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Gao J, Pan H, Guo X, Huang Y, Luo JY. Endothelial Krüppel-like factor 2/4: Regulation and function in cardiovascular diseases. Cell Signal 2025; 130:111699. [PMID: 40023301 DOI: 10.1016/j.cellsig.2025.111699] [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: 12/02/2024] [Revised: 02/09/2025] [Accepted: 02/20/2025] [Indexed: 03/04/2025]
Abstract
This review presents an overview of the regulation, function, disease-relevance and pharmacological regulation of the critical endothelial transcription factors KLF2/4 in vasculature. The regulatory mechanisms of KLF2/4 expression and activity in vascular endothelium in response to hemodynamic forces and biochemical stimuli are depicted. The functional effects mediated by direct or indirect target genes of KLF2/4 in endothelial cells are systematically summarized. The contributory roles that dysregulated KLF2/4 play in relevant cardiovascular pathologies, such as atherosclerotic vascular lesions, pulmonary arterial hypertension and vascular complications of diabetes were reviewed. Moreover, this review also discusses the pharmacological regulation of KLF2/4 by drugs used in clinics and therapeutic possibility by directly targeting these two transcription factors for treating atherosclerotic cardiovascular diseases. Finally, prospective opinions on the gaps in disclosing novel vascular function mediated by KLF2/4 and future research needs are expressed.
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Affiliation(s)
- Jing Gao
- Department of Cardiology, Sir Run Run Shaw Hospital Affiliated to Zhejiang University School of Medicine, Hangzhou, China
| | - Hongjie Pan
- Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital Affiliated to Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaogang Guo
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong Special Administrative Region, China.
| | - Jiang-Yun Luo
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Carlson WD, Bosukonda D, Keck PC, Bey P, Tessier SN, Carlson FR. Cardiac preservation using ex vivo organ perfusion: new therapies for the treatment of heart failure by harnessing the power of growth factors using BMP mimetics like THR-184. Front Cardiovasc Med 2025; 12:1535778. [PMID: 40171539 PMCID: PMC11960666 DOI: 10.3389/fcvm.2025.1535778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 02/27/2025] [Indexed: 04/03/2025] Open
Abstract
As heart transplantation continues to be the gold standard therapy for end-stage heart failure, the imbalance between the supply of hearts, and the demand for them, continues to get worse. In the US alone, with less than 4,000 hearts suitable for transplant and over 100,000 potential recipients, this therapy is only available to a very few. The use of hearts Donated after Circulatory Death (DCD) and Donation after Brain Death (DBD) using ex vivo machine perfusion (EVMP) is a promising approach that has already increased the availability of suitable organs for heart transplantation. EVMP offers the promise of enabling the expansion of the overall number of heart transplants and lower rates of early graft dysfunction. These are realized through (1) safe extension of the time between procurement and transplantation and (2) ex vivo assessment of preserved hearts. Notably, ex vivo perfusion has facilitated the donation of DCD hearts and improved the success of transplantation. Nevertheless, DCD hearts suffer from serious preharvest ischemia/reperfusion injury (IRI). Despite these developments, only 40% of hearts offered for transplantation can be utilized. These devices do offer an opportunity to evaluate donor hearts for transplantation, resuscitate organs previously deemed unsuitable for transplantation, and provide a platform for the development of novel therapeutics to limit cardiac injury. Bone Morphogenetic Protein (BMP) signaling is a new target which holds the potential for ameliorating myocardial IRI. Recent studies have demonstrated that BMP signaling has a significant role in blocking the deleterious effects of injury to the heart. We have designed novel small peptide BMP mimetics that act via activin receptor-like kinase (ALK3), a type I BMP receptor. They are capable of (1) inhibiting inflammation and apoptosis, (2) blocking/reversing the epithelial-mesenchymal transition (EMT) and fibrosis, and (3) promoting tissue regeneration. In this review, we explore the promise that novel therapeutics, including these BMP mimetics, offer for the protection of hearts against myocardial injury during ex vivo transportation for cardiac transplantation. This protection represents a significant advance and a promising ex vivo therapeutic approach to expanding the donor pool by increasing the number of transplantable hearts.
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Affiliation(s)
- William D. Carlson
- Division of Cardiology, Mass General Hospital/Harvard, Boston, MA, United States
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Therapeutics by Design, Weston, MA, United States
| | - Dattatreyamurty Bosukonda
- Division of Cardiology, Mass General Hospital/Harvard, Boston, MA, United States
- Therapeutics by Design, Weston, MA, United States
| | | | - Philippe Bey
- Therapeutics by Design, Weston, MA, United States
| | - Shannon N. Tessier
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, and Shriners Children’s Hospital, Boston, MA, United States
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Sharma A, Bansal C, Sharma KL, Kumar A. Circular RNA: The evolving potential in the disease world. World J Med Genet 2024; 12:93011. [DOI: 10.5496/wjmg.v12.i1.93011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 05/23/2024] [Accepted: 07/02/2024] [Indexed: 09/19/2024] Open
Abstract
Circular RNAs (circRNAs), a new star of noncoding RNAs, are a group of endogenous RNAs that form a covalently closed circle and occur widely in the mammalian genome. Most circRNAs are conserved throughout species and frequently show stage-specific expression during various stages of tissue development. CircRNAs were a mystery discovery, as they were initially believed to be a product of splicing errors; however, subsequent research has shown that circRNAs can perform various functions and help in the regulation of splicing and transcription, including playing a role as microRNA (miRNA) sponges. With the application of high throughput next-generation technologies, circRNA hotspots were discovered. There are emerging indications that explain the association of circRNAs with human diseases, like cancers, developmental disorders, and inflammation, and circRNAs may be a new potential biomarker for the diagnosis and treatment outcome of various diseases, including cancer. After the discoveries of miRNAs and long noncoding RNAs, circRNAs are now acting as a novel research entity of interest in the field of RNA disease biology. In this review, we aim to focus on major updates on the biogeny and metabolism of circRNAs, along with their possible/established roles in major human diseases.
