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Gao K, Xu D, Mu F, Zhao M, Zhang W, Tao X, Guo C, Wang J. Systems Pharmacology to Explore the Potential Mechanism of Ginseng Against Heart Failure. Rejuvenation Res 2025; 28:54-66. [PMID: 39504983 DOI: 10.1089/rej.2024.0051] [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] [Indexed: 11/08/2024] Open
Abstract
The aim of this study is to elucidate the pharmacological mechanism underlying the effects of Ginseng Radix et Rhizoma (ginseng) in heart failure (HF), providing a theoretical foundation for its clinical application. The potential mechanism of ginseng in the context of HF was investigated using systems pharmacology that combined network pharmacology, Gene Expression Omnibus (GEO) analysis, molecular docking, and experimental verification. Network pharmacology was employed to identify drug-disease targets. Core gene targets were subsequently subjected to enrichment analysis by integrating network pharmacology with GEO. Molecular docking was utilized to predict the binding affinities between identified targets and ginseng compounds. Furthermore, the therapeutic efficacy of ginseng was validated in an isoproterenol (ISO)-induced rat model of HF. The modulation of key signaling pathways by ginseng was confirmed through Western blot analysis. A total of 154 potential targets of ginseng in the treatment of HF were identified through network pharmacology analysis. The analysis of GSE71613 revealed that the PI3K-Akt pathway, reactive oxygen species, oxidative phosphorylation, MAPK signaling, and Ras signaling pathways are predominantly associated with patients with HF. By integrating the findings from network pharmacology and GEO analysis, ginsenoside Rg1 and ginsenoside Rb3 were identified as the potential components in ginseng, while FN1 and PRKAA2 were recognized as key targets involved in the PI3K-AKT and AMPK pathways, respectively. Molecular docking analysis revealed a strong affinity between the potential components and the identified core targets. In vivo experiments indicated that the extract of ginseng (EPG) significantly ameliorated ISO-induced cardiac dysfunction by improving cardiac parameters such as cardiac left ventricular internal systolic diameter, left ventricular end-diastolic volume, left ventricular end systolic volume, and left ventricular ejection fraction, while also reducing malondialdehyde production. In addition, EPG was found to enhance superoxide dismutase activity and ATP levels, while concurrently reducing the levels of interleukin (IL)-1β, IL-6, and TNF-α. The extract also reduced myocardial oxygen consumption, inflammatory cell infiltration, and the number of damaged myocardial fibers. Moreover, EPG was observed to upregulate the expression of p-PI3K, p-AKT, p-AMPK, and Bcl-2, while downregulating the expression of p-NFκB, TGF-β, and Bax. The therapeutic effects of ginseng on HF are primarily mediated through the PI3K-Akt and AMPK pathways. Ginsenoside Rg1 and ginsenoside Rb3 have been identified as potential therapeutic agents for HF.
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Affiliation(s)
- Kai Gao
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Dong Xu
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Fei Mu
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Meina Zhao
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Wei Zhang
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xingru Tao
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Chao Guo
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jingwen Wang
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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Fan S, Zhao M, Wang K, Deng Y, Yu X, Ma K, Zhang Y, Xiao H. Exercise training attenuates cardiac dysfunction induced by excessive sympathetic activation through an AMPK-KLF4-FMO2 axis. J Mol Cell Cardiol 2024; 197:136-149. [PMID: 39491669 DOI: 10.1016/j.yjmcc.2024.10.015] [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: 05/16/2024] [Revised: 10/07/2024] [Accepted: 10/28/2024] [Indexed: 11/05/2024]
Abstract
Cardiovascular diseases (CVDs) are a leading cause of mortality worldwide and are associated with an overactivated sympathetic system. Although exercise training has shown promise in mitigating sympathetic stress-induced cardiac remodeling, the precise mechanisms remain elusive. Here, we demonstrate that exercise significantly upregulates cardiac flavin-containing monooxygenase 2 (FMO2) expression. Notably, we find that exercise training effectively counteracts sympathetic overactivation-induced cardiac dysfunction and fibrosis by enhancing FMO2 expression via adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. Functional investigations employing FMO2 knockdown with adeno-associated virus 9 (AAV9) underscore the necessity for FMO2 expression to protect the heart during exercise in vivo. Furthermore, we identify the krüppel-like factor 4 (KLF4) as a transcriptional mediator of FMO2 that is crucial for the mechanism through which AMPK activation protects against sympathetic overactivation-induced cardiac dysfunction and fibrosis. Taken together, our study reveals a cardioprotective mechanism for exercise training through an AMPK-KLF4-FMO2 signaling pathway that underscores how exercise alleviates cardiac dysfunction induced by excessive sympathetic activation.
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Affiliation(s)
- Shiyu Fan
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University School of Medicine, Shihezi 832003, China
| | - Mingming Zhao
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Institute of Advanced Clinical Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Haihe Laboratory of Cell Ecosystem, Beijing 100191, China
| | - Kang Wang
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Institute of Advanced Clinical Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Haihe Laboratory of Cell Ecosystem, Beijing 100191, China
| | - Yawen Deng
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Institute of Advanced Clinical Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Haihe Laboratory of Cell Ecosystem, Beijing 100191, China
| | - Xiaoyue Yu
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Institute of Advanced Clinical Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Haihe Laboratory of Cell Ecosystem, Beijing 100191, China
| | - Ketao Ma
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University School of Medicine, Shihezi 832003, China
| | - Youyi Zhang
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Institute of Advanced Clinical Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Haihe Laboratory of Cell Ecosystem, Beijing 100191, China.
| | - Han Xiao
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University School of Medicine, Shihezi 832003, China; Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Institute of Advanced Clinical Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Haihe Laboratory of Cell Ecosystem, Beijing 100191, China.
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3
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Tian Y, Liu R, Yang Q, Zhang J, Liu Z, Dong B, Gao J, Wan L. Carnosol suppresses cardiomyocyte hypertrophy via promoting the activation of AMPK pathway. Biochem Biophys Res Commun 2024; 729:150343. [PMID: 38986259 DOI: 10.1016/j.bbrc.2024.150343] [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: 05/14/2024] [Revised: 06/22/2024] [Accepted: 07/02/2024] [Indexed: 07/12/2024]
Abstract
Pathological cardiac hypertrophy is associated with adverse cardiovascular events and can gradually lead to heart failure, arrhythmia, and even sudden death. However, the current development of treatment strategies has been unsatisfactory. Therefore, it is of great significance to find new and effective drugs for the treatment of myocardial hypertrophy. We found that carnosol can inhibit myocardial hypertrophy induced by PE stimulation, and the effect is very significant at 5 μM. Moreover, we demonstrated that 50 mg/kg of carnosol protect against cardiac hypertrophy and fibrosis induced by TAC surgery in mice. Mechanically, we proved that the inhibitory effect of carnosol on cardiac hypertrophy depends on its regulation on the phosphorylation activation of AMPK. In conclusion, our study suggested that carnosol may be a novel drug component for the treatment of pathological cardiac hypertrophy.
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Affiliation(s)
- Yu Tian
- Department of Neurology, Huanggang Central hospital of Yangtze University, Huanggang, China
| | - Ruhan Liu
- Department of Combine Traditional Chinese and Western Medicine, Huanggang Central Hospital of Yangtze University, Huanggang, China
| | - Qin Yang
- Department of Cardiovascular Surgery, Huanggang Central Hospital of Yangtze University, Huanggang, China; Huanggang Institute of Translational Medicine, Huanggang, China
| | - Jianqing Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhen Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Bizhen Dong
- Huanggang Institute of Translational Medicine, Huanggang, China
| | - Ju Gao
- Department of Neurology, Huanggang Central hospital of Yangtze University, Huanggang, China.
| | - Lipeng Wan
- Department of Emergency Medicine, Huanggang Central Hospital of Yangtze University, Huanggang, China.
