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Li X, Qu S. Novel insights into the central protective role of ACE2 in diabetic cardiomyopathy: from underlying signaling pathways to therapeutic perspectives. Mol Cell Biochem 2025; 480:3535-3551. [PMID: 39928210 DOI: 10.1007/s11010-024-05196-6] [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: 11/02/2024] [Accepted: 12/18/2024] [Indexed: 02/11/2025]
Abstract
Diabetic cardiomyopathy (DCM) is a cardiac complication specific to individuals with diabetes. It is defined as abnormalities of myocardial structure and function in diabetic patients who do not exhibit any obvious coronary artery disease, hypertensive heart disease, valvular heart disease, or inherited cardiomyopathy. A significant cardiovascular protective factor identified recently is angiotensin-converting enzyme 2 (ACE2), which is a rising star in the renin angiotensin system (RAS) and is responsible for the onset and progression of DCM. Nonetheless, there is not a comprehensive review outlining ACE2's effect on DCM. From the perspective of the pathogenesis of DCM, this review summarizes the myocardial protective role of ACE2 in the aspects of alleviating myocardial structure and dysfunction, correcting energy metabolism disorders, and restoring vascular function. Concurrently, we propose the connections between ACE2 and underlying signaling pathways, including ADAM17, Apelin/APJ, and Nrf2. Additionally, we highlight ACE2-related pharmaceutical treatment options and clinical application prospects for preventing and managing DCM. Further and underlying research is extensively required to completely comprehend the principal pathophysiological mechanism of DCM and the distinctive function of ACE2, switching experimental findings into clinical practice and identifying efficient therapeutic approaches.
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Affiliation(s)
- Xinyi Li
- Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Shunlin Qu
- Pathophysiology Department, Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, University of South China, Hongxiang Street, Hengyang, 421001, Hunan, China.
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2
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Wu X, Fang S. GATA3 modulation of mitochondrial oxidative stress inhibits cerebrovascular remodeling-mediated ischemic stroke by suppressing MBVSMC phenotypic transformation. Neuroscience 2025; 570:152-158. [PMID: 39961389 DOI: 10.1016/j.neuroscience.2025.02.033] [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: 05/10/2024] [Revised: 11/06/2024] [Accepted: 02/15/2025] [Indexed: 02/28/2025]
Abstract
Ischemic stroke (IS) is the most predominant type of stroke, and cerebrovascular remodeling that occurs in response to risk factors facilitates its development. Mouse brain vascular smooth muscle cells (MBVSMCs) undergo phenotypic transformation during cerebrovascular remodeling, and reactive oxygen species (ROS) are a major driver of this process. The transcription factor of GATA binding protein 3 (GATA3) has been shown to enhance the neuroprotective effect induced by ischemic preconditioning. However, its involvement in cerebrovascular remodeling and the underlying mechanism are yet to be elucidated. Our findings showed that the expression of GATA3 was reduced in the cerebrovascular remodeling model constructed using angiotensin II (AngII)-induced MBVSMCs. In addition, the overexpression of GATA3 and the treatment of MBVSMCs with AngII revealed that the activity of NADPH oxidase was decreased, mitochondrial ROS production was reduced, malondialdehyde levels were lowered, glutathione peroxidase activity was increased; the proliferative ability of MBVSMCs was decreased, and the expression levels of molecules related to phenotypic transformation were altered. Furthermore, GATA3 promoted the expression of ring finger protein 34 (RNF34) of ubiquitin ligase, which in turn enhanced the ubiquitinated degradation of oxidative stress-related molecules and inhibited the phenotypic transformation of MBVSMCs, thereby exerting a protective effect on cerebrovascular remodeling. Collectively, these results suggest that GATA3 binds to RNF34 to augment its expression and accelerate the ubiquitinated degradation of oxidative stress-related molecules, thus exerting protective effects in IS.
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Affiliation(s)
- Xiaoke Wu
- Department of Neurology, Neuroscience Centre, the First Hospital of Jilin University, Changchun, China
| | - Shaokuan Fang
- Department of Neurology, Neuroscience Centre, the First Hospital of Jilin University, Changchun, China.
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3
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Jin L, Qin Y, Zhao Y, Zhou X, Zeng Y. Endothelial cytoskeleton in mechanotransduction and vascular diseases. J Biomech 2025; 182:112579. [PMID: 39938443 DOI: 10.1016/j.jbiomech.2025.112579] [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: 11/27/2024] [Revised: 02/04/2025] [Accepted: 02/05/2025] [Indexed: 02/14/2025]
Abstract
The cytoskeleton is an important structural component that regulates various aspects of cell morphology, movement, and intracellular signaling. It plays a pivotal role in the cellular response to biomechanical stimuli, particularly in endothelial cells, which are critical for vascular homeostasis and the pathogenesis of cardiovascular diseases. Mechanical forces, such as shear and tension, activate intracellular signaling cascades that regulate transcription, translation, and cellular behaviors. Despite extensive research into cytoskeletal functions, the precise mechanisms by which the cytoskeleton transduces mechanical signals remain incompletely understood. This review focuses on the role of cytoskeletal components in membrane, cytoplasm, and nucleus in mechanotransduction, with an emphasis on their structure, mechanical and biological behaviors, dynamic interactions, and response to mechanical forces. The collaboration between membrane cytoskeleton, cytoplasmic cytoskeleton, and nucleoskeleton is indispensable for endothelial cells to respond to mechanical stimuli. Understanding their mechanoresponsive mechanisms is essential for advancing therapeutic strategies for cardiovascular diseases.
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Affiliation(s)
- Linlu Jin
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041 Sichuan, China
| | - Yixue Qin
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041 Sichuan, China
| | - Yunran Zhao
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041 Sichuan, China
| | - Xintong Zhou
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041 Sichuan, China
| | - Ye Zeng
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041 Sichuan, China.
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Huang W, Jiang M, Wang X, Pan D, Chen W, Fan L. Non-Sugar Sweetener Rubusoside Alleviates Lipid Metabolism Disorder In Vivo and In Vitro by Targeting PPARγ/α, Lgals3, and Mknk2. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:25601-25619. [PMID: 39508235 DOI: 10.1021/acs.jafc.4c06018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2024]
Abstract
Rubusoside─a high-sweetened, nonsugar sweetener─is mainly extracted from Rubus chingii var. suavissimus (S. Lee) L. T. Lu or Rubus suavissimus S. Lee (Chinese sweet leaf tea). We previously reported that rubusoside regulates lipid metabolism disorder in Syrian golden hamsters on a high-fat diet (HFD). This study aimed to reveal the underlying mechanisms through which rubusoside alleviates lipid metabolism disorder in vivo and in vitro. First, we analyzed the therapeutic properties of rubusoside in alleviating HFD-induced lipid metabolism disorder in C57BL/6J mice. Then, we analyzed the adipogenic effect of rubusoside in normal and Lgals3/Mknk2-overexpressing 3T3-L1 cells by exploring the mechanisms on peroxisome proliferator-activated receptor-γ/α (PPARγ/α), galectin-3 (Lgals3), mitogen-activated protein kinase interacting serine/threonine kinase-2 (Mknk2), p38 mitogen-activated protein kinase (p38MAPK), and extracellular regulated protein kinases 1/2 (ERK1/2) with RT-qPCR and Western blot. Our results showed a rubusoside-mediated reduction of HFD-induced weight gain, dyslipidemia, and decelerated hepatic steatosis and adipose tissue expansion in mice as well as improved adipogenesis in 3T3-L1 cells. Mechanistically, rubusoside up-regulated the PPARγ/α expression while down-regulating Lgals3 and Mknk2 expression in vivo and in vitro. Furthermore, rubusoside attenuated the adipogenic activity of PPARγ through increasing its site-specific phosphorylation mediated by p38MAPK and ERK1/2. Taken together, our findings suggest that rubusoside alleviates lipid metabolism disorder through multiple pathways and thus holds potential for future development.
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Affiliation(s)
- Wanfang Huang
- School of Pharmacy, Guangxi University of Chinese Medicine, No. 13, Wuhe Avenue, Nanning, Guangxi 530200, China
| | - Manjing Jiang
- School of Pharmacy, Guangxi University of Chinese Medicine, No. 13, Wuhe Avenue, Nanning, Guangxi 530200, China
| | - Xue Wang
- School of Pharmacy, Guangxi University of Chinese Medicine, No. 13, Wuhe Avenue, Nanning, Guangxi 530200, China
| | - Dongjin Pan
- Institute of Marine Drugs, Guangxi University of Chinese Medicine, No. 13, Wuhe Avenue, Nanning, Guangxi 530200, China
| | - Wenya Chen
- School of Pharmacy, Guangxi University of Chinese Medicine, No. 13, Wuhe Avenue, Nanning, Guangxi 530200, China
| | - Lanlan Fan
- School of Pharmacy, Guangxi University of Chinese Medicine, No. 13, Wuhe Avenue, Nanning, Guangxi 530200, China
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Etebar N, Naderpour S, Akbari S, Zali A, Akhlaghdoust M, Daghighi SM, Baghani M, Sefat F, Hamidi SH, Rahimzadegan M. Impacts of SARS-CoV-2 on brain renin angiotensin system related signaling and its subsequent complications on brain: A theoretical perspective. J Chem Neuroanat 2024; 138:102423. [PMID: 38705215 DOI: 10.1016/j.jchemneu.2024.102423] [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: 01/28/2024] [Revised: 04/08/2024] [Accepted: 04/18/2024] [Indexed: 05/07/2024]
Abstract
Cellular ACE2 (cACE2), a vital component of the renin-angiotensin system (RAS), possesses catalytic activity to maintain AngII and Ang 1-7 balance, which is necessary to prevent harmful effects of AngII/AT2R and promote protective pathways of Ang (1-7)/MasR and Ang (1-7)/AT2R. Hemostasis of the brain-RAS is essential for maintaining normal central nervous system (CNS) function. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a viral disease that causes multi-organ dysfunction. SARS-CoV-2 mainly uses cACE2 to enter the cells and cause its downregulation. This, in turn, prevents the conversion of Ang II to Ang (1-7) and disrupts the normal balance of brain-RAS. Brain-RAS disturbances give rise to one of the pathological pathways in which SARS-CoV-2 suppresses neuroprotective pathways and induces inflammatory cytokines and reactive oxygen species. Finally, these impairments lead to neuroinflammation, neuronal injury, and neurological complications. In conclusion, the influence of RAS on various processes within the brain has significant implications for the neurological manifestations associated with COVID-19. These effects include sensory disturbances, such as olfactory and gustatory dysfunctions, as well as cerebrovascular and brain stem-related disorders, all of which are intertwined with disruptions in the RAS homeostasis of the brain.
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Affiliation(s)
- Negar Etebar
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Faculty of Pharmacy - Eastern Mediterranean University Famagusta, North Cyprus via Mersin 10, Turkey
| | - Saghi Naderpour
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Faculty of Pharmacy - Eastern Mediterranean University Famagusta, North Cyprus via Mersin 10, Turkey
| | - Setareh Akbari
- Neuroscience and Research Committee, School of Advanced Technology in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Zali
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Meisam Akhlaghdoust
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran; USERN Office, Functional Neurosurgery Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Mojtaba Daghighi
- Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Matin Baghani
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farshid Sefat
- Department of Biomedical Engineering, School of Engineering, University of Bradford, Bradford, UK
| | - Seyed Hootan Hamidi
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Acharya BM Reddy College of Pharmacy, Rajiv Gandhi University of Health Sciences, Bangalore, India
| | - Milad Rahimzadegan
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Xiao Y, Vazquez-Padron RI, Martinez L, Singer HA, Woltmann D, Salman LH. Role of platelet factor 4 in arteriovenous fistula maturation failure: What do we know so far? J Vasc Access 2024; 25:390-406. [PMID: 35751379 PMCID: PMC9974241 DOI: 10.1177/11297298221085458] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The rate of arteriovenous fistula (AVF) maturation failure remains unacceptably high despite continuous efforts on technique improvement and careful pre-surgery planning. In fact, half of all newly created AVFs are unable to be used for hemodialysis (HD) without a salvage procedure. While vascular stenosis in the venous limb of the access is the culprit, the underlying factors leading to vascular narrowing and AVF maturation failure are yet to be determined. We have recently demonstrated that AVF non-maturation is associated with post-operative medial fibrosis and fibrotic stenosis, and post-operative intimal hyperplasia (IH) exacerbates the situation. Multiple pathological processes and signaling pathways are underlying the stenotic remodeling of the AVF. Our group has recently indicated that a pro-inflammatory cytokine platelet factor 4 (PF4/CXCL4) is upregulated in veins that fail to mature after AVF creation. Platelet factor 4 is a fibrosis marker and can be detected in vascular stenosis tissue, suggesting that it may contribute to AVF maturation failure through stimulation of fibrosis and development of fibrotic stenosis. Here, we present an overview of the how PF4-mediated fibrosis determines AVF maturation failure.