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Affiliation(s)
- Aarti Sharma
- Department of Research, Mayo Clinic Arizona, Phoenix, AZ 85054, United States
| | - Cherry Bansal
- Department of Pathology, Dr. S Tantia Medical College, Hospital and Research Center, Sri Ganganagar 335002, Rajasthan, India
| | - Kiran Lata Sharma
- Department of Pathology, Baylor College of Medicine, Houston, TX 77030, United States
| | - Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Shikatani EA, Wang T, Dingwell LS, White-Dzuro C, Momen A, Husain M. GDF5 deficiency prevents cardiac rupture following acute myocardial infarction in mice. Cardiovasc Pathol 2024; 68:107581. [PMID: 37838075 DOI: 10.1016/j.carpath.2023.107581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 09/19/2023] [Accepted: 10/09/2023] [Indexed: 10/16/2023] Open
Abstract
BACKGROUND We previously showed that growth differentiation factor 5 (GDF5) limits infarct expansion post-myocardial infarction (MI). We now examine the acute post-MI role of GDF5 in cardiac rupture. METHODS AND RESULTS Following permanent ligation of the left anterior descending artery, GDF5 deficiency (i.e., GDF5 knockout mice) reduced the incidence of cardiac rupture (4/24 vs. 17/24; P < .05), and improved survival over 28-d compared to wild-type (WT) mice (79% vs. 25%; P < .0001). Moreover, at 3-d post-MI, GDF5-deficient mice manifest: (a) reduced heart weight/body weight ratio (P < .0001) without differences in infarct size or cardiomyocyte size; (b) increased infarct zone expression of Col1a1 (P < .05) and Col3a1 (P < .01), suggesting increased myocardial fibrosis; and (c) reduced aortic and left ventricular peak systolic pressures (P ≤ .05), suggesting reduced afterload. Despite dysregulated inflammatory markers and reduced circulating monocytes in GDF5-deficient mice at 3-d post-MI, reciprocal bone marrow transplantation (BMT) failed to implicate GDF5 in BM-derived cells, suggesting the involvement of tissue-resident GDF5 expression in cardiac rupture. CONCLUSIONS Loss of GDF5 reduces cardiac rupture post-MI with increased myocardial fibrosis and lower afterload, albeit at the cost of chronic adverse remodeling.
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Affiliation(s)
- Eric A Shikatani
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Tao Wang
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Heart and Stroke Richard Lewar Centre of Excellence, Ted Rogers Centre for Heart Research, and Peter Munk Cardiac Centre, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Luke S Dingwell
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Heart and Stroke Richard Lewar Centre of Excellence, Ted Rogers Centre for Heart Research, and Peter Munk Cardiac Centre, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Colin White-Dzuro
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Abdul Momen
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Mansoor Husain
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Heart and Stroke Richard Lewar Centre of Excellence, Ted Rogers Centre for Heart Research, and Peter Munk Cardiac Centre, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
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Wen J, Liu G, Liu M, Wang H, Wan Y, Yao Z, Gao N, Sun Y, Zhu L. Transforming growth factor-β and bone morphogenetic protein signaling pathways in pathological cardiac hypertrophy. Cell Cycle 2023; 22:2467-2484. [PMID: 38179789 PMCID: PMC10802212 DOI: 10.1080/15384101.2023.2293595] [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: 06/01/2023] [Revised: 09/22/2023] [Accepted: 10/09/2023] [Indexed: 01/06/2024] Open
Abstract
Pathological cardiac hypertrophy (referred to as cardiac hypertrophy) is a maladaptive response of the heart to a variety of pathological stimuli, and cardiac hypertrophy is an independent risk factor for heart failure and sudden death. Currently, the treatments for cardiac hypertrophy are limited to improving symptoms and have little effect. Elucidation of the developmental process of cardiac hypertrophy at the molecular level and the identification of new targets for the treatment of cardiac hypertrophy are crucial. In this review, we summarize the research on multiple active substances related to the pathogenesis of cardiac hypertrophy and the signaling pathways involved and focus on the role of transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling in the development of cardiac hypertrophy and the identification of potential targets for molecular intervention. We aim to identify important signaling molecules with clinical value and hope to help promote the precise treatment of cardiac hypertrophy and thus improve patient outcomes.
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Affiliation(s)
- Jing Wen
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Guixiang Liu
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Mingjie Liu
- Department of Lung Function, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Huarui Wang
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yunyan Wan
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Zhouhong Yao
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Nannan Gao
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yuanyuan Sun
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Ling Zhu
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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Cimmino G, Muscoli S, De Rosa S, Cesaro A, Perrone MA, Selvaggio S, Selvaggio G, Aimo A, Pedrinelli R, Mercuro G, Romeo F, Perrone Filardi P, Indolfi C, Coronelli M. Evolving concepts in the pathophysiology of atherosclerosis: from endothelial dysfunction to thrombus formation through multiple shades of inflammation. J Cardiovasc Med (Hagerstown) 2023; 24:e156-e167. [PMID: 37186566 DOI: 10.2459/jcm.0000000000001450] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
Atherosclerosis is the anatomo-pathological substrate of most cardio, cerebro and vascular diseases such as acute and chronic coronary syndromes, stroke and peripheral artery diseases. The pathophysiology of atherosclerotic plaque and its complications are under continuous investigation. In the last 2 decades our understanding on the formation, progression and complication of the atherosclerotic lesion has greatly improved and the role of immunity and inflammation is now well documented and accepted. The conventional risk factors modulate endothelial function determining the switch to a proatherosclerotic phenotype. From this point, lipid accumulation with an imbalance from cholesterol influx and efflux, foam cells formation, T-cell activation, cytokines release and matrix-degrading enzymes production occur. Lesions with high inflammatory rate become vulnerable and prone to rupture. Once complicated, the intraplaque thrombogenic material, such as the tissue factor, is exposed to the flowing blood, thus inducing coagulation cascade activation, platelets aggregation and finally intravascular thrombus formation that leads to clinical manifestations of this disease. Nonconventional risk factors, such as gut microbiome, are emerging novel markers of atherosclerosis. Several data indicate that gut microbiota may play a causative role in formation, progression and complication of atherosclerotic lesions. The gut dysbiosis-related inflammation and gut microbiota-derived metabolites have been proposed as the main working hypothesis in contributing to disease formation and progression. The current evidence suggest that the conventional and nonconventional risk factors may modulate the degree of inflammation of the atherosclerotic lesion, thus influencing its final fate. Based on this hypothesis, targeting inflammation seems to be a promising approach to further improve our management of atherosclerotic-related diseases.