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Asar TO, Al-Abbasi FA, Sheikh RA, Zeyadi MAM, Nadeem MS, Naqvi S, Kumar V, Anwar F. Metformin's dual impact on Gut microbiota and cardiovascular health: A comprehensive analysis. Biomed Pharmacother 2024; 178:117128. [PMID: 39079259 DOI: 10.1016/j.biopha.2024.117128] [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: 06/03/2024] [Revised: 07/09/2024] [Accepted: 07/10/2024] [Indexed: 08/25/2024] Open
Abstract
Cardiovascular diseases (CVD) cause significant global morbidity, mortality and public health burden annually. CVD alters richness, diversity, and composition of Gut microbiota along with RAS and histopathological differences. Present study explores Metformin role in mitigating doxorubicin induced cardiovascular toxicity/remodeling. Animals were divided into 4 groups with n=6: Group I (N. Control) free access to diet and water; Group II (MET. Control) on oral Metformin (250 mg/kg) daily; Group III (DOX. Control) alternate day intraperitoneal Doxorubicin (3 mg/kg) totaling 18 mg/kg; Group IV (DOX. MET. Control) received both daily oral Metformin (250 mg/kg) and alternate day Doxorubicin (3 mg/kg). Gut microbial analysis was made from stool before animals were sacrificed for biochemical and histopathological analysis. Significant alterations were observed in ɑ and β-diversity with new genus from Firmicutes, specifically Clostridia_UCG-014, Eubacterium ruminantium, and Tunicibacter, were prevalent in both the DOX. Control and DOX.MET groups. Proteobacteria, represented by Succinivibrio, were absent in all groups. Additionally, Parabacteroides from the Bacteroidia phylum was absent in all groups except the N. control. In the DOX.MET Control group, levels of Angiotensin II ( 7.75± 0.49 nmol/min, p<0.01) and Renin (2.60±0.26 ng/ml/hr) were significantly reduced. Conversely, levels of CK-MB, Fibrinogen, Troponin, CRP ( p < 0.0001), and TNFɑ (p < 0.05) were elevated. Histopathological examination revealed substantial cardiac changes, including Fibrinogen and fat deposition and eosinophilic infiltration, as well as liver damage characterized by binucleated cells and damaged hepatocytes, along with altered renal tissues in the DOX.MET.Control group. The findings suggest that MET. significantly modifies gut microbiota, particularly impacting the Firmicutes and Proteobacteria phyla. The reduction in Angiotensin II levels, alongside increased inflammatory markers and myocardial damage, highlights the complex interactions and potential adverse effects associated with MET therapy on cardiovascular health.
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Affiliation(s)
- Turky Omar Asar
- Department of Biology, College of Science and Arts at Alkamil, University of Jeddah, Jeddah, Saudi Arabia.
| | - Fahad A Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - Ryan Adnan Sheikh
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | | | - Muhammad Shahid Nadeem
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - Salma Naqvi
- Department of Biomedical Sciences, College of Medicine, Gulf Medical University, Ajman, United Arab Emirates.
| | - Vikas Kumar
- Natural Product Discovery Laboratory, Department of Pharmaceutical Sciences, Shalom Institute of Health and Allied Sciences, SHUATS, Prayagraj, India.
| | - Firoz Anwar
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
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Wu Y, Zou Y, Song C, Cao K, Cai K, Chen S, Zhang Z, Geng D, Zhang N, Feng H, Tang M, Li Z, Sun G, Zhang Y, Sun Y, Zhang Y. The role of serine/threonine protein kinases in cardiovascular disease and potential therapeutic methods. Biomed Pharmacother 2024; 177:117093. [PMID: 38971012 DOI: 10.1016/j.biopha.2024.117093] [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: 04/17/2024] [Revised: 07/02/2024] [Accepted: 07/02/2024] [Indexed: 07/08/2024] Open
Abstract
Protein phosphorylation is an important link in a variety of signaling pathways, and most of the important life processes in cells involve protein phosphorylation. Based on the amino acid residues of phosphorylated proteins, protein kinases can be categorized into the following families: serine/threonine protein kinases, tyrosine-specific protein kinases, histidine-specific protein kinases, tryptophan kinases, and aspartate/glutamyl protein kinases. Of all the protein kinases, most are serine/threonine kinases, where serine/threonine protein kinases are protein kinases that catalyze the phosphorylation of serine or threonine residues on target proteins using ATP as a phosphate donor. The current socially accepted classification of serine/threonine kinases is to divide them into seven major groups: protein kinase A, G, C (AGC), CMGC, Calmodulin-dependent protein kinase (CAMK), Casein kinase (CK1), STE, Tyrosine kinase (TKL) and others. After decades of research, a preliminary understanding of the specific classification and respective functions of serine/threonine kinases has entered a new period of exploration. In this paper, we review the literature of the previous years and introduce the specific signaling pathways and related therapeutic modalities played by each of the small protein kinases in the serine/threonine protein kinase family, respectively, in some common cardiovascular system diseases such as heart failure, myocardial infarction, ischemia-reperfusion injury, and diabetic cardiomyopathy. To a certain extent, the current research results, including molecular mechanisms and therapeutic methods, are fully summarized and a systematic report is made for the prevention and treatment of cardiovascular diseases in the future.
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Affiliation(s)
- Yanjiao Wu
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Yuanming Zou
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Chunyu Song
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Kexin Cao
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Kexin Cai
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Shuxian Chen
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Zhaobo Zhang
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Danxi Geng
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Naijin Zhang
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China; Institute of health sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning Province 110001, People's Republic of China; Key Laboratory of Reproductive and Genetic Medicine (China Medical University), National Health Commission, Shenyang 110004, China.
| | - Hao Feng
- Department of Ophthalmology, The First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China.
| | - Man Tang
- Department of clinical pharmacology, College of Pharmacy, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning Province 110001, People's Republic of China.
| | - Zhao Li
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China.
| | - Guozhe Sun
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China.
| | - Yixiao Zhang
- Department of Urology Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, Liaoning Province 110004, People's Republic of China.
| | - Yingxian Sun
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China; Institute of health sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning Province 110001, People's Republic of China; Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning Province 110001, People's Republic of China.
| | - Ying Zhang
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China; Institute of health sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning Province 110001, People's Republic of China.
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Zhao Y, Du B, Chakraborty P, Denham N, Massé S, Lai PF, Azam MA, Billia F, Thavendiranathan P, Abdel‐Qadir H, Lopaschuk GD, Nanthakumar K. Impaired Cardiac AMPK (5'-Adenosine Monophosphate-Activated Protein Kinase) and Ca 2+-Handling, and Action Potential Duration Heterogeneity in Ibrutinib-Induced Ventricular Arrhythmia Vulnerability. J Am Heart Assoc 2024; 13:e032357. [PMID: 38842296 PMCID: PMC11255774 DOI: 10.1161/jaha.123.032357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 04/03/2024] [Indexed: 06/07/2024]
Abstract
BACKGROUND We recently demonstrated that acute administration of ibrutinib, a Bruton's tyrosine kinase inhibitor used in chemotherapy for blood malignancies, increases ventricular arrhythmia (VA) vulnerability. A pathway of ibrutinib-induced vulnerability to VA that can be modulated for cardioprotection remains unclear. METHODS AND RESULTS The effects of ibrutinib on cardiac electrical activity and Ca2+ dynamics were investigated in Langendorff-perfused hearts using optical mapping. We also conducted Western blotting analysis to evaluate the impact of ibrutinib on various regulatory and Ca2+-handling proteins in rat cardiac tissues. Treatment with ibrutinib (10 mg/kg per day) for 4 weeks was associated with an increased VA inducibility (72.2%±6.3% versus 38.9±7.0% in controls, P<0.002) and shorter action potential durations during pacing at various frequencies (P<0.05). Ibrutinib also decreased heart rate thresholds for beat-to-beat duration alternans of the cardiac action potential (P<0.05). Significant changes in myocardial Ca2+ transients included lower amplitude alternans ratios (P<0.05), longer times-to-peak (P<0.05), and greater spontaneous intracellular Ca2+ elevations (P<0.01). We also found lower abundance and phosphorylation of myocardial AMPK (5'-adenosine monophosphate-activated protein kinase), indicating reduced AMPK activity in hearts after ibrutinib treatment. An acute treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside ameliorated abnormalities in action potential and Ca2+ dynamics, and significantly reduced VA inducibility (37.1%±13.4% versus 72.2%±6.3% in the absence of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, P<0.05) in hearts from ibrutinib-treated rats. CONCLUSIONS VA vulnerability inflicted by ibrutinib may be mediated in part by an impairment of myocardial AMPK activity. Pharmacological activation of AMPK may be a protective strategy against ibrutinib-induced cardiotoxicity.
