phosphatase target subunit‑1, which is a non‑selective substrate of ROCK1 and ROCK2, was equivalent among the ROCK2 HKO and WT mice. In conclusion, no differences in renal interstitial fibrosis or UUO‑induced ROCK activity were identified between the ROCK2 HKO and WT mice, indicating that the genetic partial disruption of ROCK2 is insufficient for protecting against renal fibrosis.
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Affiliation(s)
- Itsuko Baba
- Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda‑Shi, Saitama 335‑8505, Japan
| | - Yasuhiro Egi
- Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda‑Shi, Saitama 335‑8505, Japan
| | - Kazuo Suzuki
- Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda‑Shi, Saitama 335‑8505, Japan
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Holmström F, Shimizu S, Shimizu T, Higashi Y, Martin DT, Honda M, Saito M. Protective effect of hydroxyfasudil, a Rho kinase inhibitor, on ventral prostatic hyperplasia in the spontaneously hypertensive rat. Prostate 2015; 75:1774-82. [PMID: 26286428 DOI: 10.1002/pros.23063] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2015] [Accepted: 08/03/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Rho kinase (ROCK) pathway is associated with various cellular functions, such as smooth muscle contraction, inflammatory response, and cell proliferation. The spontaneously hypertensive rat (SHR) is commonly used genetically hypertensive rat model which develops hyperplastic morphological abnormalities in the ventral prostate. We investigated whether administration of hydroxyfasudil, a ROCK inhibitor, could reduce the levels of growth factors, inflammatory markers, and morphological abnormalities in the ventral prostate of the SHR. METHODS Twelve-week-old SHRs were treated with hydroxyfasudil (1 mg/kg/day, i.p.) or vehicle once daily for another 6 weeks. Wistar Kyoto (WKY) rats treated with vehicle were used as normotensive controls. At 18 weeks of age, blood pressure and heart rate were measured by the tail cuff method. Then the rats were sacrificed, and the ventral prostates were removed. The levels of ROCK activity, growth factors (TGF-β1 and bFGF), a smooth muscle differentiation marker (α-SMA) and an inflammatory cytokine (IL-6) in the ventral prostate were measured by ELISA and western blot. A histological evaluation in each group was also performed. RESULTS There were significant increases in blood pressure, prostate weight, prostate body weight ratio, and tissue levels of ROCK activity, TGF-β1, bFGF, α-SMA, and IL-6 in the SHR compared to the WKY rat. Histological examination of the ventral prostate showed morphological abnormalities such as a higher degree of proliferation in the glandular epithelial and stromal area in the SHR compared to the WKY rat. Treatment with hydroxyfasudil reduced the elevated ROCK activity, TGF-β1, bFGF, α-SMA, and IL-6 found in the ventral prostate of the SHR. Moreover, treatment with hydroxyfasudil decreased the morphological abnormalies in the SHR ventral prostate. CONCLUSIONS Treatment with hydroxyfasudil decreased the growth factors, an inflammatory cytokine, and morphological abnormalies in the SHR ventral prostate. These results suggest that chronic treatment with hydroxyfasudil may inhibit the progression of prostatic hyperplasia in the SHR.
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Affiliation(s)
- Felix Holmström
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Shogo Shimizu
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Takahiro Shimizu
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Youichirou Higashi
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Darryl T Martin
- Department of Urology, Yale University School of Medicine, New Haven, Connecticut
| | - Masashi Honda
- Department of Surgery, Division of Urology, Tottori University School of Medicine, Yonago, Japan
| | - Motoaki Saito
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan
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Baba I, Egi Y, Utsumi H, Kakimoto T, Suzuki K. Inhibitory effects of fasudil on renal interstitial fibrosis induced by unilateral ureteral obstruction. Mol Med Rep 2015; 12:8010-20. [PMID: 26498136 PMCID: PMC4758322 DOI: 10.3892/mmr.2015.4467] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 08/25/2015] [Indexed: 02/07/2023] Open
Abstract
Renal fibrosis is the major cause of chronic kidney disease, and the Rho/Rho-associated coiled-coil kinase (ROCK) signaling cascade is involved in the renal fibrotic processes. Several studies have reported that ROCK inhibitors attenuate renal fibrosis. However, the mechanism of this process remains to be fully elucidated. The present study assessed the inhibitory effect of fasudil, a ROCK inhibitor using immunohistochemistry, reverse transcription-quantitative polymerase chain reaction and western blot analyses, in vivo and in vitro, to elucidate the mechanisms underlying renal interstitial fibrosis. In mice induced with unilateral ureteral obstruction (UUO), collagen accumulation, the expression of fibrosis-associated genes and the content of hydroxyproline in the kidney increased 3, 7, and 14 days following UUO. Fasudil attenuated the histological changes, and the production of collagen and extracellular matrix in the UUO kidney. The expression of α-smooth muscle actin (α-SMA) and the transforming growth factor-β (TGFβ)-Smad signaling pathway, and macrophage infiltration were suppressed by fasudil in the kidneys of the UUO mice. The present study also evaluated the role of intrinsic renal cells and infiltrated macrophages using NRK-52E, NRK-49F and RAW264.7 cells. The mRNA and protein expression levels of collagen I and α-SMA increased in the NRK-52E and NRK-49F cells stimulated by TGF-β1. Hydroxyfasudil, a bioactive metabolite of fasudil, attenuated the increase in the mRNA and protein expression levles of α-SMA in the two cell types. However, the reduction in the mRNA expression of collagen I was observed in the NRK-49F cells only. Hydroxyfasudil decreased the mRNA expression of monocyte chemoattractant protein-1 (MCP-1) induced by TGF-β1 in the NRK-52E cells, but not in the NRK-49F cells. In the RAW264.7 cells, the mRNA expression levels of MCP-1, interleukin (IL)-1β, IL-6 and tumor necrosis factor α were increased significantly following lipopolysaccharide stimulation, and were not suppressed by hydroxyfasudil. These data suggested that the inhibition of ROCK activity by fasudil suppressed the transformation of renal intrinsic cells into the myofibroblast cells, and attenuated the infiltration of macrophages, without inhibiting the expression or the activation of cytokine/chemokines, in the progression of renal interstitial fibrosis.