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Affiliation(s)
- Giovanni Cimmino
- Department of Translational Medical Sciences, University of Campania 'Luigi Vanvitelli', Naples
| | | | - Salvatore De Rosa
- Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Catanzaro
| | - Arturo Cesaro
- Department of Translational Medical Sciences, University of Campania 'Luigi Vanvitelli', Naples
- Division of Cardiology, A.O.R.N. 'Sant'Anna e San Sebastiano', Caserta
| | - Marco A Perrone
- Department of Cardiology and CardioLab, University of Rome Tor Vergata, Rome
| | | | | | - Alberto Aimo
- Fondazione Toscana Gabriele Monasterio
- Institute of Life Sciences, Scuola Superiore Sant'Anna
| | - Roberto Pedrinelli
- Critical Care Medicine-Cardiology Division, Department of Surgical, Medical and Molecular Pathology, University of Pisa, Pisa
| | - Giuseppe Mercuro
- Dipartimento di Scienze Mediche e Sanità Pubblica, Università degli Studi, Cagliari
| | | | - Pasquale Perrone Filardi
- Dipartimento di Scienze Biomediche Avanzate, Università degli Studi di Napoli 'Federico II', Napoli
| | - Ciro Indolfi
- Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Catanzaro
| | - Maurizio Coronelli
- Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy
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Murugesan P, Zhang Y, Youn JY, Cai H. Novel and robust treatment of pulmonary hypertension with netrin-1 and netrin-1-derived small peptides. Redox Biol 2022; 55:102348. [PMID: 35830752 PMCID: PMC9287481 DOI: 10.1016/j.redox.2022.102348] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/11/2022] [Accepted: 05/18/2022] [Indexed: 11/07/2022] Open
Abstract
Limited medical therapies have been implemented for the treatment of the devastating cardiorespiratory disease of pulmonary hypertension (PH) while none of which is sufficiently effective to stop or regress development of PH. We have previously shown that netrin-1, an axon-guiding protein during development, protects against ischemia reperfusion injury induced myocardial infarction via modest and stable production of nitric oxide (NO) and attenuation of oxidative stress. Since NO deficiency and oxidative stress-mediated vascular remodeling play important roles in the pathogenesis of PH, our present study investigated therapeutic effects on PH of netrin-1 and its derived small peptides. Infused into mice for 3 weeks during exposure to hypoxia, netrin-1 and netrin-1 derived small peptides V1, V2 or V3 substantially alleviated pathophysiological and molecular features of PH, as indicated by abrogated increases in mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), attenuated right ventricular hypertrophy, diminished vascular remodeling of medial thickening and upregulation in smooth muscle alpha-actin (SMA) and proliferative cell nuclear antigen (PCNA), and alleviated perivascular and peribronchial fibrosis reflected by collagen deposition. NO bioavailability was substantially improved by treatment with netrin-1 and netrin-1 derived small peptides, while hypoxia induced increases in total superoxide production and eNOS uncoupling activity were all attenuated. These dual mechanisms of increasing NO bioavailability and decreasing oxidative stress at the same time, underlie robust protective effects on PH of netrin-1 and its derived small peptides, which are different from existing medications that primarily target NO signaling alone. Our data for the first time demonstrate intriguing findings that netrin-1 and netrin-1 derived small peptides can be used as novel and robust therapeutics for the treatment of PH.
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Affiliation(s)
- Priya Murugesan
- Division of Molecular Medicine, Department of Anesthesiology, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, United States
| | - Yixuan Zhang
- Division of Molecular Medicine, Department of Anesthesiology, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, United States
| | - Ji Youn Youn
- Division of Molecular Medicine, Department of Anesthesiology, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, United States
| | - Hua Cai
- Division of Molecular Medicine, Department of Anesthesiology, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, United States.
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Luo JY, Cheng CK, He L, Pu Y, Zhang Y, Lin X, Xu A, Lau CW, Tian XY, Ma RCW, Jo H, Huang Y. Endothelial UCP2 Is a Mechanosensitive Suppressor of Atherosclerosis. Circ Res 2022; 131:424-441. [PMID: 35899624 PMCID: PMC9390236 DOI: 10.1161/circresaha.122.321187] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 07/05/2022] [Accepted: 07/11/2022] [Indexed: 12/02/2022]
Abstract
BACKGROUND Inflamed endothelial cells (ECs) trigger atherogenesis, especially at arterial regions experiencing disturbed blood flow. UCP2 (Uncoupling protein 2), a key mitochondrial antioxidant protein, improves endothelium-dependent relaxation in obese mice. However, whether UCP2 can be regulated by shear flow is unknown, and the role of endothelial UCP2 in regulating inflammation and atherosclerosis remains unclear. This study aims to investigate the mechanoregulation of UCP2 expression in ECs and the effect of UCP2 on endothelial inflammation and atherogenesis. METHODS In vitro shear stress simulation system was used to investigate the regulation of UCP2 expression by shear flow. EC-specific Ucp2 knockout mice were used to investigate the role of UCP2 in flow-associated atherosclerosis. RESULTS Shear stress experiments showed that KLF2 (Krüppel-like factor 2) mediates fluid shear stress-dependent regulation of UCP2 expression in human aortic and human umbilical vein ECs. Unidirectional shear stress, statins, and resveratrol upregulate whereas oscillatory shear stress and proinflammatory stimuli inhibit UCP2 expression through altered KLF2 expression. KLF2 directly binds to UCP2 promoter to upregulate its transcription in human umbilical vein ECs. UCP2 knockdown induced expression of genes involved in proinflammatory and profibrotic signaling, resulting in a proatherogenic endothelial phenotype. EC-specific Ucp2 deletion promotes atherogenesis and collagen production. Additionally, we found endothelial Ucp2 deficiency aggravates whereas adeno-associated virus-mediated EC-Ucp2 overexpression inhibits carotid atherosclerotic plaque formation in disturbed flow-enhanced atherosclerosis mouse model. RNA-sequencing analysis revealed FoxO1 (forkhead box protein O1) as the major proinflammatory transcriptional regulator activated by UCP2 knockdown, and FoxO1 inhibition reduced vascular inflammation and disturbed flow-enhanced atherosclerosis. We showed further that UCP2 level is critical for phosphorylation of AMPK (AMP-activated protein kinase), which is required for UCP2-induced inhibition of FoxO1. CONCLUSIONS Altogether, our studies uncover that UCP2 is novel mechanosensitive gene under the control of fluid shear stress and KLF2 in ECs. UCP2 expression is critical for endothelial proinflammatory response and atherogenesis. Therapeutic strategies enhancing UCP2 level may have therapeutic potential against atherosclerosis.
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Affiliation(s)
- Jiang-Yun Luo
- Institute for Cardiovascular Development and Regenerative Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, China (J.-Y.L.)
- Heart and Vascular Institute, Shenzhen Research Institute and School of Biomedical Sciences (J.-Y.L., C.K.C., L.H., Y.P., C.W.L., X.Y.T.), Chinese University of Hong Kong, China
| | - Chak Kwong Cheng
- Heart and Vascular Institute, Shenzhen Research Institute and School of Biomedical Sciences (J.-Y.L., C.K.C., L.H., Y.P., C.W.L., X.Y.T.), Chinese University of Hong Kong, China
- Department of Biomedical Sciences, City University of Hong Kong, China (C.K.C., L.H., Y.P., Y.H.)
| | - Lei He
- Heart and Vascular Institute, Shenzhen Research Institute and School of Biomedical Sciences (J.-Y.L., C.K.C., L.H., Y.P., C.W.L., X.Y.T.), Chinese University of Hong Kong, China
- Department of Biomedical Sciences, City University of Hong Kong, China (C.K.C., L.H., Y.P., Y.H.)
| | - Yujie Pu
- Heart and Vascular Institute, Shenzhen Research Institute and School of Biomedical Sciences (J.-Y.L., C.K.C., L.H., Y.P., C.W.L., X.Y.T.), Chinese University of Hong Kong, China
- Department of Biomedical Sciences, City University of Hong Kong, China (C.K.C., L.H., Y.P., Y.H.)
| | - Yang Zhang
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangdong, China (Y.Z.)
| | - Xiao Lin
- School of Life Sciences (X.L.), Chinese University of Hong Kong, China
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, The University of Hong Kong, China (A.X.)
| | - Chi Wai Lau
- Heart and Vascular Institute, Shenzhen Research Institute and School of Biomedical Sciences (J.-Y.L., C.K.C., L.H., Y.P., C.W.L., X.Y.T.), Chinese University of Hong Kong, China
| | - Xiao Yu Tian
- Heart and Vascular Institute, Shenzhen Research Institute and School of Biomedical Sciences (J.-Y.L., C.K.C., L.H., Y.P., C.W.L., X.Y.T.), Chinese University of Hong Kong, China
| | - Ronald Ching Wan Ma
- Department of Medicine and Therapeutics (R.C.W.M.), Chinese University of Hong Kong, China
| | - Hanjoong Jo
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (H.J.)