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MESH Headings
- Animals
- Adenine/analogs & derivatives
- Adenine/pharmacology
- Piperidines/pharmacology
- Action Potentials/drug effects
- Pyrimidines/pharmacology
- AMP-Activated Protein Kinases/metabolism
- Pyrazoles/pharmacology
- Male
- Arrhythmias, Cardiac/chemically induced
- Arrhythmias, Cardiac/metabolism
- Arrhythmias, Cardiac/physiopathology
- Arrhythmias, Cardiac/prevention & control
- Protein Kinase Inhibitors/pharmacology
- Heart Rate/drug effects
- Isolated Heart Preparation
- Calcium/metabolism
- Rats
- Disease Models, Animal
- Rats, Sprague-Dawley
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/enzymology
- Myocytes, Cardiac/pathology
- Calcium Signaling/drug effects
- Time Factors
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Affiliation(s)
- Yanan Zhao
- The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General HospitalTorontoCanada
- Toronto General Hospital Research InstituteTorontoCanada
- China‐Japan Union Hospital of Jilin UniversityChangchunChina
| | - Beibei Du
- The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General HospitalTorontoCanada
- Toronto General Hospital Research InstituteTorontoCanada
- China‐Japan Union Hospital of Jilin UniversityChangchunChina
| | - Praloy Chakraborty
- The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General HospitalTorontoCanada
- Toronto General Hospital Research InstituteTorontoCanada
| | - Nathan Denham
- The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General HospitalTorontoCanada
- Toronto General Hospital Research InstituteTorontoCanada
| | - Stéphane Massé
- The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General HospitalTorontoCanada
- Toronto General Hospital Research InstituteTorontoCanada
| | - Patrick F.H. Lai
- The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General HospitalTorontoCanada
- Toronto General Hospital Research InstituteTorontoCanada
| | - Mohammed Ali Azam
- The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General HospitalTorontoCanada
- Toronto General Hospital Research InstituteTorontoCanada
| | - Filio Billia
- Toronto General Hospital Research InstituteTorontoCanada
- Ted Rogers Centre for Heart ResearchTorontoCanada
| | | | - Husam Abdel‐Qadir
- Toronto General Hospital Research InstituteTorontoCanada
- Ted Rogers Centre for Heart ResearchTorontoCanada
| | | | - Kumaraswamy Nanthakumar
- The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General HospitalTorontoCanada
- Toronto General Hospital Research InstituteTorontoCanada
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7
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Barone M. Angiotensin-converting enzyme 2 and AMPK/mTOR pathway in the treatment of liver fibrosis: Should we consider further implications? World J Gastroenterol 2024; 30:2391-2396. [PMID: 38764773 PMCID: PMC11099390 DOI: 10.3748/wjg.v30.i18.2391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/09/2024] [Accepted: 04/17/2024] [Indexed: 05/11/2024] Open
Abstract
This editorial contains comments on the article by Zhao et al in print in the World Journal of Gastroenterology. The mechanisms responsible for hepatic fibrosis are also involved in cancerogenesis. Here, we recapitulated the complexity of the renin-angiotensin system, discussed the role of hepatic stellate cell (HSC) autophagy in liver fibrogenesis, and analyzed the possible implications in the development of hepatocarcinoma (HCC). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers definitively contribute to reducing hepatic fibrogenesis, whereas their involvement in HCC is more evident in experimental conditions than in human studies. Angiotensin-converting enzyme 2 (ACE2), and its product Angiotensin (Ang) 1-7, not only regulate HSC autophagy and liver fibrosis, but they also represent potential targets for unexplored applications in the field of HCC. Finally, ACE2 overexpression inhibits HSC autophagy through the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. In this case, Ang 1-7 acts binding to the MasR, and its agonists could modulate this pathway. However, since AMPK utilizes different targets to suppress the mTOR downstream complex mTOR complex 1 effectively, we still need to unravel the entire pathway to identify other potential targets for the therapy of fibrosis and liver cancer.
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Affiliation(s)
- Michele Barone
- Section of Gastroenterology, Department of Precision and Regenerative Medicine - Jonian Area- University of Bari, Bari 70124, Italy
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8
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Wang AH, Ma HY, Yi YL, Zhu SJ, Yu ZW, Zhu J, Mei S, Bahetibike S, Lu YQ, Huang LT, Yang RY, Rui-Wang, Xiao SL, Qi R. Oleanolic acid derivative alleviates cardiac fibrosis through inhibiting PTP1B activity and regulating AMPK/TGF-β/Smads pathway. Eur J Pharmacol 2023; 960:176116. [PMID: 38059443 DOI: 10.1016/j.ejphar.2023.176116] [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: 02/22/2023] [Revised: 10/03/2023] [Accepted: 10/12/2023] [Indexed: 12/08/2023]
Abstract
Cardiac fibrosis (CF) in response to persistent exogenous stimuli or myocardial injury results in cardiovascular diseases (CVDs). Protein tyrosine phosphatase 1B (PTP1B) can promote collagen deposition through regulating AMPK/TGF-β/Smads signaling pathway, and PTP1B knockout improves cardiac dysfunction against overload-induced heart failure. Oleanolic acid (OA) has been proven to be an inhibitor of PTP1B, and its anti-cardiac remodeling effects have been validated in different mouse models. To improve the bioactivity of OA and to clarify whether OA derivatives with stronger inhibition of PTP1B activity have greater prevention of cardiac remodeling than OA, four new OA derivatives were synthesized and among them, we found that compound B had better effects than OA in inhibiting cardiac fibrosis both in vivo in the isoproterenol (ISO)-induced mouse cardiac fibrosis and in vitro in the TGF-β/ISO-induced 3T3 cells. Combining with the results of molecular docking, surface plasmon resonance and PTP1B activity assay, we reported that OA and compound B directly bound to PTP1B and inhibited its activity, and that compound B showed comparable binding capability but stronger inhibitory effect on PTP1B activity than OA. Moreover, compound B presented much greater effects on AMPK activation and TGF-β/Smads inhibition than OA. Taken together, OA derivative compound B more significantly alleviated cardiac fibrosis than OA through much greater inhibition of PTP1B activity and thus much stronger regulation of AMPK/TGF-β/Smads signaling pathway.
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Affiliation(s)
- An-Hui Wang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China
| | - Hao-Yue Ma
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China
| | - Yan-Liang Yi
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Su-Jie Zhu
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Zhe-Wei Yu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Jie Zhu
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Si Mei
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China
| | - Shamuha Bahetibike
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China
| | - You-Qun Lu
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China
| | - Li-Ting Huang
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Ruo-Yao Yang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China
| | - Rui-Wang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China
| | - Su-Long Xiao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
| | - Rong Qi
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China.
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9
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Liu C, Guo X, Zhou Y, Wang H. AMPK Signalling Pathway: A Potential Strategy for the Treatment of Heart Failure with Chinese Medicine. J Inflamm Res 2023; 16:5451-5464. [PMID: 38026240 PMCID: PMC10676094 DOI: 10.2147/jir.s441597] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 11/10/2023] [Indexed: 12/01/2023] Open
Abstract
Heart failure (HF) is a complex clinical syndrome that represents the advanced stage of cardiovascular disease, characterized by systolic and diastolic dysfunction of the heart. Despite continuous updates in HF treatment drugs, the morbidity and mortality rates remain high, necessitating ongoing exploration for new therapeutic targets. Adenosine monophosphate-activated protein kinase (AMPK) is the serine/threonine protein kinase which responds to adenosine monophosphate (AMP) levels.Activation of AMPK shifts cellular metabolic patterns from synthesis to catabolism, enhancing energy metabolism in pathological conditions such as inflammation, ischemia, obesity, and aging. Numerous studies have identified AMPK as a vital target for HF treatment, with herbal monomers/extracts and compounds affecting key signaling factors including rapamycin targeting protein (mTOR), silencing regulator protein 1 (SIRT1), nuclear transcription factor E2-related factor 2 (Nrf2), and nuclear transcription factor-κB (NF-κB) through regulation of the AMPK signaling pathway.This modulation can achieve the effects of improving metabolism, autophagy, reducing oxidative stress and inflammatory response in the treatment of heart failure, with the advantages of multi-targeting, comprehensive action and low toxicity.The modulation of the AMPK pathway by Traditional Chinese Medicine (TCM) has emerged as a crucial research direction for the prevention and treatment of HF, but a systematic summary and generalization in this field is lacking. This article provides an overview of the composition, regulation, and mechanism of the AMPK signaling pathway's influence on HF, as well as a summary of current research on the regulation of the AMPK pathway by TCM for HF prevention and treatment. The aim is to serve as a reference for the diagnosis and treatment of HF using TCM and the development of new drugs.