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Affiliation(s)
- Yuxuan Xiao
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Roberto I Vazquez-Padron
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Laisel Martinez
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Harold A Singer
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Daniel Woltmann
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Loay H Salman
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
- Division of Nephrology and Hypertension, Albany Medical College, Albany, NY, USA
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Caputo I, Bertoldi G, Driussi G, Cacciapuoti M, Calò LA. The RAAS Goodfellas in Cardiovascular System. J Clin Med 2023; 12:6873. [PMID: 37959338 PMCID: PMC10649249 DOI: 10.3390/jcm12216873] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 10/26/2023] [Accepted: 10/29/2023] [Indexed: 11/15/2023] Open
Abstract
In the last two decades, the study of the renin-angiotensin-aldosterone system (RAAS) has revealed a counterregulatory protective axis. This protective arm is characterized by ACE2/Ang 1-7/MasR and Ang 1-9 that largely counteracts the classic arm of the RAAS mediated by ACE/Ang II/AT1R/aldosterone and plays an important role in the prevention of inflammation, oxidative stress, hypertension, and cardiovascular remodeling. A growing body of evidence suggests that enhancement of this counterregulatory arm of RAAS represents an important therapeutic approach to facing cardiovascular comorbidities. In this review, we provide an overview of the beneficial effects of ACE2, Ang 1-7/MasR, and Ang 1-9 in the context of oxidative stress, vascular dysfunction, and organ damage.
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Affiliation(s)
| | | | | | | | - Lorenzo A. Calò
- Nephrology, Dialysis and Transplantation Unit, Department of Medicine—DIMED, University of Padua, Via Giustiniani, 2, 35128 Padova, Italy; (I.C.); (G.B.); (G.D.); (M.C.)
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8
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Baldari CT, Onnis A, Andreano E, Del Giudice G, Rappuoli R. Emerging roles of SARS-CoV-2 Spike-ACE2 in immune evasion and pathogenesis. Trends Immunol 2023; 44:424-434. [PMID: 37137805 PMCID: PMC10076505 DOI: 10.1016/j.it.2023.04.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/23/2023] [Accepted: 04/03/2023] [Indexed: 05/05/2023]
Abstract
The COVID-19 pandemic, caused by SARS-CoV-2, has caused an estimated 5 billion infections and 20 million deaths by respiratory failure. In addition to the respiratory disease, SARS-CoV-2 infection has been associated with many extrapulmonary complications not easily explainable by the respiratory infection. A recent study showed that the SARS-CoV-2 spike protein, which mediates cell entry by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, signals through ACE2 to change host cell behavior. In CD8+ T cells, spike-dependent ACE2-mediated signaling suppresses immunological synapse (IS) formation and impairs their killing ability, leading to immune escape of virus-infected cells. In this opinion article, we discuss the consequences of ACE2 signaling on the immune response and propose that it contributes to the extrapulmonary manifestations of COVID-19.
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Affiliation(s)
| | - Anna Onnis
- Department of Life Sciences, University of Siena, Siena, Italy
| | - Emanuele Andreano
- Monoclonal Antibody Discovery (MAD) Lab, Fondazione Toscana Life Sciences, Siena, Italy
| | | | - Rino Rappuoli
- Fondazione Biotecnopolo di Siena, Siena, Italy; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
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Meng C, Song Z, Zhang L, Geng Y, Sun J, Miao G, Liu P. Effects of losartan in patients with NAFLD: A meta-analysis of randomized controlled trial. Open Life Sci 2023; 18:20220583. [PMID: 36970603 PMCID: PMC10031500 DOI: 10.1515/biol-2022-0583] [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: 12/08/2022] [Revised: 02/18/2023] [Accepted: 02/19/2023] [Indexed: 03/24/2023] Open
Abstract
Losartan has become a hot spot in the treatment of non-alcoholic fatty liver disease (NAFLD) among angiotensin receptor blocker drugs. We sought to conduct a systematic examination and meta-analysis to examine the effects of losartan on patients with NAFLD. We searched for potentially randomized controlled trials in PubMed, Embase, China National Knowledge Infrastructure, Wanfang, and the Cochrane database up to October 09, 2022. We used the Cochrane risk of bias tool to evaluate the study quality. Analysis of subgroups, sensitivity analysis, and publishing bias were explored. The quality of the included studies was moderate to high. Six trials involving 408 patients were included. The meta-analysis demonstrated that aspartate transaminase was significantly affected by losartan therapy (mean difference [MD] = −5.34, 95% confidence interval [CI] [−6.54, −4.13], Z = 8.70, P < 0.01). The meta-analysis subgroup showed that losartan 50 mg once daily could lower the level of alanine aminotransferase (MD = −18.92, 95% CI [−21.18, −16.66], Z = 16.41, P < 0.01). There was no statistically significant difference in serum total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein.
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Affiliation(s)
- Chang Meng
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, PR China
| | - Zejun Song
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Changping District, Beijing, 102218, PR China
| | - Lingnan Zhang
- Department of Cardiology, Affiliated Hospital of Hebei University, Hebei University, 212 Yuhua East Road, Lianchi District, Baoding City, 071000, PR China
| | - Yu Geng
- Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, NO. 168 Litang Road, Changping District, Beijing102218, P. R. China
| | - Jing Sun
- Department of Critical Care Medicine, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, PR China
| | - Guobin Miao
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, PR China
| | - Peng Liu
- Department of Cardiology, Ordos Central Hospital, Ordos School of Clinical Medicine, Inner Mongolia Medical University, 23 Yijinhuoluo West Street, Dongsheng District, Inner Mongolia, 017000, PR China
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Yang J, Chen X. SIRT6 attenuates LPS-induced inflammation and apoptosis of lung epithelial cells in acute lung injury through ACE2/STAT3/PIM1 signaling. Immun Inflamm Dis 2023; 11:e809. [PMID: 36988243 PMCID: PMC10022422 DOI: 10.1002/iid3.809] [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: 11/09/2022] [Revised: 01/10/2023] [Accepted: 02/18/2023] [Indexed: 03/19/2023] Open
Abstract
BACKGROUND Acute lung injury (ALI) is a severe and fatal respiratory disease. SIRT6 exerts pivotal activities in the process of lung diseases, but whether SIRT6 impacts ALI has not been covered. METHODS Lentivirus recombinant expressing vector SIRT6 gene (Lent-SIRT6) was constructed in mice, and there were control, lipopolysaccharide (LPS), LPS + Vehicle, and LPS + Lent SIRT6 groups. RT-qPCR and western blot detected SIRT6 expression in lung tissues. HE staining observed pathological alternations in lung tissues. Wet-to-dry ratio of the lungs was then measured. The cell count of bronchoalveolar lavage fluid (BALF) was evaluated. Serum inflammation was examined with enzyme-linked immunosorbent assay, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and western blot were to measure apoptosis. Western blot tested the expression of ACE2/STAT3/PIM1 signaling-associated factors. At the cellular level, LPS was used to induce lung epithelial cells BEAS-2B to establish cell injury models. SIRT6 was overexpressed and ACE2 expression was inhibited by cell transfection, and the mechanism of SIRT6 in LPS-induced lung injury model was further explored by Cell Counting Kit-8 (CCK-8), western blot, quantitative reverse-transcription polymerase chain reaction, TUNEL, and other techniques. RESULTS The results of animal experiments showed that SIRT6 overexpression could reduce LPS-induced lung pathological injury, pulmonary edema, and BALF cell ratio and attenuate LPS-induced inflammatory response and cell apoptosis. In the above process, ACE2, STAT3, p-STAT3, and PIM1 expression were affected. In cell experiments, SIRT6 expression was reduced in LPS-induced BEAS-2B cells. Inhibition of ACE2 expression could reverse the inhibitory effect of SIRT6 overexpression on ACE2/STAT3/PIM1 pathway, and cellular inflammatory response and apoptosis. CONCLUSION SIRT6 eased LPS-evoked inflammation and apoptosis of lung epithelial cells in ALI through ACE2/STAT3/PIM1 signaling.
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Affiliation(s)
- Juan Yang
- Department of Pediatric, Shandong Provincial HospitalShandong UniversityJinanShandongChina
| | - Xing Chen
- Department of Pediatric, Shandong Provincial HospitalShandong UniversityJinanShandongChina
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Mostafa SA, Mohammad MHS, Negm WA, Batiha GES, Alotaibi SS, Albogami SM, Waard MD, Tawfik NZ, Abdallah HY. Circulating microRNA203 and its target genes' role in psoriasis pathogenesis. Front Med (Lausanne) 2022; 9:988962. [DOI: 10.3389/fmed.2022.988962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 10/03/2022] [Indexed: 11/13/2022] Open
Abstract
Numerous microRNAs (miRNAs) have been found to have an aberrant expression in the peripheral blood or psoriasis patients' lesions. Psoriasis was shown to have the abnormal expression of microRNA-203 (miR-203). It is a skin-specific signal that governs cellular proliferation in a protein kinase C-dependent manner and is mostly generated by keratinocytes. This work evaluated the expression levels of the circulating miR-203 target genes SOCS3, SOCS6, TP63, TNF-, IL8, and IL24 in psoriasis patients. Using a relative quantitation PCR technique, we determined the expression levels of miR-203 and its target genes (SOCS3, SOCS6, TP63, TNF-, IL8, and IL24) in the plasma of 120 psoriatic patients and matched healthy controls. The disease characteristics of the patients were then correlated with the expression results. We also conducted numerous enrichment analyses for the diseases, functions, and pathways connected to the under-researched biomarkers. Compared to healthy controls, psoriatic patients had significantly increased levels of miR-203 expression; 7.1 (4.4–9.9). In contrast, psoriatic patients had significantly lower expression of all the examined genes compared to healthy controls. Regarding all the study biomarkers, the receiver operating characteristic (ROC) curve analysis demonstrated significant sensitivity and specificity for differentiating between psoriatic patients and healthy controls. According to the results of the disease matching score generated by miR-203 and its target genes, psoriasis was ranked first with a score of 4.45. The third-place finisher with a value of 3.98, it also demonstrated that miR-203 and its target genes are connected to various skin disorders. Our results show that miR-203 contributes to psoriasis pathogenesis not only locally in skin lesions but also in circulation, indicating that it may contribute to the systemic symptoms of the illness. MiR-203 overexpression in psoriasis suggests that miR-203 may be involved in an anti-inflammatory response because it targets both SOCS gene family members and pro-inflammatory cytokines.
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Leukotriene Receptor Antagonist, Montelukast Ameliorates L-NAME-Induced Pre-eclampsia in Rats through Suppressing the IL-6/Jak2/STAT3 Signaling Pathway. Pharmaceuticals (Basel) 2022; 15:ph15080914. [PMID: 35893738 PMCID: PMC9332684 DOI: 10.3390/ph15080914] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 07/19/2022] [Indexed: 12/15/2022] Open
Abstract
Aims: To investigate the potential protective role of montelukast (Mont) in the pre-eclampsia rat model induced by L-NG-Nitro arginine methyl ester (L-NAME). Methods and materials: Thirty-two pregnant female albino Wistar rats were assigned to four groups: the control group: pregnant rats received vehicles; the Mont group: pregnant rats received Mont (10 mg/kg/day, p.o.) from the 6th to the 18th day of gestation; the L-NAME group: pregnant rats received L-NAME (50 mg/kg/day, i.p.) from the 9th to the 18th day of gestation; the Mont/L-NAME group: pregnant rats received Mont (10 mg/kg/day, p.o.) from the 6th to the 18th day of gestation and L-NAME (50 mg/kg/day, i.p.) from the 9th to the 18th day of gestation. Placental, hepatic, and renal malondialdehyde (MDA), total nitrites (NOx), interleukin 6 (IL-6), and tumor necrosis factor (TNF)-α were determined. Serum alanine transaminase (ALT), aspartate transaminase (AST), creatinine, urea, 24-h urinary protein, and the placental growth factor (PGF) were measured. Histopathological examinations of the placental, hepatic, and renal tissues were also performed. In addition, placental, hepatic, and renal Janus kinase 2 (Jak2) and signal transducer and activator of transcription 3 (STAT3) immunoblotting were performed. Key findings: Mont improves oxidative stress, IL-6, TNF-α, ALT, AST, creatinine, urea, 24-h urinary protein, PGF, Jak2, and STAT3 which were all affected by L-NAME. Moreover, the histopathological assessment indicated that Mont restored the normal architecture that was markedly disturbed by L-NAME. Significance: Mont exerted the biochemical and histopathological amelioration of L-NAME-caused pre-eclampsia through its anti-inflammatory, anti-oxidant function and suppression of the IL-6/Jak2/STAT3 signaling pathway.