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, China (C.K.C., L.H., Y.P., Y.H.)
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9
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Singh RK, Yoon DS, Mandakhbayar N, Li C, Kurian AG, Lee NH, Lee JH, Kim HW. Diabetic bone regeneration with nanoceria-tailored scaffolds by recapitulating cellular microenvironment: Activating integrin/TGF-β co-signaling of MSCs while relieving oxidative stress. Biomaterials 2022; 288:121732. [PMID: 36031457 DOI: 10.1016/j.biomaterials.2022.121732] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 07/10/2022] [Accepted: 08/04/2022] [Indexed: 11/15/2022]
Abstract
Regenerating defective bone in patients with diabetes mellitus remains a significant challenge due to high blood glucose level and oxidative stress. Here we aim to tackle this issue by means of a drug- and cell-free scaffolding approach. We found the nanoceria decorated on various types of scaffolds (fibrous or 3D-printed one; named nCe-scaffold) could render a therapeutic surface that can recapitulate the microenvironment: modulating oxidative stress while offering a nanotopological cue to regenerating cells. Mesenchymal stem cells (MSCs) recognized the nanoscale (tens of nm) topology of nCe-scaffolds, presenting highly upregulated curvature-sensing membrane protein, integrin set, and adhesion-related molecules. Osteogenic differentiation and mineralization were further significantly enhanced by the nCe-scaffolds. Of note, the stimulated osteogenic potential was identified to be through integrin-mediated TGF-β co-signaling activation. Such MSC-regulatory effects were proven in vivo by the accelerated bone formation in rat calvarium defect model. The nCe-scaffolds further exhibited profound enzymatic and catalytic potential, leading to effectively scavenging reactive oxygen species in vivo. When implanted in diabetic calvarium defect, nCe-scaffolds significantly enhanced early bone regeneration. We consider the currently-exploited nCe-scaffolds can be a promising drug- and cell-free therapeutic means to treat defective tissues like bone in diabetic conditions.
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Affiliation(s)
- Rajendra K Singh
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea; Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea; Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan, 31116, Republic of Korea
| | - Dong Suk Yoon
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea; Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Nandin Mandakhbayar
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea; Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan, 31116, Republic of Korea
| | - Chengji Li
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea; Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea
| | - Amal George Kurian
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea; Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea
| | - Na-Hyun Lee
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea; Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan, 31116, Republic of Korea
| | - Jung-Hwan Lee
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea; Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea; Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan, 31116, Republic of Korea; Department of Biomaterials Science, College of Dentistry, Dankook University, Cheonan, 31116, Republic of Korea; Department of Regenerative Dental Medicine, College of Dentistry, Dankook University, Cheonan, 31116, Republic of Korea; Cell & Matter Institute, Dankook University, Cheonan, 31116, Republic of Korea; UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan, 31116, Republic of Korea.
| | - Hae-Won Kim
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea; Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea; Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan, 31116, Republic of Korea; Department of Biomaterials Science, College of Dentistry, Dankook University, Cheonan, 31116, Republic of Korea; Department of Regenerative Dental Medicine, College of Dentistry, Dankook University, Cheonan, 31116, Republic of Korea; Cell & Matter Institute, Dankook University, Cheonan, 31116, Republic of Korea; UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan, 31116, Republic of Korea.
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10
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Boamah GA, Huang Z, Shen Y, Lu Y, Wang Z, Su Y, Xu C, Luo X, Ke C, You W. Transcriptome analysis reveals fluid shear stress (FSS) and atherosclerosis pathway as a candidate molecular mechanism of short-term low salinity stress tolerance in abalone. BMC Genomics 2022; 23:392. [PMID: 35606721 PMCID: PMC9128277 DOI: 10.1186/s12864-022-08611-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 05/09/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Transcriptome sequencing is an effective tool to reveal the essential genes and pathways underlying countless biotic and abiotic stress adaptation mechanisms. Although severely challenged by diverse environmental conditions, the Pacific abalone Haliotis discus hannai remains a high-value aquaculture mollusk and a Chinese predominantly cultured abalone species. Salinity is one of such environmental factors whose fluctuation could significantly affect the abalone's cellular and molecular immune responses and result in high mortality and reduced growth rate during prolonged exposure. Meanwhile, hybrids have shown superiority in tolerating diverse environmental stresses over their purebred counterparts and have gained admiration in the Chinese abalone aquaculture industry. The objective of this study was to investigate the molecular and cellular mechanisms of low salinity adaptation in abalone. Therefore, this study used transcriptome analysis of the gill tissues and flow cytometric analysis of hemolymph of H. discus hannai (DD) and interspecific hybrid H. discus hannai ♀ x H. fulgens ♂ (DF) during low salinity exposure. Also, the survival and growth rate of the species under various salinities were assessed. RESULTS The transcriptome data revealed that the differentially expressed genes (DEGs) were significantly enriched on the fluid shear stress and atherosclerosis (FSS) pathway. Meanwhile, the expression profiles of some essential genes involved in this pathway suggest that abalone significantly up-regulated calmodulin-4 (CaM-4) and heat-shock protein90 (HSP90), and significantly down-regulated tumor necrosis factor (TNF), bone morphogenetic protein-4 (BMP-4), and nuclear factor kappa B (NF-kB). Also, the hybrid DF showed significantly higher and sustained expression of CaM and HSP90, significantly higher phagocytosis, significantly lower hemocyte mortality, and significantly higher survival at low salinity, suggesting a more active molecular and hemocyte-mediated immune response and a more efficient capacity to tolerate low salinity than DD. CONCLUSIONS Our study argues that the abalone CaM gene might be necessary to maintain ion equilibrium while HSP90 can offset the adverse changes caused by low salinity, thereby preventing damage to gill epithelial cells (ECs). The data reveal a potential molecular mechanism by which abalone responds to low salinity and confirms that hybridization could be a method for breeding more stress-resilient aquatic species.