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Affiliation(s)
- Changxing Liu
- First Clinical Medical School, Heilongjiang University of Chinese Medicine, Harbin, 150040, People’s Republic of China
| | - Xinyi Guo
- Clinical Medical School, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, People’s Republic of China
| | - Yabin Zhou
- Department of Cardiology, The First Hospital of Heilongjiang University of Chinese Medicine, Harbin, 150040, People’s Republic of China
| | - He Wang
- Department of Cardiology, The First Hospital of Heilongjiang University of Chinese Medicine, Harbin, 150040, People’s Republic of China
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10
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Liu J, Lu J, Zhang L, Liu Y, Zhang Y, Gao Y, Yuan X, Xiang M, Tang Q. The combination of exercise and metformin inhibits TGF-β1/Smad pathway to attenuate myocardial fibrosis in db/db mice by reducing NF-κB-mediated inflammatory response. Biomed Pharmacother 2023; 157:114080. [PMID: 36481406 DOI: 10.1016/j.biopha.2022.114080] [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: 10/11/2022] [Revised: 11/25/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
Persistent hyperglycemia increases inflammation response, promoting the development of myocardial fibrosis. Based on our previous research that exercise and metformin alone or their combination intervention could attenuate myocardial fibrosis in db/db mice, this study aimed to further explore the underlying mechanisms by which these interventions attenuate myocardial fibrosis in early diabetic cardiomyopathy. Forty BKS db/db mice were randomly divided into four groups. Diabetic db/db mice without intervention were in the C group. Aerobic exercise (7-12 m/min, 30-40 min/day, 5 days/week) was performed in the E group. Metformin (300 mg·kg-1·day-1) was administered in the M group. Exercise combined with metformin was performed in the EM group. Ten wild-type mice were in the WT group. All interventions were administered for 8 weeks. Results showed that the expression levels of α-SMA, Collagen I, and Collagen III were increased in 16-week-old db/db mice, which were reversed by exercise and metformin alone or their combination intervention. All interventions attenuated the level of TGF-β1/Smad2/3 pathway-related proteins and reduced the expression of inflammatory signaling pathway-regulated proteins TNF-α, p-IκBα/IκBα, and p-NF-κB p65/NF-κB p65 in db/db mice. Furthermore, metformin intervention inhibited HNF4α expression via AMPK activation, whereas exercise intervention increased the expression of IL-6 instead of activating AMPK. In conclusion, exercise and metformin alone or their combination intervention inhibited the TGF-β1/Smad pathway to attenuate myocardial fibrosis by reducing NF-κB-mediated inflammatory response. The anti-fibrotic effects were regulated by metformin-activated AMPK or exercise-induced elevation of IL-6, whereas their combination intervention showed no synergistic effects.
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Affiliation(s)
- Jingjing Liu
- School of Sports and Health, Nanjing Sport Institute, Nanjing 210014, China.
| | - Jiao Lu
- School of Sports and Health, Nanjing Sport Institute, Nanjing 210014, China; Jiangsu Collaborative Innovation Center for Sport and Health Project, Nanjing 210014, China.
| | - Liumei Zhang
- School of Sports and Health, Nanjing Sport Institute, Nanjing 210014, China.
| | - Yuting Liu
- School of Sports and Health, Nanjing Sport Institute, Nanjing 210014, China.
| | - Yuan Zhang
- School of Sports and Health, Nanjing Sport Institute, Nanjing 210014, China.
| | - Yaran Gao
- School of Sports and Health, Nanjing Sport Institute, Nanjing 210014, China.
| | - Xinmeng Yuan
- School of Sports and Health, Nanjing Sport Institute, Nanjing 210014, China.
| | - Mengqi Xiang
- School of Sports and Health, Nanjing Sport Institute, Nanjing 210014, China.
| | - Qiang Tang
- School of Sports and Health, Nanjing Sport Institute, Nanjing 210014, China; Jiangsu Collaborative Innovation Center for Sport and Health Project, Nanjing 210014, China.
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11
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Phadwal K, Koo E, Jones RA, Forsythe RO, Tang K, Tang Q, Corcoran BM, Caporali A, MacRae VE. Metformin protects against vascular calcification through the selective degradation of Runx2 by the p62 autophagy receptor. J Cell Physiol 2022; 237:4303-4316. [PMID: 36166694 DOI: 10.1002/jcp.30887] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 09/04/2022] [Accepted: 09/06/2022] [Indexed: 11/09/2022]
Abstract
Vascular calcification is associated with aging, type 2 diabetes, and atherosclerosis, and increases the risk of cardiovascular morbidity and mortality. It is an active, highly regulated process that resembles physiological bone formation. It has previously been established that pharmacological doses of metformin alleviate arterial calcification through adenosine monophosphate-activated protein kinase (AMPK)-activated autophagy, however the specific pathway remains elusive. In the present study we hypothesized that metformin protects against arterial calcification through the direct autophagic degradation of runt-related transcription factor 2 (Runx2). Calcification was blunted in vascular smooth muscle cells (VSMCs) by metformin in a dose-dependent manner (0.5-1.5 mM) compared to control cells (p < 0.01). VSMCs cultured under high-phosphate (Pi) conditions in the presence of metformin (1 mM) showed a significant increase in LC3 puncta following bafilomycin-A1 (Baf-A; 5 nM) treatment compared to control cells (p < 0.001). Furthermore, reduced expression of Runx2 was observed in the nuclei of metformin-treated calcifying VSMCs (p < 0.0001). Evaluation of the functional role of autophagy through Atg3 knockdown in VSMCs showed aggravated Pi-induced calcification (p < 0.0001), failure to induce autophagy (punctate LC3) (p < 0.001) and increased nuclear Runx2 expression (p < 0.0001) in VSMCs cultured under high Pi conditions in the presence of metformin (1 mM). Mechanistic studies employing three-way coimmunoprecipitation with Runx2, p62, and LC3 revealed that p62 binds to both LC3 and Runx2 upon metformin treatment in VSMCs. Furthermore, immunoblotting with LC3 revealed that Runx2 specifically binds with p62 and LC3-II in metformin-treated calcified VSMCs. Lastly, we investigated the importance of the autophagy pathway in vascular calcification in a clinical setting. Ex vivo clinical analyses of calcified diabetic lower limb artery tissues highlighted a negative association between Runx2 and LC3 in the vascular calcification process. These studies suggest that exploitation of metformin and its analogues may represent a novel therapeutic strategy for clinical intervention through the induction of AMPK/Autophagy Related 3 (Atg3)-dependent autophagy and the subsequent p62-mediated autophagic degradation of Runx2.
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Affiliation(s)
- Kanchan Phadwal
- The Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK
| | - Eve Koo
- The Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK
| | - Ross A Jones
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
- Euan MacDonald Centre for Motor Neurone Disease Research, The University of Edinburgh, Edinburgh, UK
| | - Rachael O Forsythe
- Centre for Cardiovascular Science, The Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK
- Department of Vascular Surgery, Edinburgh Royal Infirmary, Edinburgh, UK
| | - Keyi Tang
- The Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK
| | - Qiyu Tang
- The Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK
| | - Brendan M Corcoran
- The Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK
| | - Andrea Caporali
- Centre for Cardiovascular Science, The Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Vicky E MacRae
- The Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK
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12
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Bu Y, Peng M, Tang X, Xu X, Wu Y, Chen AF, Yang X. Protective effects of metformin in various cardiovascular diseases: Clinical evidence and AMPK-dependent mechanisms. J Cell Mol Med 2022; 26:4886-4903. [PMID: 36052760 PMCID: PMC9549498 DOI: 10.1111/jcmm.17519] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/22/2022] [Accepted: 07/29/2022] [Indexed: 11/29/2022] Open
Abstract
Metformin, a well-known AMPK agonist, has been widely used as the first-line drug for treating type 2 diabetes. There had been a significant concern regarding the use of metformin in people with cardiovascular diseases (CVDs) due to its potential lactic acidosis side effect. Currently growing clinical and preclinical evidence indicates that metformin can lower the incidence of cardiovascular events in diabetic patients or even non-diabetic patients beyond its hypoglycaemic effects. The underlying mechanisms of cardiovascular benefits of metformin largely involve the cellular energy sensor, AMPK, of which activation corrects endothelial dysfunction, reduces oxidative stress and improves inflammatory response. In this minireview, we summarized the clinical evidence of metformin benefits in several widely studied cardiovascular diseases, such as atherosclerosis, ischaemic/reperfusion injury and arrhythmia, both in patients with or without diabetes. Meanwhile, we highlighted the potential AMPK-dependent mechanisms in in vitro and/or in vivo models.