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Resveratrol exerts antiproliferative effects on high-glucose-cultured vascular smooth muscle cells via inhibition of STAT3 and upregulation of mitochondrial gene GRIM-19 which is responsible for STAT3 activation. Int J Diabetes Dev Ctries 2022. [DOI: 10.1007/s13410-021-00963-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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14
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Zhang Z, Tang J, Song J, Xie M, Liu Y, Dong Z, Liu X, Li X, Zhang M, Chen Y, Shi H, Zhong J. Elabela alleviates ferroptosis, myocardial remodeling, fibrosis and heart dysfunction in hypertensive mice by modulating the IL-6/STAT3/GPX4 signaling. Free Radic Biol Med 2022; 181:130-142. [PMID: 35122997 DOI: 10.1016/j.freeradbiomed.2022.01.020] [Citation(s) in RCA: 151] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/12/2022] [Accepted: 01/23/2022] [Indexed: 12/13/2022]
Abstract
Hypertension-mediated pathological cardiac remodeling often progresses to heart failure. Elabela, mainly expressed in the cardiac microvascular endothelial cells (CMVECs), functions as a new endogenous ligand for apelin receptor. However, the exact roles of elabela in hypertension remain largely unclear. In this study, 10-week-old male C57BL/6 mice were randomly subjected to infusion of angiotensin (Ang) II (1.5 mg/kg/d) or saline for 2 weeks. Ang II infusion led to marked increases in systolic blood pressure levels and reduction of elabela levels in hypertensive mice with augmented myocardial hypertrophy and fibrosis. Furthermore, administration of elabela or ferroptosis inhibitor ferrostatin-1 significantly prevented Ang II-mediated pathological myocardial remodeling, dysfunction, and ultrastructural injury in hypertensive mice with downregulated expression of inflammation-, hypertrophy-, and fibrosis-related genes. Notably, elabela strikingly alleviated Ang II-induced upregulation of iron levels and lipid peroxidation in hypertensive mice by suppressing cardiac interleukin-6 (IL-6)/STAT3 signaling and activating the xCT/glutathione peroxidase (GPX4) signaling. In cultured CMVECs, exposure to Ang II resulted in a marked decrease in elabela levels and obvious increases in cellular ferroptosis, proliferation, inflammation, and superoxide production, which were rescued by elabela or ferrostatin-1 while were blocked by co-treatment with rhIL-6. Furthermore, knockdown of elabela by siRNA in CMVECs contributed to Ang II-mediated augmentations in cellular proliferation, migration, and oxidative stress in cultured cardiac fibroblasts and cardiomyocytes, respectively. In conclusion, elabela antagonizes Ang II-mediated promotion of CMVECs ferroptosis, adverse myocardial remodeling, fibrosis and heart dysfunction through modulating the IL-6/STAT3/GPX4 signaling pathway. Targeting elabela-APJ axis serves as a novel strategy for hypertensive heart diseases.
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Affiliation(s)
- Zhenzhou Zhang
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Jianqiong Tang
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China
| | - Jiawei Song
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Mengshi Xie
- Department of Cardiology, Zhongshan Hospital Wusong Branch, Fudan University, Shanghai, 201900, China
| | - Ying Liu
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Zhaojie Dong
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Xiaoyan Liu
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Xueting Li
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Miwen Zhang
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Yihang Chen
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Hongyu Shi
- Department of Cardiology, Zhongshan Hospital Wusong Branch, Fudan University, Shanghai, 201900, China.
| | - Jiuchang Zhong
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
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15
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MicroRNA-122-5p promotes renal fibrosis and injury in spontaneously hypertensive rats by targeting FOXO3. Exp Cell Res 2022; 411:113017. [PMID: 34998813 DOI: 10.1016/j.yexcr.2022.113017] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 12/16/2021] [Accepted: 01/03/2022] [Indexed: 11/20/2022]
Abstract
Hypertensive renal injury is accompanied by tubular interstitial fibrosis leading to increased risk for renal failure. This study aimed to explore the influences of miR-122-5p in hypertension-mediated renal fibrosis and damage. 14-week-old male SHR and WKY rats were randomly assigned to treat with rAAV-miR-122-5p or rAAV-GFP for 8 weeks. There were marked increases in miR-122-5p and Kim-1 levels and decreases in FOXO3 and SIRT6 levels in hypertensive rats. Transfection with rAAV-miR-122-5p triggered exacerbation of renal fibrosis, apoptosis and inflammatory injury in SHR, associated with downregulated levels of FOXO3, SIRT6, ATG5 and BNIP3 as well as upregulated expression of Kim-1, NOX4, CTGF, and TGF-β1. In cultured primary mouse renal tubular interstitial fibroblasts, exposure to angiotensin II resulted in obvious downregulation of FOXO3, SIRT6, ATG5, BNIP3 and nitric oxide levels as well as augmented cellular migration, oxidative stress, and inflammation, which were exacerbated by miR-122-5p mimic while rescued by miR-122-5p inhibitor and rhFOXO3, respectively. Notably, knockdown of FOXO3 strikingly blunted cellular protective effects of miR-122-5p inhibitor. In summary, miR-122-5p augments renal fibrosis, inflammatory and oxidant injury in hypertensive rats by suppressing the expression of FOXO3. Pharmacological inhibition of miR-122-5p has potential therapeutic significance for hypertensive renal injury and fibrosis-related kidney diseases.
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16
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Research Progress on Pulmonary Arterial Hypertension and the Role of the Angiotensin Converting Enzyme 2-Angiotensin-(1-7)-Mas Axis in Pulmonary Arterial Hypertension. Cardiovasc Drugs Ther 2022; 36:363-370. [PMID: 33394361 PMCID: PMC7779643 DOI: 10.1007/s10557-020-07114-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/13/2020] [Indexed: 01/31/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease with a complex aetiology and high mortality. Functional and structural changes in the small pulmonary arteries lead to elevated pulmonary arterial pressure, resulting in right heart failure. The pathobiology of PAH is not fully understood, and novel treatment targets in PAH are desperately needed. The renin-angiotensin system is critical for maintaining homeostasis of the cardiovascular system. The system consists of the angiotensin converting enzyme (ACE)-angiotensin (Ang) II-angiotensin type 1 receptor (AT1R) axis and the ACE2-Ang-(1-7)-Mas receptor axis. The former, the ACE-Ang II-AT1R axis, is involved in vasoconstrictive and hypertensive actions along with cardiac and vascular remodelling. The latter, the ACE2-Ang-(1-7)-Mas axis, generally mediates counterbalancing effects against those mediated by the ACE-Ang II-AT1R axis. Based on established functions, the ACE2-Ang-(1-7)-Mas axis may represent a novel target for the treatment of PAH. This review focuses on recent advances in pulmonary circulation science and the role of the ACE2-Ang-(1-7)-Mas axis in PAH.
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17
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Xiao ZL, Ma LP, Yang DF, Yang M, Li ZY, Chen MF. Profilin-1 is involved in macroangiopathy induced by advanced glycation end products via vascular remodeling and inflammation. World J Diabetes 2021; 12:1875-1893. [PMID: 34888013 PMCID: PMC8613658 DOI: 10.4239/wjd.v12.i11.1875] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/29/2021] [Accepted: 08/20/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The accumulation of advanced glycation end products (AGEs) have been implicated in the development and progression of diabetic vasculopathy. However, the role of profilin-1 as a multifunctional actin-binding protein in AGEs-induced atherosclerosis (AS) is largely unknown.
AIM To explore the potential role of profilin-1 in the pathogenesis of AS induced by AGEs, particularly in relation to the Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) signaling pathway.
METHODS Eighty-nine individuals undergoing coronary angiography were enrolled in the study. Plasma cytokine levels were detected using ELISA kits. Rat aortic vascular smooth muscle cells (RASMCs) were incubated with different compounds for different times. Cell proliferation was determined by performing the MTT assay and EdU staining. An AGEs-induced vascular remodeling model was established in rats and histological and immunohistochemical analyses were performed. The mRNA and protein levels were detected using real-time PCR and Western blot analysis, respectively. In vivo, shRNA transfection was performed to verify the role of profilin-1 in AGEs-induced proatherogenic mediator release and aortic remodeling. Statistical analyses were performed using SPSS 22.0 software.
RESULTS Compared with the control group, plasma levels of profilin-1 and receptor for AGEs (RAGE) were significantly increased in patients with coronary artery disease, especially in those complicated with diabetes mellitus (P < 0.01). The levels of profilin-1 were positively correlated with the levels of RAGE (P < 0.01); additionally, the levels of both molecules were positively associated with the degree of coronary artery stenosis (P < 0.01). In vivo, tail vein injections of AGEs induced the release of proatherogenic mediators, such as asymmetric dimethylarginine, intercellular adhesion molecule-1, and the N-terminus of procollagen III peptide, concomitant with apparent aortic morphological changes and significantly upregulated expression of the profilin-1 mRNA and protein in the thoracic aorta (P < 0.05 or P < 0.01). Downregulation of profilin-1 expression with an shRNA significantly attenuated AGEs-induced proatherogenic mediator release (P < 0.05) and aortic remodeling. In vitro, incubation of vascular smooth muscle cells (VSMCs) with AGEs significantly promoted cell proliferation and upregulated the expression of the profilin-1 mRNA and protein (P < 0.05). AGEs (200 μg/mL, 24 h) significantly upregulated the expression of the STAT3 mRNA and protein and JAK2 protein, which was blocked by a JAK2 inhibitor (T3042-1) and/or STAT3 inhibitor (T6308-1) (P < 0.05). In addition, pretreatment with T3042-1 or T6308-1 significantly inhibited AGEs-induced RASMC proliferation (P < 0.05).
CONCLUSION AGEs induce proatherogenic events such as VSMC proliferation, proatherogenic mediator release, and vascular remodeling, changes that can be attenuated by silencing profilin-1 expression. These results suggest a crucial role for profilin-1 in AGEs-induced vasculopathy.
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Affiliation(s)
- Zhi-Lin Xiao
- Department of Geriatric Cardiology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Li-Ping Ma
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong Province, China
| | - Da-Feng Yang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Mei Yang
- Department of Geriatric Cardiology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Zhen-Yu Li
- Department of Geriatric Cardiology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Mei-Fang Chen
- Department of Geriatric Cardiology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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18
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Ni GH, Cheng JF, Li YJ, Xie QY, Yang TL, Chen MF. Effect of profilin-1 on the asymmetric dimethylarginine-induced vascular lesion-associated hypertension. Kaohsiung J Med Sci 2021; 38:149-156. [PMID: 34741409 DOI: 10.1002/kjm2.12468] [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: 02/22/2021] [Revised: 09/15/2021] [Accepted: 09/21/2021] [Indexed: 11/07/2022] Open
Abstract
Previous studies have demonstrated that the levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis, are strongly associated with hypertension, diabetes, and cardiovascular diseases. Profilin-1, an actin-binding protein, has been documented to be involved in endothelial injury and in the proliferation of vascular smooth muscle cells resulting from hypertension. However, the role of profilin-1 in ADMA-induced vascular injury in hypertension remains largely unknown. Forty healthy subjects and forty-two matched patients with essential hypertension were enrolled, and the related indexes of vascular injury in plasma were detected. Rat aortic smooth muscle cells (RASMCs) were treated with different concentrations of ADMA for different periods of time and transfected with profilin-1 small hairpin RNA to interrupt the expression of profilin-1. To determine the role of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, RASMCs were pretreated with AG490 or rapamycin. The expression of profilin-1 was tested using real-time polymerase chain reaction (PCR) and western blot analysis. Cell proliferation was measured by flow cytometry and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazoliumbromide assays. Compared with healthy subjects, the levels of ADMA and profilin-1 were markedly elevated in hypertensive individuals, while the levels of NO were significantly decreased (p < 0.05). In vitro, studies showed ADMA-induced profilin-1 expression in a concentration- and time-dependent manner in RASMCs (p < 0.05), concomitantly with promoting the proliferation of RASMCs. Furthermore, ADMA-mediated proliferation of RASMCs and upregulation expression of profilin-1 were inhibited by blockade of the JAK2/STAT3 pathway or knockdown of profilin-1. Profilin-1 implicated in the ADMA-mediated vascular lesions in hypertension.
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Affiliation(s)
- Guo-Hua Ni
- Health Management Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (Chengdu Jinjiang Sohome Comprehensive Outpatient Clinic), Chengdu, China
| | - Jin-Fang Cheng
- Department of Cardiology, Shanxi Baiqiuen Hospital, Taiyuan, China
| | - Yuan-Jian Li
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Qi-Ying Xie
- Department of Geriatric Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Tian-Lun Yang
- Department of Geriatric Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Mei-Fang Chen
- Department of Geriatric Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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19
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Abstract
Dynamic remodeling of the actin cytoskeleton is an essential feature for virtually all actin-dependent cellular processes, including cell migration, cell cycle progression, chromatin remodeling and gene expression, and even the DNA damage response. An altered actin cytoskeleton is a structural hallmark associated with numerous pathologies ranging from cardiovascular diseases to immune disorders, neurological diseases and cancer. The actin cytoskeleton in cells is regulated through the orchestrated actions of a myriad of actin-binding proteins. In this Review, we provide a brief overview of the structure and functions of the actin-monomer-binding protein profilin-1 (Pfn1) and then discuss how dysregulated expression of Pfn1 contributes to diseases associated with the cardiovascular system.