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Affiliation(s)
- Grace Afumwaa Boamah
- State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, 361102 People’s Republic of China
- Fujian Key Laboratory of Genetics and Breeding of Marine Organisms, Xiamen University, Xiamen, 361102 People’s Republic of China
- College of Ocean and Earth Sciences, Xiamen University, Xiamen, 361102 People’s Republic of China
| | - Zekun Huang
- State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, 361102 People’s Republic of China
- Fujian Key Laboratory of Genetics and Breeding of Marine Organisms, Xiamen University, Xiamen, 361102 People’s Republic of China
- College of the Environment and Ecology, Xiamen University, 361102 Xiamen, PR China
| | - Yawei Shen
- State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, 361102 People’s Republic of China
- Fujian Key Laboratory of Genetics and Breeding of Marine Organisms, Xiamen University, Xiamen, 361102 People’s Republic of China
- College of Ocean and Earth Sciences, Xiamen University, Xiamen, 361102 People’s Republic of China
| | - Yisha Lu
- State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, 361102 People’s Republic of China
- Fujian Key Laboratory of Genetics and Breeding of Marine Organisms, Xiamen University, Xiamen, 361102 People’s Republic of China
- College of Ocean and Earth Sciences, Xiamen University, Xiamen, 361102 People’s Republic of China
| | - Zhixuan Wang
- State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, 361102 People’s Republic of China
- Fujian Key Laboratory of Genetics and Breeding of Marine Organisms, Xiamen University, Xiamen, 361102 People’s Republic of China
- College of Ocean and Earth Sciences, Xiamen University, Xiamen, 361102 People’s Republic of China
| | - Ying Su
- State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, 361102 People’s Republic of China
- Fujian Key Laboratory of Genetics and Breeding of Marine Organisms, Xiamen University, Xiamen, 361102 People’s Republic of China
- College of Ocean and Earth Sciences, Xiamen University, Xiamen, 361102 People’s Republic of China
| | - Changan Xu
- Third Institute of Oceanography, MNR, Xiamen, 361005 China
| | - Xuan Luo
- State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, 361102 People’s Republic of China
- Fujian Key Laboratory of Genetics and Breeding of Marine Organisms, Xiamen University, Xiamen, 361102 People’s Republic of China
- College of Ocean and Earth Sciences, Xiamen University, Xiamen, 361102 People’s Republic of China
| | - Caihuan Ke
- State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, 361102 People’s Republic of China
- Fujian Key Laboratory of Genetics and Breeding of Marine Organisms, Xiamen University, Xiamen, 361102 People’s Republic of China
- College of Ocean and Earth Sciences, Xiamen University, Xiamen, 361102 People’s Republic of China
| | - Weiwei You
- State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, 361102 People’s Republic of China
- Fujian Key Laboratory of Genetics and Breeding of Marine Organisms, Xiamen University, Xiamen, 361102 People’s Republic of China
- College of Ocean and Earth Sciences, Xiamen University, Xiamen, 361102 People’s Republic of China
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11
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Tang Q, McNair AJ, Phadwal K, Macrae VE, Corcoran BM. The Role of Transforming Growth Factor-β Signaling in Myxomatous Mitral Valve Degeneration. Front Cardiovasc Med 2022; 9:872288. [PMID: 35656405 PMCID: PMC9152029 DOI: 10.3389/fcvm.2022.872288] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 04/12/2022] [Indexed: 02/03/2023] Open
Abstract
Mitral valve prolapse (MVP) due to myxomatous degeneration is one of the most important chronic degenerative cardiovascular diseases in people and dogs. It is a common cause of heart failure leading to significant morbidity and mortality in both species. Human MVP is usually classified into primary or non-syndromic, including Barlow’s Disease (BD), fibro-elastic deficiency (FED) and Filamin-A mutation, and secondary or syndromic forms (typically familial), such as Marfan syndrome (MFS), Ehlers-Danlos syndrome, and Loeys–Dietz syndrome. Despite different etiologies the diseased valves share pathological features consistent with myxomatous degeneration. To reflect this common pathology the condition is often called myxomatous mitral valve degeneration (disease) (MMVD) and this term is universally used to describe the analogous condition in the dog. MMVD in both species is characterized by leaflet thickening and deformity, disorganized extracellular matrix, increased transformation of the quiescent valve interstitial cell (qVICs) to an activated state (aVICs), also known as activated myofibroblasts. Significant alterations in these cellular activities contribute to the initiation and progression of MMVD due to the increased expression of transforming growth factor-β (TGF-β) superfamily cytokines and the dysregulation of the TGF-β signaling pathways. Further understanding the molecular mechanisms of MMVD is needed to identify pharmacological manipulation strategies of the signaling pathway that might regulate VIC differentiation and so control the disease onset and development. This review briefly summarizes current understanding of the histopathology, cellular activities, molecular mechanisms and pathogenesis of MMVD in dogs and humans, and in more detail reviews the evidence for the role of TGF-β.
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Affiliation(s)
- Qiyu Tang
- The Roslin Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Andrew J. McNair
- The Roslin Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Kanchan Phadwal
- The Roslin Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Vicky E. Macrae
- The Roslin Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Brendan M. Corcoran
- The Roslin Institute, The University of Edinburgh, Edinburgh, United Kingdom
- Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Edinburgh, United Kingdom
- *Correspondence: Brendan M. Corcoran,
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12
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Wang L, Cheng CK, Yi M, Lui KO, Huang Y. Targeting endothelial dysfunction and inflammation. J Mol Cell Cardiol 2022; 168:58-67. [PMID: 35460762 DOI: 10.1016/j.yjmcc.2022.04.011] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/05/2022] [Accepted: 04/14/2022] [Indexed: 12/15/2022]
Abstract
Vascular endothelium maintains vascular homeostasis through liberating a spectrum of vasoactive molecules, both protective and harmful regulators of vascular tone, structural remodeling, inflammation and atherogenesis. An intricate balance between endothelium-derived relaxing factors (nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor) and endothelium-derived contracting factors (superoxide anion, endothelin-1 and constrictive prostaglandins) tightly regulates vascular function. Disruption of such balance signifies endothelial dysfunction, a critical contributor in aging and chronic cardiometabolic disorders, such as obesity, diabetes, hypertension, dyslipidemia and atherosclerotic vascular diseases. Among many proposed cellular and molecular mechanisms causing endothelial dysfunction, oxidative stress and inflammation are often the pivotal players and they are naturally considered as useful targets for intervention in patients with cardiovascular and metabolic diseases. In this article, we provide a recent update on the therapeutic values of pharmacological agents, such as cyclooxygenase-2 inhibitors, renin-angiotensin-system inhibitors, bone morphogenic protein 4 inhibitors, peroxisome proliferator-activated receptor δ agonists, and glucagon-like peptide 1-elevating drugs, and the physiological factors, particularly hemodynamic forces, that improve endothelial function by targeting endothelial oxidative stress and inflammation.
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Affiliation(s)
- Li Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Chak Kwong Cheng
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Min Yi
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Kathy O Lui
- Department of Chemical Pathology and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
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13
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Russo K, Wharton KA. BMP/TGF-β signaling as a modulator of neurodegeneration in ALS. Dev Dyn 2022; 251:10-25. [PMID: 33745185 PMCID: PMC11929146 DOI: 10.1002/dvdy.333] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/12/2021] [Accepted: 03/12/2021] [Indexed: 12/19/2022] Open
Abstract
This commentary focuses on the emerging intersection between BMP/TGF-β signaling roles in nervous system function and the amyotrophic lateral sclerosis (ALS) disease state. Future research is critical to elucidate the molecular underpinnings of this intersection of the cellular processes disrupted in ALS and those influenced by BMP/TGF-β signaling, including synapse structure, neurotransmission, plasticity, and neuroinflammation. Such knowledge promises to inform us of ideal entry points for the targeted modulation of dysfunctional cellular processes in an effort to abrogate ALS pathologies. It is likely that different interventions are required, either at discrete points in disease progression, or across multiple dysfunctional processes which together lead to motor neuron degeneration and death. We discuss the challenging, but intriguing idea that modulation of the pleiotropic nature of BMP/TGF-β signaling could be advantageous, as a way to simultaneously treat defects in more than one cell process across different forms of ALS.