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Affiliation(s)
- Yizhi Bu
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Mei Peng
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Xinyi Tang
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Xu Xu
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Yifeng Wu
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Alex F Chen
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China.,Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoping Yang
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
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13
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Chen R, Huang L, Zheng W, Zhang M, Xin Z, Liu L, Chen Z. Lactoferrin ameliorates myocardial fibrosis by inhibiting inflammatory response via the AMPK/NF-κB pathway in aged mice. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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14
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Han Q, Zheng T, Zhang L, Wu N, Liang J, Wu H, Li G. Metformin loaded injectable silk fibroin microsphere for the treatment of spinal cord injury. JOURNAL OF BIOMATERIALS SCIENCE. POLYMER EDITION 2022; 33:747-768. [PMID: 34865608 DOI: 10.1080/09205063.2021.2014113] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The repair of spinal cord injury is a great challenge in clinical. Improving the microenvironment of the injured site is the key strategy for accelerating axon regeneration and synaptic formation. Herein, a kind of silk fibroin microspheres functionalized by metformin through dopamine was developed using water-in-oil emulsification-diffusion method and surface modification technique, and the effect on cortical neuron was evaluated. The results showed that the microspheres showed a uniform size distribution with the diameter of around 60 μm and a concave structure. Moreover, the microspheres possessed good injectability and stability. In addition, the metformin could be successfully immobilized in the silk fibroin microspheres. The cell culture results displayed that the growth and morphology of cortical neurons on the microspheres with metformin concentration of 5 mg/mL and 10 mg/mL were obviously better than that on other samples. Notably, the spread area of single cortical cell on silk fibroin microspheres was increased with the ascending metformin concentration. Therefore, the results indicated that the metformin loaded silk fibroin microsphere could obviously improve the growth and spreading behavior of cortical neuron. The study may provide an important experimental basis for the development of drug loaded injectable biomaterials scaffolds for the treatment of spinal cord injury and have great potential for spinal cord regeneration.
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Affiliation(s)
- Qi Han
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong, P.R. China.,Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, P.R. China.,NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, P.R. China
| | - Tiantian Zheng
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong, P.R. China.,Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, P.R. China.,NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, P.R. China
| | - Linhui Zhang
- School of Medical, Nantong University, Nantong, P.R. China
| | - Ningling Wu
- School of Medical, Nantong University, Nantong, P.R. China
| | - Jiaqi Liang
- School of Medical, Nantong University, Nantong, P.R. China
| | - Hong Wu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong, P.R. China.,Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, P.R. China.,NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, P.R. China
| | - Guicai Li
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong, P.R. China.,Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, P.R. China.,NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, P.R. China
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15
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Metformin: Expanding the Scope of Application-Starting Earlier than Yesterday, Canceling Later. Int J Mol Sci 2022; 23:ijms23042363. [PMID: 35216477 PMCID: PMC8875586 DOI: 10.3390/ijms23042363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/29/2022] [Accepted: 02/18/2022] [Indexed: 12/15/2022] Open
Abstract
Today the area of application of metformin is expanding, and a wealth of data point to its benefits in people without carbohydrate metabolism disorders. Already in the population of people leading an unhealthy lifestyle, before the formation of obesity and prediabetes metformin smooths out the adverse effects of a high-fat diet. Being prescribed at this stage, metformin will probably be able to, if not prevent, then significantly reduce the progression of all subsequent metabolic changes. To a large extent, this review will discuss the proofs of the evidence for this. Another recent important change is a removal of a number of restrictions on its use in patients with heart failure, acute coronary syndrome and chronic kidney disease. We will discuss the reasons for these changes and present a new perspective on the role of increasing lactate in metformin therapy.
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16
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Liu Q, Wang R, Ma N, Wang C, Chen W. Telmisartan inhibits bladder smooth muscle fibrosis in neurogenic bladder rats. Exp Ther Med 2022; 23:216. [PMID: 35126719 PMCID: PMC8796288 DOI: 10.3892/etm.2022.11140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 12/07/2021] [Indexed: 12/15/2022] Open
Abstract
Hypertension is associated with bladder symptoms. The present study investigated whether an angiotensin receptor blocker could improve the symptoms and pathological changes associated with a neurogenic bladder (NB). A Sprague-Dawley rat model of NB was constructed. Rats in the sham and model groups were gavaged with saline, and rats in the treatment group were gavaged with telmisartan. Urodynamic parameters, including maximum cystometric capacity, residual urine volume, bladder wet weight, bladder compliance and detrusor pressure, were detected. Masson and H&E staining were performed to assess bladder fibrosis and histopathological changes. The expression levels of basic fibroblast growth factor (bFGF), TGF-β1, Collagen I, Collagen III, and α-smooth muscle actin (α-SMA) were also measured by reverse transcription-quantitative PCR, western blotting and immunohistochemistry. The model rats exhibited symptoms and pathological changes associated with NB. Treatment with telmisartan reduced maximum cystometric capacity, residual urine volume, bladder compliance and bladder wet weight, and increased detrusor pressure in model rats. The tissue staining results showed that telmisartan exerted an antifibrotic effect. In addition, telmisartan inhibited the expression of bFGF, TGF-β1, Collagen I, Collagen III and α-SMA in model rats. Therefore, the results of the present study indicated that telmisartan may serve as a potential therapeutic agent for NB.
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Affiliation(s)
- Qian Liu
- Department of Pediatric Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Ruoyi Wang
- Department of Pediatric Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Nan Ma
- Department of Pediatric Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Chuntian Wang
- Department of Pediatric Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Weixiu Chen
- Department of Pediatric Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
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17
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Zhou HM, Ti Y, Wang H, Shang YY, Liu YP, Ni XN, Wang D, Wang ZH, Zhang W, Zhong M. Cell death-inducing DFFA-like effector C/CIDEC gene silencing alleviates diabetic cardiomyopathy via upregulating AMPKa phosphorylation. FASEB J 2021; 35:e21504. [PMID: 33913563 DOI: 10.1096/fj.202002562r] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 02/17/2021] [Accepted: 02/19/2021] [Indexed: 11/11/2022]
Abstract
Cell death-inducing DFFA-like effector C (CIDEC) is responsible for metabolic disturbance and insulin resistance, which are considered to be important triggers in the development of diabetic cardiomyopathy (DCM). To investigate whether CIDEC plays a critical role in DCM, DCM rat model was induced by a high-fat diet and a single injection of low-dose streptozotocin (27.5 mg/kg). DCM rats showed severe metabolic disturbance, insulin resistance, myocardial hypertrophy, interstitial fibrosis, ectopic lipid deposition, inflammation and cardiac dysfunction, accompanied by CIDEC elevation. With CIDEC gene silencing, the above pathophysiological characteristics were significantly ameliorated accompanied by significant improvements in cardiac function in DCM rats. Enhanced AMP-activated protein kinase (AMPK) α activation was involved in the underlying pathophysiological molecular mechanisms. To further explore the underlying mechanisms that CIDEC facilitated collagen syntheses in vitro, insulin-resistant cardiac fibroblast (CF) model was induced by high glucose (15.5 mmol/L) and high insulin (104 μU/mL). We observed that insulin-resistant stimulation dramatically raised CIDEC expression and promoted CIDEC nuclear translocation in CFs. Meanwhile, AMPKα2 was observed to distribute almost completely inside CF nucleus. The results further proved that CIDEC biochemically interacted and co-localized with AMPKα2 rather than AMPKα1 in CF nucleus, which provided a novel mechanism of CIDEC in promoting collagen syntheses. This study suggested that CIDEC gene silencing alleviates DCM via AMPKα signaling both in vivo and in vitro, implicating CIDEC may be a promising target for treatment of human DCM.