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Affiliation(s)
| | - David Gau
- Bioengineering, University of Pittsburgh
| | - Partha Roy
- Bioengineering, University of Pittsburgh.,Pathology, University of Pittsburgh, 306 Center for Bioengineering, University of Pittsburgh, 300 Technology Drive, Pittsburgh, PA 15219, USA
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20
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Oz M, Lorke DE, Kabbani N. A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor. Pharmacol Ther 2021; 221:107750. [PMID: 33275999 PMCID: PMC7854082 DOI: 10.1016/j.pharmthera.2020.107750] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 02/06/2023]
Abstract
The recent emergence of coronavirus disease-2019 (COVID-19) as a global pandemic has prompted scientists to address an urgent need for defining mechanisms of disease pathology and treatment. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, employs angiotensin converting enzyme 2 (ACE2) as its primary target for cell surface attachment and likely entry into the host cell. Thus, understanding factors that may regulate the expression and function of ACE2 in the healthy and diseased body is critical for clinical intervention. Over 66% of all adults in the United States are currently using a prescription drug and while earlier findings have focused on possible upregulation of ACE2 expression through the use of renin angiotensin system (RAS) inhibitors, mounting evidence suggests that various other widely administered drugs used in the treatment of hypertension, heart failure, diabetes mellitus, hyperlipidemias, coagulation disorders, and pulmonary disease may also present a varied risk for COVID-19. Specifically, we summarize mechanisms on how heparin, statins, steroids and phytochemicals, besides their established therapeutic effects, may also interfere with SARS-CoV-2 viral entry into cells. We also describe evidence on the effect of several vitamins, phytochemicals, and naturally occurring compounds on ACE2 expression and activity in various tissues and disease models. This comprehensive review aims to provide a timely compendium on the potential impact of commonly prescribed drugs and pharmacologically active compounds on COVID-19 pathology and risk through regulation of ACE2 and RAS signaling.
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Key Words
- adam17, a disintegrin and metalloprotease 17
- ace, angiotensin i converting enzyme
- ace-inh., angiotensin i converting enzyme inhibitor
- ampk, amp-activated protein kinase
- ang-ii, angiotensin ii
- arb, angiotensin ii type 1-receptor blocker
- ards, acute respiratory distress syndrome
- at1-r, angiotensin ii type 1-receptor
- βarb, β-adrenergic receptor blockers
- bk, bradykinin
- ccb, calcium channel blockers
- ch25h, cholesterol-25-hydroxylase
- copd, chronic obstructive lung disease
- cox, cyclooxygenase
- covid-19, coronavirus disease-2019
- dabk, [des-arg9]-bradykinin
- erk, extracellular signal-regulated kinase
- 25hc, 25-hydroxycholesterol
- hs, heparan sulfate
- hspg, heparan sulfate proteoglycan
- ibd, inflammatory bowel disease
- map, mitogen-activated protein
- mers, middle east respiratory syndrome
- mrb, mineralocorticoid receptor blocker
- nos, nitric oxide synthase
- nsaid, non-steroid anti-inflammatory drug
- ras, renin-angiotensin system
- sars-cov, severe acute respiratory syndrome coronavirus
- sh, spontaneously hypertensive
- s protein, spike protein
- sirt1, sirtuin 1
- t2dm, type 2 diabetes mellitus
- tcm, traditional chinese medicine
- tmprss2, transmembrane protease, serine 2
- tnf, tumor necrosis factor
- ufh, unfractionated heparin
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Affiliation(s)
- Murat Oz
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat 13110, Kuwait.
| | - Dietrich Ernst Lorke
- Department of Anatomy and Cellular Biology, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates; Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Nadine Kabbani
- School of Systems Biology, George Mason University, Fairfax, VA 22030, USA
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21
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Physiological cyclic stretch up-regulates angiotensin-converting enzyme 2 expression to reduce proliferation and migration of vascular smooth muscle cells. Biosci Rep 2021; 40:225043. [PMID: 32463098 PMCID: PMC7295630 DOI: 10.1042/bsr20192012] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 04/29/2020] [Accepted: 05/13/2020] [Indexed: 12/24/2022] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2) is considered as an endogenous negative regulator of renin–angiotensin system (RAS), exerting multiple cardiovascular protective roles. Whether mechanical stretch modulates ACE2 expression remains unknown. The present study aimed at investigating whether ACE2 is involved in physiological stretch (10% elongation, 1 Hz) mediated cellular functions and the underlying mechanism. Cultured human aortic smooth muscle cells (HASMCs) were exposed to 10% stretch for indicated time, and real-time PCR and Western blot analysis showed 10% stretch increased ACE2 expression and activity significantly compared with static conditions and increased Ang-(1-7) level, but decreased Ang II level; Brdu incorporation assay and Scratch test showed that ACE2 was involved in the inhibition of HASMCs proliferation and migration by 10% stretch; the Dual-Luciferase Reporter Assay demonstrated that 10% increased ACE2 promoter activity, but had no effect on ACE2 mRNA stability; kinase inhibition study and Electrophoretic mobility shift assay (EMSA) showed that JNK1/2 and PKCβII pathway, as well as their downstream transcription factors, AP-1 and NF-κB, were involved in 10% stretch induced ACE2 expression. In conclusion, our study indicates ACE2 is a mechanosensitive gene, and may represent a potential therapeutic target for mechanical forces related vascular diseases.
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22
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Kuriakose J, Montezano A, Touyz R. ACE2/Ang-(1-7)/Mas1 axis and the vascular system: vasoprotection to COVID-19-associated vascular disease. Clin Sci (Lond) 2021; 135:387-407. [PMID: 33511992 PMCID: PMC7846970 DOI: 10.1042/cs20200480] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 01/07/2021] [Accepted: 01/11/2021] [Indexed: 12/13/2022]
Abstract
The two axes of the renin-angiotensin system include the classical ACE/Ang II/AT1 axis and the counter-regulatory ACE2/Ang-(1-7)/Mas1 axis. ACE2 is a multifunctional monocarboxypeptidase responsible for generating Ang-(1-7) from Ang II. ACE2 is important in the vascular system where it is found in arterial and venous endothelial cells and arterial smooth muscle cells in many vascular beds. Among the best characterized functions of ACE2 is its role in regulating vascular tone. ACE2 through its effector peptide Ang-(1-7) and receptor Mas1 induces vasodilation and attenuates Ang II-induced vasoconstriction. In endothelial cells activation of the ACE2/Ang-(1-7)/Mas1 axis increases production of the vasodilator's nitric oxide and prostacyclin's and in vascular smooth muscle cells it inhibits pro-contractile and pro-inflammatory signaling. Endothelial ACE2 is cleaved by proteases, shed into the circulation and measured as soluble ACE2. Plasma ACE2 activity is increased in cardiovascular disease and may have prognostic significance in disease severity. In addition to its enzymatic function, ACE2 is the receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV) and SARS-Cov-2, which cause SARS and coronavirus disease-19 (COVID-19) respectively. ACE-2 is thus a double-edged sword: it promotes cardiovascular health while also facilitating the devastations caused by coronaviruses. COVID-19 is associated with cardiovascular disease as a risk factor and as a complication. Mechanisms linking COVID-19 and cardiovascular disease are unclear, but vascular ACE2 may be important. This review focuses on the vascular biology and (patho)physiology of ACE2 in cardiovascular health and disease and briefly discusses the role of vascular ACE2 as a potential mediator of vascular injury in COVID-19.
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Affiliation(s)
- Jithin Kuriakose
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
| | - Augusto C. Montezano
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
| | - Rhian M. Touyz
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
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23
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The Two-Way Switch Role of ACE2 in the Treatment of Novel Coronavirus Pneumonia and Underlying Comorbidities. Molecules 2020; 26:molecules26010142. [PMID: 33396184 PMCID: PMC7794970 DOI: 10.3390/molecules26010142] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/13/2020] [Accepted: 12/16/2020] [Indexed: 01/11/2023] Open
Abstract
December 2019 saw the emergence of the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has spread across the globe. The high infectivity and ongoing mortality of SARS-CoV-2 emphasize the demand of drug discovery. Angiotensin-converting enzyme II (ACE2) is the functional receptor for SARS-CoV-2 entry into host cells. ACE2 exists as a membrane-bound protein on major viral target pulmonary epithelial cells, and its peptidase domain (PD) interacts SARS-CoV-2 spike protein with higher affinity. Therefore, targeting ACE2 is an important pharmacological intervention for a SARS-CoV-2 infection. In this review, we described the two-way switch role of ACE2 in the treatment of novel coronavirus pneumonia and underlying comorbidities, and discussed the potential effect of the ACE inhibitor and angiotensin receptor blocker on a hypertension patient with the SARS-CoV-2 infection. In addition, we analyzed the S-protein-binding site on ACE2 and suggested that blocking hot spot-31 and hot spot-353 on ACE2 could be a therapeutic strategy for preventing the spread of SARS-CoV-2. Besides, the recombinant ACE2 protein could be another potential treatment option for SARS-CoV-2 induced acute severe lung failure. This review could provide beneficial information for the development of anti-SARS-CoV-2 agents via targeting ACE2 and the clinical usage of renin-angiotensin system (RAS) drugs for novel coronavirus pneumonia treatment.
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24
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Wazny V, Siau A, Wu KX, Cheung C. Vascular underpinning of COVID-19. Open Biol 2020; 10:200208. [PMID: 32847471 PMCID: PMC7479931 DOI: 10.1098/rsob.200208] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 08/11/2020] [Indexed: 12/21/2022] Open
Abstract
COVID-19 management guidelines have largely attributed critically ill patients who develop acute respiratory distress syndrome, to a systemic overproduction of pro-inflammatory cytokines. Cardiovascular dysfunction may also represent a primary phenomenon, with increasing data suggesting that severe COVID-19 reflects a confluence of vascular dysfunction, thrombosis and dysregulated inflammation. Here, we first consolidate the information on localized microvascular inflammation and disordered cytokine release, triggering vessel permeability and prothrombotic conditions that play a central role in perpetuating the pathogenic COVID-19 cascade. Secondly, we seek to clarify the gateways which SARS-CoV-2, the causative COVID-19 virus, uses to enter host vascular cells. Post-mortem examinations of patients' tissues have confirmed direct viral endothelial infection within several organs. While there have been advances in single-cell RNA sequencing, endothelial cells across various vascular beds express low or undetectable levels of those touted SARS-CoV-2 entry factors. Emerging studies postulate alternative pathways and the apicobasal distribution of host cell surface factors could influence endothelial SARS-CoV-2 entry and replication. Finally, we provide experimental considerations such as endothelial polarity, cellular heterogeneity in organoids and shear stress dynamics in designing cellular models to facilitate research on viral-induced endothelial dysfunctions. Understanding the vascular underpinning of COVID-19 pathogenesis is crucial to managing outcomes and mortality.
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Affiliation(s)
- Vanessa Wazny
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 59 Nanyang Drive, Singapore636921, Singapore
| | - Anthony Siau
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 59 Nanyang Drive, Singapore636921, Singapore
| | - Kan Xing Wu
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 59 Nanyang Drive, Singapore636921, Singapore
| | - Christine Cheung
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 59 Nanyang Drive, Singapore636921, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Singapore138673, Singapore
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Ibrahim H, Perl A, Smith D, Lewis T, Kon Z, Goldenberg R, Yarta K, Staniloae C, Williams M. Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine. Clin Immunol 2020; 219:108544. [PMID: 32707089 PMCID: PMC7374140 DOI: 10.1016/j.clim.2020.108544] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 07/17/2020] [Accepted: 07/17/2020] [Indexed: 02/06/2023]
Abstract
Glucose 6-phosphate dehydrogenase (G6PD) deficiency facilitates human coronavirus infection due to glutathione depletion. G6PD deficiency may especially predispose to hemolysis upon coronavirus disease-2019 (COVID-19) infection when employing pro-oxidant therapy. However, glutathione depletion is reversible by N-acetylcysteine (NAC) administration. We describe a severe case of COVID-19 infection in a G6PD-deficient patient treated with hydroxychloroquine who benefited from intravenous (IV) NAC beyond reversal of hemolysis. NAC blocked hemolysis and elevation of liver enzymes, C-reactive protein (CRP), and ferritin and allowed removal from respirator and veno-venous extracorporeal membrane oxygenator and full recovery of the G6PD-deficient patient. NAC was also administered to 9 additional respirator-dependent COVID-19-infected patients without G6PD deficiency. NAC elicited clinical improvement and markedly reduced CRP in all patients and ferritin in 9/10 patients. NAC mechanism of action may involve the blockade of viral infection and the ensuing cytokine storm that warrant follow-up confirmatory studies in the setting of controlled clinical trials.