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Affiliation(s)
- Kathryn Russo
- Department of Neuroscience, Brown University, Providence, Rhode Island, USA
- Robert J. and Nancy D. Carney Institute for Brain Science, Brown University, Providence, Rhode Island, USA
| | - Kristi A Wharton
- Robert J. and Nancy D. Carney Institute for Brain Science, Brown University, Providence, Rhode Island, USA
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA
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14
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Salvianolic acid B ameliorates vascular endothelial dysfunction through influencing a bone morphogenetic protein 4-ROS cycle in diabetic mice. Life Sci 2021; 286:120039. [PMID: 34637797 DOI: 10.1016/j.lfs.2021.120039] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/31/2021] [Accepted: 09/08/2021] [Indexed: 11/21/2022]
Abstract
AIM This study investigated the roles of bone morphogenetic protein-4 (BMP4) and ROS in diabetic endothelial dysfunction and explored whether Salvianolic acid B (Sal B) improved endothelial function by affecting BMP4-ROS in diabetic mice. MAIN METHODS db/db mice were orally administrated with Sal B (10 mg/kg/day) for one week while db/m + mice were injected with adenoviral vectors delivering BMP4 (3 × 108 pfu) and then received one week-Sal B treatment. ROS levels were assayed by DHE staining. Protein expression and phosphorylation were evaluated by Western blot. Aortic rings were suspended in myograph for force measurement. Flow-mediated dilatations in the second-order mesenteric arteries were determined by pressure myograph. KEY FINDINGS We first revealed the existence of a BMP4-ROS cycle in db/db mice, which stimulated p38 MAPK/JNK/caspase 3 and thus participated in endothelial dysfunction. One week-treatment or 24 h-incubation with Sal B disrupted the cycle, suppressed p38 MAPK/JNK/caspase 3 cascade, and improved endothelium-dependent relaxations (EDRs) in db/db mouse aortas. Importantly, in vivo Sal B treatment also improved flow-mediated dilatation in db/db mouse second order mesenteric arteries. Furthermore, in vivo BMP4 overexpression induced oxidative stress, stimulated p38 MAPK/JNK/caspase 3, and impaired EDRs in db/m + mouse aortas, which were all reversed by Sal B. SIGNIFICANCE The present study demonstrates that Sal B ameliorates endothelial dysfunction through breaking the BMP4-ROS cycle and subsequently inhibiting p38 MAPK/JNK/caspase 3 in diabetic mice and provides evidence for the additional new mechanism underlying the benefit of Sal B against diabetic vasculopathy.
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15
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Bahrami R, Dastgheib SA, Niktabar SM, Amooee A, Lookzadeh MH, Mirjalili SR, Noorishadkam M, Bahrololoomi Z, Neamatzadeh H. Association of BMP4 rs17563 Polymorphism with Nonsyndromic Cleft Lip with or without Cleft Palate Risk: Literature Review and Comprehensive Meta-Analysis. Fetal Pediatr Pathol 2021; 40:305-319. [PMID: 31909686 DOI: 10.1080/15513815.2019.1707916] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Although published individual studies have reported associations between BMP4 rs17563 polymorphism and nonsyndromic cleft lip with or without cleft palate (NSCLP) risk, the results are conflicting. This meta-analysis was conducted to assess the association based on multiple studies. Methods: A comprehensive literature search up to October 1st, 2019 was performed using PubMed, Science Direct, China National Knowledge Infrastructure (CNKI), and Wanfang databases. Results: Fourteen case-control studies with 2,058 NSCLP cases and 2,557 controls were selected. There was no significant association between BMP4 rs17563 polymorphism and risk of NSCLP overall. Subgroup analysis revealed that BMP4 rs17563 polymorphism was associated with NSCLP risk in Chinese and Brazilian populations. Conclusions: This meta-analysis suggests that BMP4 rs17563 polymorphism was not associated with NSCLP risk in overall population. However, BMP4 rs17563 polymorphism may be a risk factor for development of NSCLP in Chinese and Brazilians.
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Affiliation(s)
- Reza Bahrami
- Neonatal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Alireza Dastgheib
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Abdolhamid Amooee
- Department of Surgery, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mohammad Hosein Lookzadeh
- Department of Pediatrics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Mother and Newborn Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Seyed Reza Mirjalili
- Department of Pediatrics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Mother and Newborn Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mahmood Noorishadkam
- Department of Pediatrics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Mother and Newborn Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Zahra Bahrololoomi
- Department of Pediatric Dentistry, School of Dentistry, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hossein Neamatzadeh
- Mother and Newborn Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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16
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Cai B, Du J. Role of bone morphogenic protein-4 in gestational diabetes mellitus-related hypertension. Exp Ther Med 2021; 22:762. [PMID: 34035859 DOI: 10.3892/etm.2021.10194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 04/14/2021] [Indexed: 12/16/2022] Open
Abstract
Hyperglycaemia stimulates the synthesis and release of bone morphogenetic protein-4 (BMP-4) in vascular endothelial cells, which further induces peroxide production and inflammatory responses, leading to vascular endothelial dysfunction. However, the role of BMP-4 in gestational diabetes mellitus (GDM)-related vascular endothelial dysfunction remains unclear. In the present study, the hypothesis that the overexpression of BMP-4 would induce GDM-related hypertension by impairing vascular endothelial function was evaluated. An animal model of GDM was established in Sprague-Dawley (SD) rats. Based on blood pressure, rats were divided into control, GDM and GDM + hypertension (HT) groups. The expression levels of BMP-4, cyclooxygenase-2 (COX-2), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX-1) and vascular cell adhesion molecule 1 (VCAM-1) in the endothelium of the abdominal aorta of rats in each group were determined via immunohistochemistry and western blotting. Pregnant SD rats were divided into four groups, separately infused with BMP-4, BMP-4 + noggin, noggin or vehicle by osmotic pumps, and blood pressure and vasorelaxation were examined. Immunohistochemistry indicated that the expression levels of the four proteins were lower in the control group than in the GDM and GDM + HT groups. The positive expression rate of VCAM-1 was significantly lower in the control group than in the GDM and GDM+HT groups, and the differences were statistically significant (χ2=17.325, P<0.05; χ2=10.080, P<0.05). Western blotting revealed that the expression level of the COX-2 protein exhibited a sequential increase in the three groups. The expression level of COX-2 in the control and GDM groups was significantly lower than that in the GDM+HT group (3.358±1.286; P<0.05 and P<0.05, respectively). The expression level of VCAM-1 protein in the three groups also exhibited a significant sequential increase (F=31.732; P≤0.001). The expression level of VCAM-1 in the control and GDM groups was significantly lower than that in the GDM+HT group (2.698±0.223; P≤0.001 and P≤0.001, respectively). Infusion of BMP-4 increased systolic blood pressure (from 82 to 112 mmHg) and impaired vasorelaxation in pregnant SD rats after 2 weeks. Co-treatment with noggin completely blocked BMP-4-induced effects. Thus, the BMP-4/NOX-1/COX-2 signalling pathway may be involved in GDM-related hypertension, but VCAM-1 may be substantially associated with GDM-related hypertension. Furthermore, overexpression of BMP-4 could lead to hypertension by impairing endothelial function in pregnancy.