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Affiliation(s)
- Hui-Min Zhou
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yun Ti
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Hui Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Geriatric Medicines, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yuan-Yuan Shang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ya-Peng Liu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiao-Ning Ni
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Di Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zhi-Hao Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong key Laboratory of Cardiovascular Proteomics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wei Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ming Zhong
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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18
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Elrashidy RA, Ibrahim SE. Cinacalcet as a surrogate therapy for diabetic cardiomyopathy in rats through AMPK-mediated promotion of mitochondrial and autophagic function. Toxicol Appl Pharmacol 2021; 421:115533. [PMID: 33848515 DOI: 10.1016/j.taap.2021.115533] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/26/2021] [Accepted: 04/09/2021] [Indexed: 10/21/2022]
Abstract
Decreased activity of AMP-activated protein kinase (AMPK) is implicated in the pathogenesis of diabetic cardiomyopathy (DCM). Recent evidence suggests a crosstalk between cinacalcet and AMPK activation. This study investigated the effects of cinacalcet on cardiac remodeling and dysfunction in type 2 diabetic rats (T2DM). High fat diet for 4 weeks combined with single intraperitoneal injection of streptozotocin (30 mg/kg) was used to induce type 2 diabetes in rats. Diabetic rats were either orally treated with vehicle, 5 or 10 mg/kg cinacalcet for 4 weeks. Control rats were fed standard chow diet and intraperitoneally injected with citrate buffer. T2DM rats showed lower body weight (BW), hyperglycemia and dyslipidemia, along with increased heart weight (HW) and HW/BW ratio. Masson's trichrome stained cardiac sections revealed massive fibrosis in T2DM rats. There were increased TGF-β1 and hydroxyproline levels, coupled with up-regulation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in hearts of T2DM rats. These alterations were associated with redox imbalance and impaired cardiac functions. Decreased phosphorylation of AMPK at threonine172 residue was found in T2DM hearts. Cinacalcet for 4 weeks significantly activated AMPK and alleviated cardiac remodeling and dysfunction in a dose-dependent manner, without affecting blood glucose, serum calcium and phosphorus levels. Cinacalcet increased the mitochondrial DNA content, and expressions of PGC-1α, UCP-3, beclin-1 and LC3-II/LC3-I ratio. Cinacalcet decreased the pro-apoptotic Bax, while increased the anti-apoptotic Bcl-2 in cardiac tissue of T2DM rats. These findings might highlight cinacalcet as an alternative therapy to combat the development and progression of DCM.
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MESH Headings
- AMP-Activated Protein Kinases/metabolism
- Animals
- Apoptosis/drug effects
- Autophagy/drug effects
- Cinacalcet/pharmacology
- Diabetes Mellitus, Experimental/chemically induced
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/enzymology
- Diabetes Mellitus, Experimental/physiopathology
- Diabetes Mellitus, Type 2/chemically induced
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/enzymology
- Diabetes Mellitus, Type 2/physiopathology
- Diabetic Cardiomyopathies/enzymology
- Diabetic Cardiomyopathies/etiology
- Diabetic Cardiomyopathies/physiopathology
- Diabetic Cardiomyopathies/prevention & control
- Fibrosis
- Hemodynamics/drug effects
- Male
- Mitochondria, Heart/drug effects
- Mitochondria, Heart/enzymology
- Mitochondria, Heart/pathology
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/enzymology
- Myocytes, Cardiac/pathology
- Oxidative Stress/drug effects
- Rats, Wistar
- Signal Transduction
- Streptozocin
- Ventricular Remodeling/drug effects
- Rats
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Affiliation(s)
- Rania A Elrashidy
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
| | - Samah E Ibrahim
- Physiology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
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19
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Hashemi P, Pezeshki S. Repurposing metformin for covid-19 complications in patients with type 2 diabetes and insulin resistance. Immunopharmacol Immunotoxicol 2021; 43:265-270. [PMID: 34057870 DOI: 10.1080/08923973.2021.1925294] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Understanding the exact role of current drugs in Covid-19 disease is essential in the era of global pandemics. Metformin which prescribed as the first-line treatment of type 2 diabetes has beneficial effects on Sars-cov2 infection. These effects are including regulation of immune system, Renin-Angiotensin System and Dipeptidyl Peptidase 4 function in Covid-19 infection. It also activates ACE2, the main receptor of Sars-cov2, in the epithelial cells of respiratory tissue through AMPK signaling and subsequently decreases the rate of viral adhesion. Metformin also declines the adherence of Sars-cov2 to DPP4 (the other receptor of the virus) on T cells. Hence, regulatory effects of metformin on membranous ACE2, and DPP4 can modulate immune reaction against Sars-cov2. Also, immunometabolic effects of metformin on inflammatory cells impair hyper-reactive immune response against the virus through reduction of glycolysis and propagation of mitochondrial oxidation. Metformin also decreases platelet aggravation and risk of thrombosis. In this article, we argue that metformin has beneficial effects on Covid-19 infection in patients with type 2 diabetes and insulin resistance. This opinion should be investigated in future clinical trials.
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Affiliation(s)
- Payam Hashemi
- Faculty of Medicine, Tehran University of Medical Science (TUMS), Tehran, Iran
| | - Shaghayegh Pezeshki
- Department of Immunology, School of Medicine, Iran University of Medical Science (IUMS), Tehran, Iran
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20
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Zou J, Li C, Jiang S, Luo L, Yan X, Huang D, Luo Z. AMPK inhibits Smad3-mediated autoinduction of TGF-β1 in gastric cancer cells. J Cell Mol Med 2021; 25:2806-2815. [PMID: 33538080 PMCID: PMC7957200 DOI: 10.1111/jcmm.16308] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 12/09/2020] [Accepted: 01/06/2021] [Indexed: 12/18/2022] Open
Abstract
We have previously shown that adenine monophosphate‐activated protein kinase (AMPK) regulates transforming growth factor β (TGF‐β)‐triggered Smad3 phosphorylation. Here we report that AMPK inhibits TGF‐β1 production. First, metformin reduced mRNA levels of TGF‐β1 in gastric cancer cells, in parallel to the decrease of its protein abundance. The effects were more prominent in the cells containing LKB1, an upstream kinase of AMPK. Second, knockdown of Smad3 by siRNA abrogated the expression of TGF‐β1. Third, metformin suppressed firefly luciferase activity whose transcription was driven by TGF‐β1 promoter. In accordance, deletion of the putative binding site of Smad3 in the TGF‐β1 promoter region severely impaired the promoter activity and response to metformin. Fourth, in support of our in vitro study, clinical treatment of type 2 diabetes with metformin significantly reduced the plasma level of TGF‐β1. Finally, immunohistochemical studies revealed that TGF‐β1 was highly expressed in human gastric cancer tissues as compared with adjacent normal tissues. In contrast, p‐AMPK exhibited opposite changes. Furthermore, the survival rate of gastric cancer patients was positively correlated with p‐AMPK and negative with TGF‐β1. Therefore, our present studies depict a mechanism underlying AMPK suppression of TGF‐β1 autoinduction, which is mediated through inhibition of Smad3 phosphorylation and activation. Collectively, our study sheds a light on the potential usage of AMPK activators in the treatment of TGF‐β1‐mediated gastric cancer progression.