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Affiliation(s)
- Homam Ibrahim
- New York University Grossman School of Medicine, NY, New York, United States of America.
| | - Andras Perl
- Upstate Medical University Hospital, Syracuse, New York, United States of America.
| | - Deane Smith
- New York University Grossman School of Medicine, NY, New York, United States of America
| | - Tyler Lewis
- New York University Grossman School of Medicine, NY, New York, United States of America
| | - Zachary Kon
- New York University Grossman School of Medicine, NY, New York, United States of America
| | - Ronald Goldenberg
- New York University Grossman School of Medicine, NY, New York, United States of America
| | - Kinan Yarta
- New York University Grossman School of Medicine, NY, New York, United States of America
| | - Cezar Staniloae
- New York University Grossman School of Medicine, NY, New York, United States of America
| | - Mathew Williams
- New York University Grossman School of Medicine, NY, New York, United States of America
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Euscaphic acid and Tormentic acid protect vascular endothelial cells against hypoxia-induced apoptosis via PI3K/AKT or ERK 1/2 signaling pathway. Life Sci 2020; 252:117666. [PMID: 32298737 DOI: 10.1016/j.lfs.2020.117666] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 04/03/2020] [Accepted: 04/09/2020] [Indexed: 01/05/2023]
Abstract
AIMS Euscaphic acid and Tormentic acid are aglycones of Kaji-ichigoside F1 and Rosamultin, respectively. These four compounds are pentacyclic triterpenoid, isolated from the subterranean root of the Potentilla anserina L. Based on the protective roles against hypoxia-induced apoptosis of Euscaphic acid and Tormentic acid in vascular endothelial cells, this study was designed to determine the mechanisms. MAIN METHODS The model of hypoxic injuries in EA. hy926 cells was established. Through applications of PI3K/AKT inhibitor, LY294002 and ERK1/2 inhibitor, PD98059, we explored the relationships between pharmacodynamic mechanisms and PI3K/AKT or ERK 1/2 signaling pathway. The anti-hypoxic effects were studied by methyl-thiazolyl-tetrazolium (MTT) assay, Hematoxylin-Eosin (HE) staining, DAPI staining, and flow cytometry. The mechanisms of anti-mitochondrial apoptosis were explored by western blot. The expressions of p-ERK 1/2, ERK 1/2, p-AKT, AKT, p-NF-κB, NF-κB, Bcl-2, Bax, Cyt C, cleaved caspase-9 and cleaved caspase-3 were detected. KEY FINDINGS Euscaphic acid protected vascular endothelial cells against hypoxia-induced apoptosis via ERK1/2 signaling pathway, and Tormentic acid brought its efficacy into full play via PI3K/AKT and ERK1/2 signaling pathways. In addition, PI3K/AKT signaling pathway positively regulated ERK1/2 pathway, and ERK1/2 pathway negatively regulated PI3K/AKT pathway. SIGNIFICANCE This evidence provides theoretical and experimental basis for the following research on anti-hypoxic drugs of Potentilla anserina L.
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Kaji-Ichigoside F1 and Rosamultin Protect Vascular Endothelial Cells against Hypoxia-Induced Apoptosis via the PI3K/AKT or ERK1/2 Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6837982. [PMID: 32318240 PMCID: PMC7153006 DOI: 10.1155/2020/6837982] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 02/14/2020] [Accepted: 03/10/2020] [Indexed: 01/23/2023]
Abstract
As a pair of differential isomers, Kaji-ichigoside F1 and Rosamultin are both pentacyclic triterpenoids isolated from the subterranean root of Potentilla anserina L., a plant used in folk medicine in western China as antihypoxia and anti-inflammatory treatments. We demonstrated that Kaji-ichigoside F1 and Rosamultin effectively prevented hypoxia-induced apoptosis in vascular endothelial cells. We established a hypoxia model, using EA.hy926 cells, to further explore the mechanisms. Hypoxia promoted the phosphorylation of AKT, ERK1/2, and NF-κB. In hypoxic cells treated with Kaji-ichigoside F1, p-ERK1/2 and p-NF-κB levels were increased, while the level of p-AKT was decreased. Treatment with Rosamultin promoted phosphorylation of ERK1/2, NF-κB, and AKT in hypoxic cells. Following the addition of LY294002, the levels of p-AKT, p-ERK1/2, and p-NF-κB decreased significantly. Addition of PD98059 resulted in reduced levels of p-ERK1/2 and p-NF-κB, while p-AKT levels were increased. Pharmacodynamic analysis demonstrated that both LY294002 and PD98059 significantly inhibited the positive effects of Kaji-ichigoside F1 on cell viability during hypoxia, consistent with the results of hematoxylin-eosin (H&E) staining, DAPI staining, and flow cytometry. The antihypoxia effects of Rosamultin were remarkably inhibited by LY294002 but promoted by PD98059. In Kaji-ichigoside F1- and Rosamultin-treated cells, Bcl2 expression was significantly upregulated, while expression of Bax and cytochrome C and levels of cleaved caspase-9 and cleaved caspase-3 were reduced. Corresponding to pharmacodynamic analysis, LY294002 inhibited the regulatory effects of Kaji-ichigoside F1 and Rosamultin on the above molecules, while PD98059 inhibited the regulatory effects of Kaji-ichigoside F1 but enhanced the regulatory effects of Rosamultin. In conclusion, Kaji-ichigoside F1 protected vascular endothelial cells against hypoxia-induced apoptosis by activating the ERK1/2 signaling pathway, which positively regulated the NF-κB signaling pathway and negatively regulated the PI3K/AKT signaling pathway. Rosamultin protected vascular endothelial cells against hypoxia-induced apoptosis by activating the PI3K/AKT signaling pathway and positively regulating ERK1/2 and NF-κB signaling pathways.
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Poria cocos polysaccharides attenuated ox-LDL-induced inflammation and oxidative stress via ERK activated Nrf2/HO-1 signaling pathway and inhibited foam cell formation in VSMCs. Int Immunopharmacol 2020; 80:106173. [DOI: 10.1016/j.intimp.2019.106173] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 12/24/2019] [Accepted: 12/28/2019] [Indexed: 12/31/2022]
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Alanazi AZ, Clark MA. Effects of angiotensin III on c-Jun N terminal kinase in Wistar and hypertensive rat vascular smooth muscle cells. Peptides 2020; 123:170204. [PMID: 31738968 DOI: 10.1016/j.peptides.2019.170204] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 11/12/2019] [Accepted: 11/13/2019] [Indexed: 12/15/2022]
Abstract
Proliferation of vascular smooth muscle cells (VSMCs) and inflammation are well known actions associated with hypertension. Angiotensin (Ang) II mediates these physiological actions through the c-Jun N terminal Kinase (JNK), mitogen-activated proteins kinase (MAPK) pathway. Ang III effects on this pathway in VSMCs are unknown. The aim of this study was to determine whether Ang III activates JNK MAPK in Wistar VSMCs and determined whether the response was different in spontaneously hypertensive rat (SHR) VSMCs. We also ascertained whether this effect leads to VSMC proliferation. Western blots were used to determine the time and concentration effects of Ang II on JNK MAPK phosphorylation in Wistar VSMCs. Similar studies were conducted for Ang III in Wistar and SHR VSMCs. Both peptides induced JNK phosphorylation in a concentration- and time-dependent manner in Wistar VSMCs. Ang III also increased JNK phosphorylation in a concentration- and time-dependent fashion in SHR VSMCs as well. However, the ability of Ang III to induce JNK MAPK was different in SHR VSMCs as the phosphorylation levels of JNK were significantly higher in Wistar VSMCs as compared to SHR VSMCs at several time points and concentrations. Further, Ang III-mediated DNA synthesis, a measure of VSMC proliferation, occurred through activation of JNK MAPK. This study is the first to show Ang III effects on the JNK MAPK pathway in VSMCs and the role of JNK in Ang III-mediated cellular proliferation. These findings impart key information for the understanding of Ang III functions, especially in VSMCs and possible cardiovascular diseases.
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Affiliation(s)
- Ahmed Z Alanazi
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL, 33328, United States
| | - Michelle A Clark
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL, 33328, United States.
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Chen Q, Lv J, Yang W, Xu B, Wang Z, Yu Z, Wu J, Yang Y, Han Y. Targeted inhibition of STAT3 as a potential treatment strategy for atherosclerosis. Theranostics 2019; 9:6424-6442. [PMID: 31588227 PMCID: PMC6771242 DOI: 10.7150/thno.35528] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 07/10/2019] [Indexed: 02/06/2023] Open
Abstract
Atherosclerosis is the main pathological basis of ischemic cardiovascular and cerebrovascular diseases and has attracted more attention in recent years. Multiple studies have demonstrated that the signal transducer and activator of transcription 3 (STAT3) plays essential roles in the process of atherosclerosis. Moreover, aberrant STAT3 activation has been shown to contribute to the occurrence and development of atherosclerosis. Therefore, the study of STAT3 inhibitors has gradually become a focal research topic. In this review, we describe the crucial roles of STAT3 in endothelial cell dysfunction, macrophage polarization, inflammation, and immunity during atherosclerosis. STAT3 in mitochondria is mentioned as well. Then, we present a summary and classification of STAT3 inhibitors, which could offer potential treatment strategies for atherosclerosis. Furthermore, we enumerate some of the problems that have interfered with the development of mature therapies utilizing STAT3 inhibitors to treat atherosclerosis. Finally, we propose ideas that may help to solve these problems to some extent. Collectively, this review may be useful for developing future STAT3 inhibitor therapies for atherosclerosis.
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Lu QB, Wang HP, Tang ZH, Cheng H, Du Q, Wang YB, Feng WB, Li KX, Cai WW, Qiu LY, Sun HJ. Nesfatin-1 functions as a switch for phenotype transformation and proliferation of VSMCs in hypertensive vascular remodeling. Biochim Biophys Acta Mol Basis Dis 2018; 1864:2154-2168. [PMID: 29627363 DOI: 10.1016/j.bbadis.2018.04.002] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 03/11/2018] [Accepted: 04/03/2018] [Indexed: 12/12/2022]
Abstract
The phenotypic transformation from differentiated to dedifferentiated vascular smooth muscle cells (VSMCs) plays a crucial role in VSMC proliferation and vascular remodeling in many cardiovascular diseases including hypertension. Nesfatin-1, a multifunctional adipocytokine, is critically involved in the regulation of blood pressure. However, it is still largely unexplored whether nesfatin-1 is a potential candidate in VSMC phenotypic switch and proliferation in hypertension. Experiments were carried out in Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), human VSMCs and primary rat aortic VSMCs. We showed that the expression of nesfatin-1 was upregulated in media layer of the aorta in SHR and SHR-derived VSMCs. Nesfatin-1 promoted VSMC phenotypic transformation, accelerated cell cycle progression and proliferation. Knockdown of nesfatin-1 inhibited the VSMC phenotype switch from a contractile to a synthetic state, attenuated cell cycle progression and retarded VSMC proliferation in SHR-derived VSMCs. Moreover, nesfatin-1-activated PI3K/Akt/mTOR signaling was abolished by JAK/STAT inhibitor WP1066, and the increased phosphorylation levels of JAK2/STAT3 in response to nesfatin-1 were suppressed by inhibition of PI3K/Akt/mTOR in VSMCs. Pharmacological blockade of the forming feedback loop between PI3K/Akt/mTOR and JAK2/STAT3 prevented the proliferation of nesfatin-1-incubated VSMCs and primary VSMCs from SHR. Chronic intraperitoneal injection of nesfatin-1 caused severe hypertension and cardiovascular remodeling in normal rats. In contrast, silencing of nesfatin-1 gene ameliorated hypertension, phenotype switching, and vascular remodeling in the aorta of SHR. Therefore, our data identified nesfatin-1 as a key modulator in hypertension and vascular remodeling by facilitating VSMC phenotypic switching and proliferation.
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Affiliation(s)
- Qing-Bo Lu
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, PR China
| | - Hui-Ping Wang
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Zi-Han Tang
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Han Cheng
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Qiong Du
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Yuan-Ben Wang
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Wu-Bing Feng
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Ke-Xue Li
- Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China
| | - Wei-Wei Cai
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, PR China
| | - Li-Ying Qiu
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, PR China.
| | - Hai-Jian Sun
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, PR China.