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Affiliation(s)
- Benshuo Cai
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Juan Du
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
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17
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Chen CC, Wong TY, Chin TY, Lee WH, Kuo CY, Hsu YC. Systems biology approach to exploring the effect of cyclic stretching on cardiac cell physiology. Aging (Albany NY) 2020; 12:16035-16045. [PMID: 32759460 PMCID: PMC7485730 DOI: 10.18632/aging.103465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 05/27/2020] [Indexed: 01/10/2023]
Abstract
Although mechanical forces are involved in pressure-overloaded cardiomyopathy, their effects on gene transcription profiles are not fully understood. Here, we used next-generation sequencing (NGS) to investigate changes in genomic profiles after cyclic mechanical stretching of human cardiomyocytes. We found that 85, 87, 32, 29, and 28 genes were differentially expressed after 1, 4, 12, 24, and 48 hours of stretching. Furthermore, 10 of the 29 genes that were up-regulated and 11 of the 28 that were down-regulated after 24 h showed the same changes after 48 h. We then examined expression of the genes that encode serpin family E member 1 (SERPINE1), DNA-binding protein inhibitor 1 (ID1), DNA-binding protein inhibitor 3 (ID3), and CCL2, a cytokine that acts as chemotactic factor in monocytes, in an RT-PCR experiment. The same changes were observed for all four genes after all cyclic stretching durations, confirming the NGS results. Taken together, these findings suggest that cyclical stretching can alter cardiac cell physiology by activating cardiac cell metabolism and impacting cholesterol biosynthesis signaling.
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Affiliation(s)
- Chien-Cheng Chen
- Department of Cardiology, Show Chwan Memorial Hospital, Changhua, Taiwan
| | - Tzyy-Yue Wong
- International Center for Wound Repair and Regeneration National Cheng Kung University, Tainan, Taiwan
| | - Tzu-Yun Chin
- Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan
| | - Wen-Hsien Lee
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chan-Yen Kuo
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
| | - Yi-Chiung Hsu
- Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan
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18
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Li L, Wang X, Mullins MC, Umulis DM. Evaluation of BMP-mediated patterning in a 3D mathematical model of the zebrafish blastula embryo. J Math Biol 2020; 80:505-520. [PMID: 31773243 PMCID: PMC7203969 DOI: 10.1007/s00285-019-01449-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 10/28/2019] [Indexed: 02/03/2023]
Abstract
Bone Morphogenetic Proteins (BMPs) play an important role in dorsal-ventral (DV) patterning of the early zebrafish embryo. BMP signaling is regulated by a network of extracellular and intracellular factors that impact the range and signaling of BMP ligands. Recent advances in understanding the mechanism of pattern formation support a source-sink mechanism, however it is not clear how the source-sink mechanism shapes patterns in 3D, nor how sensitive the pattern is to biophysical rates and boundary conditions along both the anteroposterior (AP) and DV axes of the embryo. We propose a new three-dimensional growing Partial Differential Equation (PDE)-based model to simulate the BMP patterning process during the blastula stage. This model provides a starting point to elucidate how different mechanisms and components work together in 3D to create and maintain the BMP gradient in the embryo. We also show how the 3D model fits the BMP signaling gradient data at multiple time points along both axes. Furthermore, sensitivity analysis of the model suggests that the spatiotemporal patterns of Chordin and BMP ligand gene expression are dominant drivers of shape in 3D and more work is needed to quantify the spatiotemporal profiles of gene and protein expression to further refine the models.
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Affiliation(s)
- Linlin Li
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, USA
| | - Xu Wang
- Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, USA
| | - Mary C Mullins
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
| | - David M Umulis
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, USA.
- Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, USA.
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19
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Sánchez-de-Diego C, Valer JA, Pimenta-Lopes C, Rosa JL, Ventura F. Interplay between BMPs and Reactive Oxygen Species in Cell Signaling and Pathology. Biomolecules 2019; 9:E534. [PMID: 31561501 PMCID: PMC6843432 DOI: 10.3390/biom9100534] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/12/2019] [Accepted: 09/24/2019] [Indexed: 12/12/2022] Open
Abstract
The integration of cell extrinsic and intrinsic signals is required to maintain appropriate cell physiology and homeostasis. Bone morphogenetic proteins (BMPs) are cytokines that belong to the transforming growth factor-β (TGF-β) superfamily, which play a key role in embryogenesis, organogenesis and regulation of whole-body homeostasis. BMPs interact with membrane receptors that transduce information to the nucleus through SMAD-dependent and independent pathways, including PI3K-AKT and MAPKs. Reactive oxygen species (ROS) are intracellular molecules derived from the partial reduction of oxygen. ROS are highly reactive and govern cellular processes by their capacity to regulate signaling pathways (e.g., NF-κB, MAPKs, KEAP1-NRF2 and PI3K-AKT). Emerging evidence indicates that BMPs and ROS interplay in a number of ways. BMPs stimulate ROS production by inducing NOX expression, while ROS regulate the expression of several BMPs. Moreover, BMPs and ROS influence common signaling pathways, including PI3K/AKT and MAPK. Additionally, dysregulation of BMPs and ROS occurs in several pathologies, including vascular and musculoskeletal diseases, obesity, diabetes and kidney injury. Here, we review the current knowledge on the integration between BMP and ROS signals and its potential applications in the development of new therapeutic strategies.
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Affiliation(s)
- Cristina Sánchez-de-Diego
- Departament de Ciències Fisiològiques, Universitat de Barcelona, Carrer Feixa Llarga s/n, 08907 L'Hospitalet Llobregat, Spain.
| | - José Antonio Valer
- Departament de Ciències Fisiològiques, Universitat de Barcelona, Carrer Feixa Llarga s/n, 08907 L'Hospitalet Llobregat, Spain.
| | - Carolina Pimenta-Lopes
- Departament de Ciències Fisiològiques, Universitat de Barcelona, Carrer Feixa Llarga s/n, 08907 L'Hospitalet Llobregat, Spain.
| | - José Luis Rosa
- Departament de Ciències Fisiològiques, Universitat de Barcelona, Carrer Feixa Llarga s/n, 08907 L'Hospitalet Llobregat, Spain.