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Affiliation(s)
- Junrong Zou
- Jiangxi Provincial Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang, China.,Institute of Urology, the First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Cong Li
- Jiangxi Provincial Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang, China.,Pharmacy Department, Xiangyang Stomatological Hospital, Affiliated Stomatological Hospital of Hubei University of Arts and Science, Xiangyang, China
| | - Shanshan Jiang
- Jiangxi Provincial Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang, China.,Institute of Hematological Research, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Lingyu Luo
- Department of Gastroenterology, Research Institute of Digestive Diseases, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiaohua Yan
- Department of Biochemistry, School of Basic Medical Sciences, Nanchang University, Nanchang, China
| | - Deqiang Huang
- Department of Gastroenterology, Research Institute of Digestive Diseases, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhijun Luo
- Jiangxi Provincial Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang, China
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21
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Wu M, Xu H, Liu J, Tan X, Wan S, Guo M, Long Y, Xu Y. Metformin and Fibrosis: A Review of Existing Evidence and Mechanisms. J Diabetes Res 2021; 2021:6673525. [PMID: 34007848 PMCID: PMC8102119 DOI: 10.1155/2021/6673525] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 04/01/2021] [Accepted: 04/05/2021] [Indexed: 12/16/2022] Open
Abstract
Fibrosis is a physiological response to organ injury and is characterized by the excessive deposition of connective tissue components in an organ, which results in the disruption of physiological architecture and organ remodeling, ultimately leading to organ failure and death. Fibrosis in the lung, kidney, and liver accounts for a substantial proportion of the global burden of disability and mortality. To date, there are no effective therapeutic strategies for controlling fibrosis. A class of metabolically targeted chemicals, such as adenosine monophosphate-activated protein kinase (AMPK) activators and peroxisome proliferator-activated receptor (PPAR) agonists, shows strong potential in fighting fibrosis. Metformin, which is a potent AMPK activator and is the only recommended first-line drug for the treatment of type 2 diabetes, has emerged as a promising method of fibrosis reduction or reversion. In this review, we first summarize the key experimental and clinical studies that have specifically investigated the effects of metformin on organ fibrosis. Then, we discuss the mechanisms involved in mediating the antifibrotic effects of metformin in depth.
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Affiliation(s)
- Maoyan Wu
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China 646000
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, Sichuan, China 646000
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, China 646000
| | - Huiwen Xu
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China 646000
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, Sichuan, China 646000
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, China 646000
| | - Jingyu Liu
- Southwest Medical University, Luzhou, Sichuan, China 646000
| | - Xiaozhen Tan
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, Sichuan, China 646000
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, China 646000
| | - Shengrong Wan
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China 646000
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, Sichuan, China 646000
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, China 646000
| | - Man Guo
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, Sichuan, China 646000
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, China 646000
| | - Yang Long
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China 646000
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, Sichuan, China 646000
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, China 646000
| | - Yong Xu
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China 646000
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, Sichuan, China 646000
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, China 646000
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22
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Zhao Q, Zhang CL, Xiang RL, Wu LL, Li L. CTRP15 derived from cardiac myocytes attenuates TGFβ1-induced fibrotic response in cardiac fibroblasts. Cardiovasc Drugs Ther 2020; 34:591-604. [PMID: 32424654 DOI: 10.1007/s10557-020-06970-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE Cardiac fibrosis is characterized by net accumulation of extracellular matrix (ECM) components in the myocardium and facilitates the development of heart failure. C1q/tumor necrosis factor-related protein 15 (CTRP15) is a novel member of the CTRP family, and its gene expression is detected in adult mouse hearts. The present study was performed to determine the effect of CTRP15 on pressure overload-induced fibrotic remodeling. METHODS Mice were subjected to transverse aortic constriction (TAC) surgery, and adeno-associated virus serotype 9 (AAV9)-carrying mouse CTRP15 gene was injected into mice to achieve CTRP15 overexpression in the myocardium. Adenovirus carrying the gene encoding CTRP15 or small interfering RNA (siRNA) of interest was infected into cultured neonatal mouse ventricular cardiomyocytes (NMVCs) or cardiac fibroblasts (CFs). Gene expression was measured by quantitative real-time PCR, and protein expression and distribution were determined by Western blotting, immunocytochemistry, and immunofluorescence staining. RESULTS CTRP15 was predominantly produced by cardiac myocytes. CTRP15 expression in the left ventricles was downregulated in mice that underwent TAC. AAV9-mediated CTRP15 overexpression alleviated ventricular remodeling and dysfunction in the pressure-overloaded mice. Treatment of CFs with recombinant CTRP15 or the conditioned medium containing CTRP15 inhibited transforming growth factor (TGF)-β1-induced Smad3 activation and myofibroblast differentiation. CTRP15 increased phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and Akt. Blockade of IR/IRS-1/Akt pathway reversed the inhibitory effect of CTRP15 on TGF-β1-induced Smad3 activation. CONCLUSION CTRP15 exerts an anti-fibrotic effect on pressure overload-induced cardiac remodeling. The activation of IR/IRS-1/Akt pathway contributes to the anti-fibrotic effect of CTRP15 through targeting Smad3.
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Affiliation(s)
- Qian Zhao
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China
| | - Cheng-Lin Zhang
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China
| | - Ruo-Lan Xiang
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China
| | - Li-Ling Wu
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China
| | - Li Li
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
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23
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Wang H, Wang C, Lu Y, Yan Y, Leng D, Tian S, Zheng D, Wang Z, Bai Y. Metformin Shortens Prolonged QT Interval in Diabetic Mice by Inhibiting L-Type Calcium Current: A Possible Therapeutic Approach. Front Pharmacol 2020; 11:614. [PMID: 32595491 PMCID: PMC7300225 DOI: 10.3389/fphar.2020.00614] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 04/20/2020] [Indexed: 12/11/2022] Open
Abstract
The incidence and mortality of cardiovascular disease in diabetic patients are 2-3 times higher than those in non-diabetic patients. Abnormal function of the L-type calcium channel in myocardial tissue might result in multiple cardiac disorders such as a prolonged QT interval. Therefore, QT prolongation is an independent risk factor of cardiovascular disease in patients with diabetes mellitus. Metformin, a hypoglycemic agent, is widely known to effectively reduce the occurrence of macrovascular diseases. The aim of the present study was to evaluate the effect of metformin on prolonged QT interval and to explore potential ionic mechanisms induced by diabetes. Diabetic mouse models were established with streptozotocin and an electrocardiogram was used to monitor the QT interval after 4 weeks of metformin treatment in each group. Action potential duration (APD) and L-type calcium current (I Ca-L) were detected by patch-clamp in isolated mice ventricular cardiomyocytes and neonatal cardiomyocytes of mice. The expression levels of CACNA1C mRNA and Cav1.2 were measured by real-time PCR, western blot and immunofluorescence. A shortened QT interval was observed after 4 weeks of metformin treatment in diabetic mice. Patch-clamp results revealed that both APD and I Ca-L were shortened in mouse cardiomyocytes. Furthermore, the expression levels of CACNA1C mRNA and Cav1.2 were decreased in the metformin group. The same results were also obtained in cultured neonatal mice cardiomyocytes. Overall, these results verify that metformin could shorten a prolonged QT interval by inhibiting the calcium current, suggesting that metformin may play a role in the electrophysiology underlying diabetic cardiopathy.
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Affiliation(s)
- Hui Wang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Cao Wang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Yuan Lu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Yan Yan
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Dongjing Leng
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Shanshan Tian
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Dongjie Zheng
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Zhiguo Wang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Yunlong Bai
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
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24
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Feng Y, Li M, Wang S, Cong W, Hu G, Song Y, Xiao H, Dong E, Zhang Y. Paired box 6 inhibits cardiac fibroblast differentiation. Biochem Biophys Res Commun 2020; 528:561-566. [PMID: 32505347 DOI: 10.1016/j.bbrc.2020.05.146] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 05/13/2020] [Indexed: 01/09/2023]
Abstract
Cardiac fibroblast (CF) differentiation plays a crucial role in cardiac fibrosis, which is a specific manifestation distinguishing pathological cardiac hypertrophy from physiological hypertrophy. The DNA-binding activity of paired box 6 (Pax6) has been shown to be oppositely regulated in physiological and pathological hypertrophy; however, it remains unclear whether Pax6 is involved in CF differentiation during cardiac fibrosis. We found that Pax6 is expressed in the heart of and CFs isolated from adult mice. Moreover, angiotensin II (Ang II) induced the downregulation of Pax6 mRNA and protein expression in fibrotic heart tissue and cardiac myofibroblasts. Pax6 knockdown in CFs promoted the expression of the myofibroblast marker α-smooth muscle actin (α-SMA) and the synthesis of the extracellular matrix (ECM) proteins collagen I and fibronectin. Furthermore, we validated the ability of Pax6 to bind to the promoter regions of Cxcl10 and Il1r2 and the intronic region of Tgfb1. Pax6 knockdown in CFs decreased CXC chemokine 10 (CXCL10) and interleukin-1 receptor 2 (IL-1R2) expression and increased transforming growth factor β1 (TGFβ1) expression, mimicking the effects of Ang II. In conclusion, Pax6 exerts an inhibitory effect on CF differentiation and ECM synthesis by transcriptionally activating the expression of the anti-fibrotic factors CXCL10 and IL-1R2 and repressing the expression of the pro-fibrotic factor TGFβ1. Therefore, maintaining Pax6 expression in CFs is essential for preventing CF differentiation, and provides a new therapeutic target for cardiac fibrosis.