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Huang G, Huang X, Liu M, Hua Y, Deng B, Jin W, Yan W, Tan Z, Wu Y, Liu B, Zhou Y. Secoisolariciresinol diglucoside prevents the oxidative stress-induced apoptosis of myocardial cells through activation of the JAK2/STAT3 signaling pathway. Int J Mol Med 2018; 41:3570-3576. [PMID: 29568942 DOI: 10.3892/ijmm.2018.3560] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 01/10/2018] [Indexed: 11/05/2022] Open
Abstract
Myocardial cell apoptosis mediated by oxidative stress has previously been identified as a key process in ischemic heart disease. Secoisolariciresinol diglucoside (SDG), a polyphenolic plant lignan primarily found in flaxseed, has been demonstrated to effectively protect myocardial cells from apoptosis. In the present study, the role of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) was investigated in mediating the protective effect of SDG. Findings of the present study revealed that treatment with H2O2 reduced cell viability and induced apoptosis in H9C2 rat cardiomyocytes. However, SDG was able to reduce the effect of H2O2 in a dose‑dependent manner. H2O2 reduced the expression level of phosphorylated STAT3 and inhibited the levels of B‑cell lymphoma‑extra‑large and induced myeloid leukemia cell differentiation protein, which are the STAT3 target genes. Conversely, SDG rescued phosphorylation of STAT3 and increased the levels of STAT3 target genes. Treatment with SDG alone led to a dose‑dependent increased phosphorylation of JAK2 and STAT3, without activating Src. Furthermore, the anti‑apoptotic effects of SDG were partially abolished by a JAK2/STAT3 inhibitor. In addition, molecular docking revealed that SDG may bind to the protein kinase domain of JAK2, at a binding energy of ‑8.258 kcal/mol. Molecular dynamics simulations revealed that JAK2‑SDG binding was stable. In conclusion, activation of the JAK2/STAT3 signaling pathway contributed to the anti‑apoptotic activity of SDG, which may be a potential JAK2 activator.
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Affiliation(s)
- Guiqiong Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Xiaofang Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Min Liu
- School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yue Hua
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Bo Deng
- Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China
| | - Wen Jin
- Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Wen Yan
- Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Zhangbin Tan
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yifen Wu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Bin Liu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yingchun Zhou
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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Zheng X, Liu G, Cui G, Cheng M, Zhang N, Hu S. Angiotensin-Converting Enzyme Gene Deletion Polymorphism is Associated with Lymph Node Metastasis in Colorectal Cancer Patients in a Chinese Population. Med Sci Monit 2017; 23:4926-4931. [PMID: 29032382 PMCID: PMC5655539 DOI: 10.12659/msm.903312] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background The purpose of this study was to assess the effect of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism on the risk of lymph node metastasis (LNM) in colorectal cancer (CRC) patients. Material/Methods We enrolled 146 CRC patients and 106 healthy controls in this study. ACE gene I/D polymorphism was genotyped by polymerase chain reaction (PCR). Hardy-Weinberg equilibrium (HWE) was used to assess the goodness of fit of the genotypes. χ2 test was used to calculate the differences of genotype and allele distributions. Odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) were used to analyze the association between ACE I/D polymorphism and LNM in CRC patients. Results Insertion/deletion (ID) and deletion/deletion (DD) genotypes were frequently observed in CRC patients, but only DD genotype and D allele were related to the susceptibility of CRC (P=0.038, OR=2.158, 95%CI=1.039–4.480; P=0.026, OR=1.501, 95%CI=1.048–2.150). DD genotype and D allele also increased the risk of LNM in CRC patients (P=0.028, OR=2.844, 95%CI=1.107–7.038; P=0.026, OR=1.692, 95%CI=1.063–2.693). Conclusions DD genotype and D allele of ACE gene I/D polymorphism might increase the risk of LNM in CRC patients.
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Affiliation(s)
- Xiao Zheng
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland).,Department of General Surgery, Taian City Central Hospital, Taian, Shandong, China (mainland)
| | - Guoli Liu
- First Department of Geriatrics, Taian City Central Hospital, Taian, Shandong, China (mainland)
| | - Gang Cui
- Department of General Surgery, Taian City Central Hospital, Taian, Shandong, China (mainland)
| | - Ming Cheng
- Department of General Surgery, Taian City Central Hospital, Taian, Shandong, China (mainland)
| | - Nan Zhang
- Department of General Surgery, Taian City Central Hospital, Taian, Shandong, China (mainland)
| | - Sanyuan Hu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland)
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Xu Y, Ji Y, Lan X, Gao X, Chen HD, Geng L. miR-203 contributes to IL-17-induced VEGF secretion by targeting SOCS3 in keratinocytes. Mol Med Rep 2017; 16:8989-8996. [DOI: 10.3892/mmr.2017.7759] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 06/09/2017] [Indexed: 11/06/2022] Open
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Azilsartan ameliorates diabetic cardiomyopathy in young db/db mice through the modulation of ACE-2/ANG 1-7/Mas receptor cascade. Biochem Pharmacol 2017; 144:90-99. [PMID: 28789938 DOI: 10.1016/j.bcp.2017.07.022] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 07/28/2017] [Indexed: 12/12/2022]
Abstract
Hyperglycemia up-regulates intracellular angiotensin II (ANG-II) production in cardiac myocytes. This study investigated the hemodynamic and metabolic effects of azilsartan (AZL) treatment in a mouse model of diabetic cardiomyopathy and whether the cardioprotective effects of AZL are mediated by the angiotensin converting enzyme (ACE)-2/ANG 1-7/Mas receptor (R) cascade. Control db/+ and db/db mice (n=5 per group) were treated with vehicle or AZL (1 or 3mg/kg/d oral gavage) from the age of 8 to 16weeks. Echocardiography was then performed and myocardial protein levels of ACE-2, Mas R, AT1R, AT2R, osteopontin, connective tissue growth factor (CTGF), atrial natriuretic peptide (ANP) and nitrotyrosine were measured by Western blotting. Oxidative DNA damage and inflammatory markers were assessed by immunofluorescence of 8-hydroxy-2'-deoxyguanosine (8-OHdG), tumor necrosis factor (TNF)-α and interleukin 6 (IL-6). Compared with db/+ mice, the vehicle-treated db/db mice developed obesity, hyperglycemia, hyperinsulinemia and diastolic dysfunction along with cardiac hypertrophy and fibrosis. AZL treatment lowered blood pressure, fasting blood glucose and reduced peak plasma glucose during an oral glucose tolerance test. AZL-3 treatment resulted in a significant decrease in the expression of cytokines, oxidative DNA damage and cardiac dysfunction. Moreover, AZL-3 treatment significantly abrogated the downregulation of ACE-2 and Mas R protein levels in db/db mice. Furthermore, AZL treatment significantly reduced cardiac fibrosis, hypertrophy and their marker molecules (osteopontin, CTGF, TGF-β1 and ANP). Short-term treatment with AZL-3 reversed abnormal cardiac structural remodeling and partially improved glucose metabolism in db/db mice by modulating the ACE-2/ANG 1-7/Mas R pathway.
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QGQS Granule in SHR Serum Metabonomics Study Based on Tools of UPLC-Q-TOF and Renin-Angiotensin-Aldosterone System Form Protein Profilin-1. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:4854720. [PMID: 28367224 PMCID: PMC5358465 DOI: 10.1155/2017/4854720] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2016] [Revised: 01/15/2017] [Accepted: 01/24/2017] [Indexed: 01/09/2023]
Abstract
QGQS granule is effective for the therapeutic of hypertension in clinic. The aim of this research is to observe the antihypertension effect of QGQS granule on SHR and explain the mechanism of its lowering blood pressure. 30 SHR were selected as model group, captopril group, and QGQS group, 10 WKYr were used as control group, and RBP were measured on tail artery consciously. And all the serum sample analysis was carried out on UPLC-TOF-MS system to determine endogenous metabolites and to find the metabonomics pathways. Meanwhile, ELISA kits for the determination pharmacological indexes of PRA, AngI, AngII, and ALD were used for pathway confirmatory; WB for determination of profilin-1 protein expression was conducted for Ang II pathway analysis as well. It is demonstrated that QGQS granule has an excellent therapeutic effect on antihypertension, which exerts effect mainly on metabonomics pathway by regulating glycerophospholipid, sphingolipid, and arachidonic acid metabolism, and it could inhibit the overexpression of the profilin-1 protein. We can come to a conclusion that RAAS should be responsible mainly for the metabonomics pathway of QGQS granule on antihypertension, and it plays a very important role in protein of profilin-1 inhibition.
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Surapongchai J, Prasannarong M, Bupha-Intr T, Saengsirisuwan V. Angiotensin II induces differential insulin action in rat skeletal muscle. J Endocrinol 2017; 232:547-560. [PMID: 28096436 DOI: 10.1530/joe-16-0579] [Citation(s) in RCA: 4] [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: 01/13/2017] [Accepted: 01/17/2017] [Indexed: 02/05/2023]
Abstract
Angiotensin II (ANGII) is reportedly involved in the development of skeletal muscle insulin resistance. The present investigation evaluated the effects of two ANGII doses on the phenotypic characteristics of insulin resistance syndrome and insulin action and signaling in rat skeletal muscle. Male Sprague-Dawley rats were infused with either saline (SHAM) or ANGII at a commonly used pressor dose (100 ng/kg/min; ANGII-100) or a higher pressor dose (500 ng/kg/min; ANGII-500) via osmotic minipumps for 14 days. We demonstrated that ANGII-100-infused rats exhibited the phenotypic features of non-obese insulin resistance syndrome, including hypertension, impaired glucose tolerance and insulin resistance of glucose uptake in the soleus muscle, whereas ANGII-500-treated rats exhibited diabetes-like symptoms, such as post-prandial hyperglycemia, impaired insulin secretion and hypertriglyceridemia. At the cellular level, insulin-stimulated glucose uptake in the soleus muscle of the ANGII-100 group was 33% lower (P < 0.05) than that in the SHAM group and was associated with increased insulin-stimulated IRS-1 Ser307 and decreased Akt Ser473 and AS160 Thr642 phosphorylation and GLUT-4 expression. However, ANGII-500 infusion did not induce skeletal muscle insulin resistance or impair insulin signaling elements as initially anticipated. Moreover, we found that insulin-stimulated glucose uptake in the ANGII-500 group was accompanied by the enhanced expression of ACE2 and MasR proteins, which are the key elements in the non-classical pathway of the renin-angiotensin system. Collectively, this study demonstrates for the first time that chronic infusion with these two pressor doses of ANGII induced differential metabolic responses at both the systemic and skeletal muscle levels.
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Affiliation(s)
- Juthamard Surapongchai
- Exercise Physiology LaboratoryDepartment of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Mujalin Prasannarong
- Department of Physical TherapyFaculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Tepmanas Bupha-Intr
- Exercise Physiology LaboratoryDepartment of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Vitoon Saengsirisuwan
- Exercise Physiology LaboratoryDepartment of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
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Mikrut K, Kupsz J, Kozlik J, Krauss H, Pruszynska-Oszmałek E, Gibas-Dorna M. Angiotensin-converting enzyme inhibitors reduce oxidative stress intensity in hyperglicemic conditions in rats independently from bradykinin receptor inhibitors. Croat Med J 2017; 57:371-80. [PMID: 27586552 PMCID: PMC5048232 DOI: 10.3325/cmj.2016.57.371] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Aim To investigate whether bradykinin-independent antioxidative effects of angiotensin-converting enzyme inhibitors (ACEIs) exist in acute hyperglycemia. Methods Male Wistar rats were divided into the normoglycemic group (n = 40) and the hyperglycemic group (n = 40). Hyperglycemia was induced by a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg body weight) dissolved in 0.1 mol/L citrate buffer (pH 4.5) 72 hours before sacrifice. The normoglycemic group received the same volume of citrate buffer. Each group was divided into five subgroups (n = 8): control group, captopril group, captopril + bradykinin B1 and B2 receptor antagonists group, enalapril group, and enalapril + bradykinin B1 and B2 receptor antagonists group. Captopril, enalapril, B1 and B2 receptor antagonists, or 0.15 mol/L NaCl were given at 2 and 1 hour before sacrifice. Oxidative status was determined by measuring the concentration of malondialdehyde and H2O2, and the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Results In STZ-induced hyperglycemic rats ACEIs significantly reduced H2O2 and MDA concentration, while they significantly enhanced SOD and GPx activity. The hyperglycemic group treated simultaneously with ACEIs and bradykinin B1 and B2 receptor antagonists showed a significant decrease in H2O2 concentration compared to the control hyperglycemic group. Conclusion These results suggest the existence of additional antioxidative effect of ACEIs in hyperglycemic conditions, which is not related to the bradykinin mediation and the structure of the drug molecule.
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Affiliation(s)
- Kinga Mikrut
- Kinga Mikrut, Department of Physiology, Poznan University of Medical Sciences, Swiecickiego St., 6, 60-781 Poznan, Poland,
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Thatcher SE. A Brief Introduction into the Renin-Angiotensin-Aldosterone System: New and Old Techniques. Methods Mol Biol 2017; 1614:1-19. [PMID: 28500591 DOI: 10.1007/978-1-4939-7030-8_1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
The renin-angiotensin-aldosterone system (RAAS) is a complex system of enzymes, receptors, and peptides that help to control blood pressure and fluid homeostasis. Techniques in studying the RAAS can be difficult due to such factors as peptide/enzyme stability and receptor localization. This paper gives a brief account of the different components of the RAAS and current methods in measuring each component. There is also a discussion of different methods in measuring stem and immune cells by flow cytometry, hypertension, atherosclerosis, oxidative stress, energy balance, and other RAAS-activated phenotypes. While studies on the RAAS have been performed for over 100 years, new techniques have allowed scientists to come up with new insights into this system. These techniques are detailed in this Methods in Molecular Biology Series and give students new to studying the RAAS the proper controls and technical details needed to perform each procedure.