- IDIBELL, Avinguda Granvia de l'Hospitalet 199, 08908 L'Hospitalet de Llobregat, Spain.
| | - Francesc Ventura
- Departament de Ciències Fisiològiques, Universitat de Barcelona, Carrer Feixa Llarga s/n, 08907 L'Hospitalet Llobregat, Spain.
- IDIBELL, Avinguda Granvia de l'Hospitalet 199, 08908 L'Hospitalet de Llobregat, Spain.
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Ishida M. Genetic Prediction of Atherosclerosis - Significance of Polymorphisms in Bone Morphogenetic Protein Signaling Molecule Genes. Circ J 2019; 83:709-710. [PMID: 30814434 DOI: 10.1253/circj.cj-19-0073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2024]
Affiliation(s)
- Mari Ishida
- Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University
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Ye J, Wang Z, Wang M, Xu Y, Zeng T, Ye D, Liu J, Jiang H, Lin Y, Wan J. Increased kielin/chordin-like protein levels are associated with the severity of heart failure. Clin Chim Acta 2018; 486:381-386. [PMID: 30144436 DOI: 10.1016/j.cca.2018.08.033] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 08/20/2018] [Accepted: 08/20/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND Previous studies demonstrated that the transforming growth factor (TGF) β superfamily, including TGF-βs and bone morphogenetic proteins (BMPs), plays important roles in cardiovascular diseases. The kielin/chordin-like protein (KCP) is a secreted protein that regulates the expression and function of TGF-βs and BMPs. However, the role of KCP during heart failure (HF) remains unknown. The present study aimed to investigate the cardiac expression of KCP in human failing hearts. METHODS The human failing heart samples from patients with dilated cardiomyopathy (DCM, n = 12) and ischemic cardiomyopathy (ICM, n = 12) were collected, and normal heart (n = 8) samples from unmatched donors were collected as controls. Collagen volume, KCP levels, and mRNA levels of several BMPs in left ventricles (LV) of all hearts were measured. RESULTS The KCP levels were significantly higher in human failing hearts than in normal hearts. KCP levels were positively associated with hypertrophy markers, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC). In addition, KCP levels were also positively associated with left ventricular end-diastolic dimension (LVEDD), collagen Iα and collagen IIIα expression but were negatively associated with left ventricular ejection fraction (LVEF). Furthermore, increased TGF-β1, BMP2/4/6/10 and reduced BMP7 levels were observed, and positive correlations between KCP and TGF-β1 and negative correlation between KCP and BMP2/7 were found, but not for BMP4/6/10. CONCLUSIONS KCP was closely associated with heart failure. The regulation of BMP2/7 and TGF-β1 expression may be the possible mechanisms.
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Affiliation(s)
- Jing Ye
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Zhen Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Menglong Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Yao Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Tao Zeng
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Di Ye
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Jianfang Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Huimin Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Yingzhong Lin
- Department of Cardiology, the People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China.
| | - Jun Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan 430060, China.
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New developments in mechanotransduction: Cross talk of the Wnt, TGF-β and Notch signalling pathways in reaction to shear stress. CURRENT OPINION IN BIOMEDICAL ENGINEERING 2018. [DOI: 10.1016/j.cobme.2018.03.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Herrera B, Addante A, Sánchez A. BMP Signalling at the Crossroad of Liver Fibrosis and Regeneration. Int J Mol Sci 2017; 19:ijms19010039. [PMID: 29295498 PMCID: PMC5795989 DOI: 10.3390/ijms19010039] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 12/15/2017] [Accepted: 12/18/2017] [Indexed: 12/16/2022] Open
Abstract
Bone Morphogenetic Proteins (BMPs) belong to the Transforming Growth Factor-β (TGF-β) family. Initially identified due to their ability to induce bone formation, they are now known to have multiple functions in a variety of tissues, being critical not only during development for tissue morphogenesis and organogenesis but also during adult tissue homeostasis. This review focus on the liver as a target tissue for BMPs actions, devoting most efforts to summarize our knowledge on their recently recognized and/or emerging roles on regulation of the liver regenerative response to various insults, either acute or chronic and their effects on development and progression of liver fibrosis in different pathological conditions. In an attempt to provide the basis for guiding research efforts in this field both the more solid and more controversial areas of research were highlighted.
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Affiliation(s)
- Blanca Herrera
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
| | - Annalisa Addante
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
| | - Aránzazu Sánchez
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
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Li WQ, Li XH, Du J, Zhang W, Li D, Xiong XM, Li YJ. Rutaecarpine attenuates hypoxia-induced right ventricular remodeling in rats. Naunyn Schmiedebergs Arch Pharmacol 2016; 389:757-67. [PMID: 27052575 DOI: 10.1007/s00210-016-1240-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 03/29/2016] [Indexed: 01/06/2023]
Abstract
Rutaecarpine has been shown to exhibit wide pharmacological effects in the cardiovascular system via stimulation of calcitonin gene-related peptide (CGRP) release. In the present study, the effect of rutaecarpine on hypoxia-induced right ventricular (RV) remodeling and the underlying mechanisms were evaluated. RV remodeling was induced by hypoxia (10 % O2, 3 weeks) in rats. Rats were treated with rutaecarpine (20 or 40 mg/kg) by intragastric administration. Proliferation of cardiac fibroblasts was induced by TGF-β1 (5 ng/mL) and determined by MTS and EdU incorporation method. Cardiac fibroblasts were treated with exogenous CGRP (10 or 100 nM). The concentrations of CGRP and TGF-β1 in plasma were measured by ELISA. The expression of eIF3a, p27, α-SMA, collagen-I/III, ANP, and BNP were measured by real-time PCR or western blot. Hypoxia induced an increase of right ventricle systolic pressure (RVSP), ration of RV/LV+S, and RV/tibial length in rats, while cardiac hypertrophy, apoptosis, and fibrosis were detected. The expression of ANP, BNP, α-SMA, collagen-I, collagen-III, eIF3a, and TGF-β1 was up-regulated, and the expression of p27 was down-regulated in the right ventricle of hypoxia-treated rats. The plasma concentration of CGRP was decreased and TGF-β1 was increased in hypoxia-treated rats. All of these effects induced by hypoxia were attenuated by rutaecarpine in a dose-dependent manner. In cultured cardiac fibroblasts, TGF-β1 significantly promoted the proliferation and up-regulated the expression of α-SMA and collagen-I/III, while the expression of eIF3a was up-regulated and the expression of p27 was down-regulated. The effects of TGF-β1 were attenuated by CGRP. CGRP8-37, a selective CGRP receptor antagonist, abolished the effects of CGRP. Rutaecarpine attenuates hypoxia-induced RV remodeling via stimulation of CGRP release, and the effects of rutaecarpine involve the eIF3a/p27 pathway.
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Affiliation(s)
- Wen-Qun Li
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Xiao-Hui Li
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Jie Du
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Wang Zhang
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Dai Li
- National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, Changsha, 410078, China
| | - Xiao-Ming Xiong
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Yuan-Jian Li
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
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