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Affiliation(s)
- Itsuko Baba
- Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda‑shi, Saitama 335‑8505, Japan
| | - Yasuhiro Egi
- Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda‑shi, Saitama 335‑8505, Japan
| | - Hiroyuki Utsumi
- Safety Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda‑shi, Saitama 335‑8505, Japan
| | - Tetsuhiro Kakimoto
- Safety Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda‑shi, Saitama 335‑8505, Japan
| | - Kazuo Suzuki
- Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda‑shi, Saitama 335‑8505, Japan
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Waddingham MT, Edgley AJ, Astolfo A, Inagaki T, Fujii Y, Du CK, Zhan DY, Tsuchimochi H, Yagi N, Kelly DJ, Shirai M, Pearson JT. Chronic Rho-kinase inhibition improves left ventricular contractile dysfunction in early type-1 diabetes by increasing myosin cross-bridge extension. Cardiovasc Diabetol 2015; 14:92. [PMID: 26194354 PMCID: PMC4509700 DOI: 10.1186/s12933-015-0256-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 06/25/2015] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Impaired actin-myosin cross-bridge (CB) dynamics correlate with impaired left ventricular (LV) function in early diabetic cardiomyopathy (DCM). Elevated expression and activity of Rho kinase (ROCK) contributes to the development of DCM. ROCK targets several sarcomeric proteins including myosin light chain 2, myosin binding protein-C (MyBP-C), troponin I (TnI) and troponin T that all have important roles in regulating CB dynamics and contractility of the myocardium. Our aim was to examine if chronic ROCK inhibition prevents impaired CB dynamics and LV dysfunction in a rat model of early diabetes, and whether these changes are associated with changes in myofilament phosphorylation state. METHODS Seven days post-diabetes induction (65 mg/kg ip, streptozotocin), diabetic rats received the ROCK inhibitor, fasudil (10 mg/kg/day ip) or vehicle for 14 days. Rats underwent cardiac catheterization to assess LV function simultaneous with X-ray diffraction using synchrotron radiation to assess in situ CB dynamics. RESULTS Compared to controls, diabetic rats developed mild systolic and diastolic dysfunction, which was attenuated by fasudil. End-diastolic and systolic myosin proximity to actin filaments were significantly reduced in diabetic rats (P < 0.05). In all rats there was an inverse correlation between ROCK1 expression and the extension of myosin CB in diastole, with the lowest ROCK expression in control and fasudil-treated diabetic rats. In diabetic and fasudil-treated diabetic rats changes in relative phosphorylation of TnI and MyBP-C were not significant from controls. CONCLUSIONS Our results demonstrate a clear role for ROCK in the development of LV dysfunction and impaired CB dynamics in early DCM.
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Affiliation(s)
- Mark T Waddingham
- Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia.
| | - Amanda J Edgley
- Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia. .,Department of Physiology, Monash University, Clayton, VIC, Australia.
| | - Alberto Astolfo
- Australian Synchrotron, Clayton, VIC, Australia. .,Department of Medical Physics and Bioengineering, University College of London, London, England, UK.
| | - Tadakatsu Inagaki
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
| | - Yutaka Fujii
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
| | - Cheng-Kun Du
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
| | - Dong-Yun Zhan
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
| | - Hirotsugu Tsuchimochi
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
| | - Naoto Yagi
- Japan Synchrotron Radiation Research Institute, Harima, Hyogo, Japan.
| | - Darren J Kelly
- Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia.
| | - Mikiyasu Shirai
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
| | - James T Pearson
- Department of Physiology, Monash University, Clayton, VIC, Australia. .,Australian Synchrotron, Clayton, VIC, Australia. .,Monash Biomedical Imaging Facility, Monash University, Clayton, VIC, Australia.
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