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Affiliation(s)
- Sean E Thatcher
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Charles T. Wethington Bldg, 593, 900 South Limestone Street, Lexington, KY, 40536, USA.
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Wang X, Chen L, Liu J, Yan T, Wu G, Xia Y, Zong G, Li F. In vivo treatment of rat arterial adventitia with interleukin‑1β induces intimal proliferation via the JAK2/STAT3 signaling pathway. Mol Med Rep 2016; 13:3451-8. [PMID: 26955959 PMCID: PMC4805072 DOI: 10.3892/mmr.2016.4982] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2015] [Accepted: 02/09/2016] [Indexed: 11/09/2022] Open
Abstract
Previous studies have indicated that adventitial inflammation is involved in the development of atherosclerosis. The aim of this study was to investigate the effect of arterial adventitia inflammation induced by interleukin (IL)-1β on intimal proliferation and the mechanisms involved in this process. The left common carotid artery adventitia of male rats in the experimental and control groups (25 rats/group) was wrapped with agar containing or without a sustained-release suspension of 2.5 µg IL-1β, respectively. Five animals in each group were randomly selected for sacrifice at 2 h, 8 h, 24 h, 48 h, and 1 week post-treatment. Hematoxylin and eosin staining was performed for to analyze the morphology of the adventitia. The expression of janus kinase (JAK)2, signal transducer and activator of transcription (STAT)3, phosphorylated (p-)JAK2 and p-STAT3 were detected by western blot analysis or immunohistochemistry staining. A model of adventitial inflammation was successfully created by wrapping IL-1β around the rat carotid artery. IL-1β treatment induced vascular smooth muscle cell proliferation and migration as well as intimal proliferation. In addition, the expression of p-JAK2 and p-STAT3 increased after IL-1β treatment. Furthermore, an inhibitor of JAK2/STAT3 pathway, AG490, suppressed IL-1β-induced intimal proliferation and phosphorylation of JAK2 and STAT3. Thus, the JAK2/STAT3 signaling pathway is involved in intimal proliferation caused by vascular adventitial inflammation. Inhibiting the JAK2/STAT3 signaling pathway may be a novel method for the clinical treatment of artery atherosclerosis.
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Affiliation(s)
- Xiao Wang
- Department of Cardiovascular Diseases, The 101st Hospital of PLA, Wuxi, Jiangsu 214044, P.R. China
| | - Lihua Chen
- Department of Radiology, The 101st Hospital of PLA, Wuxi, Jiangsu 214044, P.R. China
| | - Jie Liu
- Department of Cardiovascular Diseases, The 101st Hospital of PLA, Wuxi, Jiangsu 214044, P.R. China
| | - Tao Yan
- Central Laboratories, The Second Artillery General Hospital, Beijing 100088, P.R. China
| | - Gangyong Wu
- Department of Cardiovascular Diseases, The 101st Hospital of PLA, Wuxi, Jiangsu 214044, P.R. China
| | - Yang Xia
- Department of Cardiovascular Diseases, The 101st Hospital of PLA, Wuxi, Jiangsu 214044, P.R. China
| | - Gangjun Zong
- Department of Cardiovascular Diseases, The 101st Hospital of PLA, Wuxi, Jiangsu 214044, P.R. China
| | - Fengsheng Li
- Central Laboratories, The Second Artillery General Hospital, Beijing 100088, P.R. China
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Wang Y, Chen J, Yang B, Qiao H, Gao L, Su T, Ma S, Zhang X, Li X, Liu G, Cao J, Chen X, Chen Y, Cao F. In vivo MR and Fluorescence Dual-modality Imaging of Atherosclerosis Characteristics in Mice Using Profilin-1 Targeted Magnetic Nanoparticles. Theranostics 2016; 6:272-86. [PMID: 26877785 PMCID: PMC4729775 DOI: 10.7150/thno.13350] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 10/29/2015] [Indexed: 01/27/2023] Open
Abstract
Aims: This study aims to explore non-invasive imaging of atherosclerotic plaque through magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) by using profilin-1 targeted magnetic iron oxide nanoparticles (PF1-Cy5.5-DMSA-Fe3O4-NPs, denoted as PC-NPs) as multimodality molecular imaging probe in murine model of atherosclerosis. Methods and Results: PC-NPs were constructed by conjugating polyclonal profilin-1 antibody and NHS-Cy5.5 fluorescent dye to the surface of DMSA-Fe3O4-nanoparticles via condensation reaction. Murine atherosclerosis model was induced in apoE-/- mice by high fat and cholesterol diet (HFD) for 16 weeks. The plaque areas in aortic artery were detected with Oil Red O staining. Immunofluorescent staining and Western blot analysis were applied respectively to investigate profilin-1 expression. CCK-8 assay and transwell migration experiment were performed to detect vascular smooth muscle cells (VSMCs) proliferation. In vivo MRI and NIRF imaging of atherosclerotic plaque were carried out before and 36 h after intravenous injection of PC-NPs. Oil Red O staining showed that the plaque area was significantly increased in HFD group (p<0.05). Immunofluorescence staining revealed that profilin-1 protein was highly abundant within plaque in HFD group and co-localized with α-smooth muscle actin. Profilin-1 siRNA intervention could inhibit VSMCs proliferation and migration elicited by ox-LDL (p<0.05). In vivo MRI and NIRF imaging revealed that PC-NPs accumulated in atherosclerotic plaque of carotid artery. There was a good correlation between the signals of MRI and ex vivo fluorescence intensities of NIRF imaging in animals with PC-NPs injection. Conclusion: PC-NPs is a promising dual modality imaging probe, which may improve molecular diagnosis of plaque characteristics and evaluation of pharmaceutical interventions for atherosclerosis.
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Yang K, Lu W, Jia J, Zhang J, Zhao M, Wang S, Jiang H, Xu L, Wang J. Noggin inhibits hypoxia-induced proliferation by targeting store-operated calcium entry and transient receptor potential cation channels. Am J Physiol Cell Physiol 2015; 308:C869-78. [PMID: 25740156 PMCID: PMC4451349 DOI: 10.1152/ajpcell.00349.2014] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 02/20/2015] [Indexed: 02/08/2023]
Abstract
Abnormally elevated bone morphogenetic protein 4 (BMP4) expression and mediated signaling play a critical role in the pathogenesis of chronic hypoxia-induced pulmonary hypertension (CHPH). In this study, we investigated the expression level and functional significance of four reported naturally occurring BMP4 antagonists, noggin, follistatin, gremlin1, and matrix gla protein (MGP), in the lung and distal pulmonary arterial smooth muscle cell (PASMC). A 21-day chronic hypoxic (10% O2) exposure rat model was utilized, which has been previously shown to successfully establish experimental CHPH. Among the four antagonists, noggin, but not the other three, was selectively downregulated by hypoxic exposure in both the lung tissue and PASMC, in correlation with markedly elevated BMP4 expression, suggesting that the loss of noggin might account for the hypoxia-triggered BMP4 signaling transduction. Then, by using treatment of extrogenous recombinant noggin protein, we further found that noggin significantly normalized 1) BMP4-induced phosphorylation of cellular p38 and ERK1/2; 2) BMP4-induced phosphorylation of cellular JAK2 and STAT3; 3) hypoxia-induced PASMC proliferation; 4) hypoxia-induced store-operated calcium entry (SOCE), and 5) hypoxia-increased expression of transient receptor potential cation channels (TRPC1 and TRPC6) in PASMC. In combination, these data strongly indicated that the hypoxia-suppressed noggin accounts, at least partially, for hypoxia-induced excessive PASMC proliferation, while restoration of noggin may be an effective way to inhibit cell proliferation by suppressing SOCE and TRPC expression.
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Affiliation(s)
- Kai Yang
- Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and
| | - Wenju Lu
- Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jing Jia
- Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jie Zhang
- Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Mingming Zhao
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, Maryland
| | - Sabrina Wang
- Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and
| | - Haiyang Jiang
- Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and
| | - Lei Xu
- Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and
| | - Jian Wang
- Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and
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Yang P, Gu H, Zhao Z, Wang W, Cao B, Lai C, Yang X, Zhang L, Duan Y, Zhang S, Chen W, Zhen W, Cai M, Penninger JM, Jiang C, Wang X. Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci Rep 2014; 4:7027. [PMID: 25391767 PMCID: PMC4229671 DOI: 10.1038/srep07027] [Citation(s) in RCA: 217] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Accepted: 10/13/2014] [Indexed: 11/09/2022] Open
Abstract
Since March 2013, the emergence of an avian-origin influenza A (H7N9) virus has raised concern in China. Although most infections resulted in respiratory illness, some severe cases resulted in acute respiratory distress syndrome (ARDS), which is a severe form of acute lung injury (ALI) that further contributes to morbidity. To date, no effective drugs that improve the clinical outcome of influenza A (H7N9) virus-infected patients have been identified. Angiotensin-converting enzyme (ACE) and ACE2 are involved in several pathologies such as cardiovascular functions, renal disease, and acute lung injury. In the current study, we report that ACE2 could mediate the severe acute lung injury induced by influenza A (H7N9) virus infection in an experimental mouse model. Moreover, ACE2 deficiency worsened the disease pathogenesis markedly, mainly by targeting the angiotensin II type 1 receptor (AT1). The current findings demonstrate that ACE2 plays a critical role in influenza A (H7N9) virus-induced acute lung injury, and suggest that might be a useful potential therapeutic target for future influenza A (H7N9) outbreaks.
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Affiliation(s)
- Penghui Yang
- 1] State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China [2] Beijing 302 Hospital, Beijing, 100039, China
| | - Hongjing Gu
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
| | - Zhongpeng Zhao
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
| | - Wei Wang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry and Molecular Biology, Peking Union Medical College, Tsinghua University, Beijing 100005, China
| | - Bin Cao
- Beijing Chao-Yang Hospital, Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing 100020, China
| | - Chengcai Lai
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
| | - Xiaolan Yang
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
| | - LiangYan Zhang
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
| | - Yueqiang Duan
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
| | | | - Weiwen Chen
- Quanzhou First Hospital, Fujian 362321, China
| | - Wenbo Zhen
- Quanzhou First Hospital, Fujian 362321, China
| | | | - Josef M Penninger
- Institute of Molecular Biotechnology in the Austrian Academy of Sciences, Vienna, A-1030, Austria
| | - Chengyu Jiang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry and Molecular Biology, Peking Union Medical College, Tsinghua University, Beijing 100005, China
| | - Xiliang Wang
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
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Zhang Z, Chen L, Zhong J, Gao P, Oudit GY. ACE2/Ang-(1–7) signaling and vascular remodeling. SCIENCE CHINA-LIFE SCIENCES 2014; 57:802-8. [DOI: 10.1007/s11427-014-4693-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 05/20/2014] [Indexed: 02/06/2023]
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Patel VB, Zhong JC, Fan D, Basu R, Morton JS, Parajuli N, McMurtry MS, Davidge ST, Kassiri Z, Oudit GY. Angiotensin-converting enzyme 2 is a critical determinant of angiotensin II-induced loss of vascular smooth muscle cells and adverse vascular remodeling. Hypertension 2014; 64:157-64. [PMID: 24799609 DOI: 10.1161/hypertensionaha.114.03388] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Angiotensin-converting enzyme (ACE) 2 is a key negative regulator of the renin-angiotensin system and metabolizes angiotensin II (Ang II) into Ang 1 to 7. Ang II is a vasoactive peptide, which plays an important role in vascular disease. The objective of the present study was to define the role of ACE2 in pathological vascular remodeling. We found upregulation of ACE2 in dilated human aorta with bicuspid aortic valve and in murine aorta in response to Ang II. Ex vivo pressure myography showed increased vascular stiffness in ACE2 knockout (KO) mesenteric arteries in response to Ang II (1.5 mg/kg per day) and with aging. Histological analyses revealed reduced media-to-lumen ratio in ACE2KO mesenteric arteries with loss of vascular smooth muscle cells. Aortic vascular smooth muscle cells from ACE2KO mice showed markedly increased reactive oxygen species and apoptosis in response to Ang II along with increased cleaved caspase-3 and cleaved caspase-8 levels in the ACE2KO aorta. Ang II type 1 receptor blockade and Ang 1 to 7 supplementation prevented the increase in Ang II-induced reactive oxygen species and apoptotic cell death. In the aorta, Ang II resulted in thoracic and abdominal aortic dilation with loss of vascular smooth muscle cell density in ACE2KO aorta as revealed by α-smooth muscle actin, calponin staining, and electron microscopy with increased promatrix metalloproteinase 2, matrix metalloproteinase 2, and matrix metalloproteinase 9 levels. ACE2 is upregulated in vascular diseases, and ACE2 deficiency exacerbates Ang II-mediated vascular remodeling driven by increased reactive oxygen species and vascular smooth muscle cell apoptosis. In conclusion, the key counter-regulatory role of ACE2 against an activated renin-angiotensin system provides novel insights into the role of ACE2 in vascular diseases.
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Affiliation(s)
- Vaibhav B Patel
- From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.)
| | - Jiu-Chang Zhong
- From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.)
| | - Dong Fan
- From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.)
| | - Ratnadeep Basu
- From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.)
| | - Jude S Morton
- From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.)
| | - Nirmal Parajuli
- From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.)
| | - Michael Sean McMurtry
- From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.)
| | - Sandra T Davidge
- From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.)
| | - Zamaneh Kassiri
- From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.)
| | - Gavin Y Oudit
- From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.).
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Parajuli N, Ramprasath T, Patel VB, Wang W, Putko B, Mori J, Oudit GY. Targeting angiotensin-converting enzyme 2 as a new therapeutic target for cardiovascular diseases. Can J Physiol Pharmacol 2014; 92:558-65. [PMID: 24861775 DOI: 10.1139/cjpp-2013-0488] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that metabolizes several vasoactive peptides, including angiotensin II (Ang-II; a vasoconstrictive/proliferative peptide), which it converts to Ang-(1-7). Ang-(1-7) acts through the Mas receptor to mediate vasodilatory/antiproliferative actions. The renin-angiotensin system involving the ACE-Ang-II-Ang-II type-1 receptor (AT1R) axis is antagonized by the ACE2-Ang-(1-7)-Mas receptor axis. Loss of ACE2 enhances adverse remodeling and susceptibility to pressure and volume overload. Human recombinant ACE2 may act to suppress myocardial hypertrophy, fibrosis, inflammation, and diastolic dysfunction in heart failure patients. The ACE2-Ang-(1-7)-Mas axis may present a new therapeutic target for the treatment of heart failure patients. This review is mainly focused on the analysis of ACE2, including its influence and potentially positive effects, as well as the potential use of human recombinant ACE2 as a novel therapy for the treatment cardiovascular diseases, such as hypertension and heart failure.
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Affiliation(s)
- Nirmal Parajuli
- a Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB T6G 2S2, Canada
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Smith IJ, Godinez GL, Singh BK, McCaughey KM, Alcantara RR, Gururaja T, Ho MS, Nguyen HN, Friera AM, White KA, McLaughlin JR, Hansen D, Romero JM, Baltgalvis KA, Claypool MD, Li W, Lang W, Yam GC, Gelman MS, Ding R, Yung SL, Creger DP, Chen Y, Singh R, Smuder AJ, Wiggs MP, Kwon OS, Sollanek KJ, Powers SK, Masuda ES, Taylor VC, Payan DG, Kinoshita T, Kinsella TM. Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation-induced diaphragm dysfunction. FASEB J 2014; 28:2790-803. [PMID: 24671708 PMCID: PMC4062832 DOI: 10.1096/fj.13-244210] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Controlled mechanical ventilation (CMV) is associated with the development of diaphragm atrophy and contractile dysfunction, and respiratory muscle weakness is thought to contribute significantly to delayed weaning of patients. Therefore, therapeutic strategies for preventing these processes may have clinical benefit. The aim of the current study was to investigate the role of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in CMV-mediated diaphragm wasting and weakness in rats. CMV-induced diaphragm atrophy and contractile dysfunction coincided with marked increases in STAT3 phosphorylation on both tyrosine 705 (Tyr705) and serine 727 (Ser727). STAT3 activation was accompanied by its translocation into mitochondria within diaphragm muscle and mitochondrial dysfunction. Inhibition of JAK signaling during CMV prevented phosphorylation of both target sites on STAT3, eliminated the accumulation of phosphorylated STAT3 within the mitochondria, and reversed the pathologic alterations in mitochondrial function, reduced oxidative stress in the diaphragm, and maintained normal diaphragm contractility. In addition, JAK inhibition during CMV blunted the activation of key proteolytic pathways in the diaphragm, as well as diaphragm atrophy. These findings implicate JAK/STAT3 signaling in the development of diaphragm muscle atrophy and dysfunction during CMV and suggest that the delayed extubation times associated with CMV can be prevented by inhibition of Janus kinase signaling.-Smith, I. J., Godinez, G. L., Singh, B. K., McCaughey, K. M., Alcantara, R. R., Gururaja, T., Ho, M. S., Nguyen, H. N., Friera, A. M., White, K. A., McLaughlin, J. R., Hansen, D., Romero, J. M., Baltgalvis, K. A., Claypool, M. D., Li, W., Lang, W., Yam, G. C., Gelman, M. S., Ding, R., Yung, S. L., Creger, D. P., Chen, Y., Singh, R., Smuder, A. J., Wiggs, M. P., Kwon, O.-S., Sollanek, K. J., Powers, S. K., Masuda, E. S., Taylor, V. C., Payan, D. G., Kinoshita, T., Kinsella, T. M. Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation-induced diaphragm dysfunction.
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Affiliation(s)
- Ira J Smith
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | | | - Baljit K Singh
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | | | | | | | - Melissa S Ho
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - Henry N Nguyen
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | | | - Kathy A White
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | | | - Derek Hansen
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - Jason M Romero
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | | | - Mark D Claypool
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - Wei Li
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - Wayne Lang
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - George C Yam
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - Marina S Gelman
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - Rongxian Ding
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - Stephanie L Yung
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - Daniel P Creger
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - Yan Chen
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - Rajinder Singh
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - Ashley J Smuder
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA
| | - Michael P Wiggs
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA
| | - Oh-Sung Kwon
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA
| | - Kurt J Sollanek
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA
| | - Scott K Powers
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA
| | - Esteban S Masuda
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - Vanessa C Taylor
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - Donald G Payan
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - Taisei Kinoshita
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
| | - Todd M Kinsella
- Rigel Pharmaceuticals, South San Francisco, California, USA; and
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48
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Wysocki J, Ortiz‐Melo DI, Mattocks NK, Xu K, Prescott J, Evora K, Ye M, Sparks MA, Haque SK, Batlle D, Gurley SB. ACE2 deficiency increases NADPH-mediated oxidative stress in the kidney. Physiol Rep 2014; 2:e00264. [PMID: 24760518 PMCID: PMC4002244 DOI: 10.1002/phy2.264] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Revised: 02/11/2014] [Accepted: 02/16/2014] [Indexed: 12/24/2022] Open
Abstract
Abstract Angiotensin-converting enzyme 2 (ACE2) is highly expressed in the kidney and hydrolyzes angiotensin II (Ang II) to Ang(1-7). Since Ang II is a strong activator of oxidative stress, we reasoned that ACE2 could be involved in the regulation of renal oxidative stress by governing the levels of Ang II. We, therefore, assessed levels of oxidative stress in kidney cortex of ACE2 knockout and wild-type littermate mice under baseline conditions. We found multiple markers of increased oxidative stress in ACE2KO mice. NADPH oxidase activity was increased in kidney cortex from ACE2KO mice as compared to WT (227 ± 24% vs.100 ± 19%, P < 0.001). However, kidney catalase and superoxide dismutase activities were not different between groups. Exogenous Ang II was degraded less efficiently by kidneys from ACE2KO mice than WT mice, and administration of an AT1R blocker (losartan 30 mg/kg/day) resulted in normalization of NADPH oxidase activity in the ACE2KO. These findings suggest that an AT1R-dependent mechanism contributes to increased ROS observed in the ACE2KO. This study demonstrates that genetic deficiency of ACE2 activity in mice fosters oxidative stress in the kidney in the absence of overt hypertension and is associated with reduced kidney capacity to hydrolyze Ang II. ACE2KO mice serve as a novel in vivo model to examine the role of overactivity of NADPH oxidase in kidney function.
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Affiliation(s)
- Jan Wysocki
- Department of MedicineDivision of Nephrology and HypertensionThe Feinberg School of MedicineNorthwestern UniversityChicagoIllinois
| | - David I. Ortiz‐Melo
- Department of MedicineDivision of NephrologyDuke University and Durham VA Medical CentersDurhamNorth Carolina
| | - Natalie K. Mattocks
- Department of MedicineDivision of NephrologyDuke University and Durham VA Medical CentersDurhamNorth Carolina
| | - Katherine Xu
- Department of MedicineDivision of NephrologyDuke University and Durham VA Medical CentersDurhamNorth Carolina
| | - Jessica Prescott
- Department of MedicineDivision of NephrologyDuke University and Durham VA Medical CentersDurhamNorth Carolina
| | - Karla Evora
- Department of MedicineDivision of Nephrology and HypertensionThe Feinberg School of MedicineNorthwestern UniversityChicagoIllinois
| | - Minghao Ye
- Department of MedicineDivision of Nephrology and HypertensionThe Feinberg School of MedicineNorthwestern UniversityChicagoIllinois
| | - Matthew A. Sparks
- Department of MedicineDivision of NephrologyDuke University and Durham VA Medical CentersDurhamNorth Carolina
| | - Syed K. Haque
- Department of MedicineDivision of Nephrology and HypertensionThe Feinberg School of MedicineNorthwestern UniversityChicagoIllinois
| | - Daniel Batlle
- Department of MedicineDivision of Nephrology and HypertensionThe Feinberg School of MedicineNorthwestern UniversityChicagoIllinois
| | - Susan B. Gurley
- Department of MedicineDivision of NephrologyDuke University and Durham VA Medical CentersDurhamNorth Carolina
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49
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Hemodynamic regulator and mitogenic growth factor: re-visiting the age old question with ACE2 and Jak2. ACTA ACUST UNITED AC 2014; 189:v-vi. [PMID: 24631470 DOI: 10.1016/j.regpep.2014.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Accepted: 03/04/2014] [Indexed: 11/23/2022]
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50
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Zhang ZZ, Shang QH, Jin HY, Song B, Oudit GY, Lu L, Zhou T, Xu YL, Gao PJ, Zhu DL, Penninger JM, Zhong JC. Cardiac protective effects of irbesartan via the PPAR-gamma signaling pathway in angiotensin-converting enzyme 2-deficient mice. J Transl Med 2013; 11:229. [PMID: 24067190 PMCID: PMC3850664 DOI: 10.1186/1479-5876-11-229] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Accepted: 09/24/2013] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Angiotensin-converting enzyme 2 (ACE2), a monocarboxypeptidase which metabolizes angiotensin II (Ang II) to generate Ang-(1-7), has been shown to prevent cardiac hypertrophy and injury but the mechanism remains elusive. Irbesartan has the dual actions of angiotensin receptor blockade and peroxisome proliferator-activated receptor-γ (PPARγ) activation. We hypothesized that irbesartan would exert its protective effects on ACE2 deficiency-mediated myocardial fibrosis and cardiac injury via the PPARγ signaling. METHODS 10-week-old ACE2 knockout (ACE2KO; Ace2(-/y)) mice received daily with irbesartan (50 mg/kg) or saline for 2 weeks. The wild-type mice (Ace2(+/y)) were used to the normal controls. We examined changes in myocardial ultrastructure, fibrosis-related genes and pathological signaling by real-time PCR gene array, Western blotting, Masson trichrome staining and transmission electron microscope analyses, respectively. RESULTS Compared with the Ace2(+/y) mice, cardiac expression of PPARα and PPARγ were reduced in Ace2(-/y) mice and the myocardial collagen volume fraction (CVF) and expression of fibrosis-related genes were increased, including transforming growth factor-β1 (TGFβ1), connective tissue growth factor (CTGF), collagen I and collagen III. Moreover, ACE2 deficiency triggered cardiac hypertrophy, increased myocardial fibrosis and adverse ultrastructure injury in ACE2KO hearts with higher levels of atrial natriuretic factor (ANF) and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), without affecting cardiac systolic function. Intriguingly, treatment with irbesartan significantly reversed ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in Ace2(-/y) mice linked with enhancement of plasma Ang-(1-7) level and downregulation of AT1 receptor in heart. Consistent with attenuation of myocardial fibrosis and ultrastructure injury, the myocardial CVF and levels of ANF, TGFβ1, CTGF, collagen I, collagen III and phosphorylated ERK1/2 were lower, and expression of PPARγ was higher in ACE2KO mice in response to irbesartan treatment, without affecting cardiac expression of PPARα, PPARδ, β-myosin heavy chain, TGFβ2 and fibronectin. CONCLUSIONS We conclude that irbesartan prevents ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in ACE2 mutant mice via activation of the PPARγ signaling and suppression of the TGFβ-CTGF-ERK signaling, resulting in attenuation of myocardial injury. Drugs targeting ACE2 and PPARγ represent potential candidates to prevent and treat myocardial injury and related cardiac disorders.
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Affiliation(s)
- Zhen-Zhou Zhang
- State Key Laboratory of Medical Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Hypertension, 197 Ruijin 2nd Road, Shanghai, 200025, China.
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