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Affiliation(s)
- Yenan Feng
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
| | - Mingzhe Li
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
| | - Shuaixing Wang
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
| | - Wenwen Cong
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Department of Physiology, School of Medicine Shihezi University, Shihezi, 832000, China.
| | - Guomin Hu
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
| | - Yao Song
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
| | - Han Xiao
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
| | - Erdan Dong
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
| | - Youyi Zhang
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
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25
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Deng M, Su D, Xu S, Little PJ, Feng X, Tang L, Shen A. Metformin and Vascular Diseases: A Focused Review on Smooth Muscle Cell Function. Front Pharmacol 2020; 11:635. [PMID: 32457625 PMCID: PMC7227439 DOI: 10.3389/fphar.2020.00635] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 04/21/2020] [Indexed: 12/16/2022] Open
Abstract
Metformin has been used in diabetes for more than 60 years and has excellent safety in the therapy of human type 2 diabetes (T2D). There is growing evidence that the beneficial health effects of metformin are beyond its ability to improve glucose metabolism. Metformin not only reduces the incidence of cardiovascular diseases (CVD) in T2D patients, but also reduces the burden of atherosclerosis (AS) in pre-diabetes patients. Vascular smooth muscle cells (VSMCs) function is an important factor in determining the characteristics of the entire arterial vessel. Its excessive proliferation contributes to the etiology of several types of CVD, including AS, restenosis, and pulmonary hypertension. Current studies show that metformin has a beneficial effect on VSMCs function. Therefore, this review provides a timely overview of the role and molecular mechanisms by which metformin acts through VSMCs to protect CVD.
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Affiliation(s)
- Mingying Deng
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Dan Su
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Suowen Xu
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Peter J Little
- School of Pharmacy, The University of Queensland, Woolloongabba, QLD, Australia.,Department of Pharmacy, Xinhua College of Sun Yat-sen University, Guangzhou, China
| | - Xiaojun Feng
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Liqin Tang
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Aizong Shen
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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26
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Nataf S. The Demonstration of an Aqp4/Tgf-beta 1 Pathway in Murine Astrocytes Holds Implications for Both Neuromyelitis Optica and Progressive Multiple Sclerosis. Int J Mol Sci 2020; 21:ijms21031035. [PMID: 32033173 PMCID: PMC7037715 DOI: 10.3390/ijms21031035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/31/2020] [Accepted: 02/03/2020] [Indexed: 01/25/2023] Open
Abstract
The role exerted by Aquaporin 4 (AQP4) as a regulator of astrocyte immune functions has been poorly explored. A recent report demonstrates that under neuroinflammatory conditions, the expression of Aqp4 on murine astrocytes is mandatory for the effective control of acute inflammation in the central nervous system. Such an immunomodulatory function appears to be mediated by a promotion of the transforming growth factor beta 1 (Tgfb1) pathway. Here, these results are discussed in the context of neuromyelitis optica (NMO) and multiple sclerosis (MS) progressive forms. It is proposed that NMO and progressive MS might rely on opposite molecular mechanisms involving, in NMO, an acutely-defective AQP4/TGFB1 pathway and, in progressive MS, a chronically-stimulated AQP4/TGFB1 pathway. Data supporting the involvement of angiotensin II as a molecular link between AQP4 and TGFB1 are also reviewed.
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Affiliation(s)
- Serge Nataf
- Bank of Tissues and Cells, Lyon University Hospital (Hospices Civils de Lyon), F-69000 Lyon, France; ; Tel.: +33-4-72-11-76-67; Fax: 33-4-72-11-96-49
- CarMeN Laboratory, INSERM 1060, INRA 1397, 69600 INSA Oullins, France
- Lyon-Est School of Medicine, University Claude Bernard Lyon-1, F-69000 Lyon, France
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27
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Yang S, Ma C, Wu H, Zhang H, Yuan F, Yang G, Yang Q, Jia L, Liang Z, Kang L. Tectorigenin attenuates diabetic nephropathy by improving vascular endothelium dysfunction through activating AdipoR1/2 pathway. Pharmacol Res 2020; 153:104678. [PMID: 32014572 DOI: 10.1016/j.phrs.2020.104678] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 01/17/2020] [Accepted: 01/30/2020] [Indexed: 01/10/2023]
Abstract
Diabetic nephropathy (DN), a kind of microvascular complication, is a primary cause of end-stage renal disease worldwide. However, therapeutic drugs for DN treatment are still in lack. The glomerular endothelium is essential to maintain selective permeability of glomerular filtration barrier and glomerular vasculature function. Growing evidences show that endothelial dysfunction or injury is the initial stage of vascular damage in DN, which can be induced by hyperglycemia, lipotoxicity, and inflammation. Therefore, to improve the function of vascular endothelium in kidney is a key point for treatment of DN. As a plant isoflavone, tectorigenin (TEC) has attracted considerable attention due to its anti-proliferative and anti-inflammatory functions. However, whether TEC could inhibit the DN development remains unknown. In this study, we examined the effects of TEC on DN development in db/db mice, a type of genetic defect diabetic mice that can spontaneously develop into severe renal dysfunction. Intriguingly, TEC treatment restored diabetes-induced glucose and lipid metabolic disorder; and improved the deterioration of renal function, particularly the renal endothelium function in db/db mice. Additionally, TEC inhibited the renal inflammation via reducing macrophages infiltration and M1 polarization. Moreover, TEC inhibited lipopolysaccharide (LPS)-induced endothelial injury and M1 polarization in vitro. Mechanistically, TEC partially restored the reduction in expression of adiponectin receptor 1/2 (AdipoR1/2), pi-LKB1, pi-AMPKα, and PPARα in vitro and in vivo. Noteworthy, these beneficial pharmacological activities mediated by TEC were significantly attenuated after AdipoR1/2 knockdown by siRNA, indicating that AdipoR1/2 plays a critical role in protection against DN. Collectively, these results suggested that TEC have a potently effect for retarding type 2 diabetes-associated DN.
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Affiliation(s)
- Shu Yang
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Chuanrui Ma
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China
| | - Han Wu
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China; Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Hao Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China
| | - Fengyi Yuan
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Guangyan Yang
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Qi Yang
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Lijing Jia
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China.
| | - Zhen Liang
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China.
| | - Lin Kang
- Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China.
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28
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Yeh MM, Bosch DE, Daoud SS. Role of hepatocyte nuclear factor 4-alpha in gastrointestinal and liver diseases. World J Gastroenterol 2019; 25:4074-4091. [PMID: 31435165 PMCID: PMC6700705 DOI: 10.3748/wjg.v25.i30.4074] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 07/15/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocyte nuclear factor 4-alpha (HNF4α) is a highly conserved member of nuclear receptor superfamily of ligand-dependent transcription factors that is expressed in liver and gastrointestinal organs (pancreas, stomach, and intestine). In liver, HNF4α is best known for its role as a master regulator of liver-specific gene expression and essential for adult and fetal liver function. Dysregulation of HNF4α expression has been associated with many human diseases such as ulcerative colitis, colon cancer, maturity-onset diabetes of the young, liver cirrhosis, and hepatocellular carcinoma. However, the precise role of HNF4α in the etiology of these human pathogenesis is not well understood. Limited information is known about the role of HNF4α isoforms in liver and gastrointestinal disease progression. There is, therefore, a critical need to know how disruption of the expression of these isoforms may impact on disease progression and phenotypes. In this review, we will update our current understanding on the role of HNF4α in human liver and gastrointestinal diseases. We further provide additional information on possible use of HNF4α as a target for potential therapeutic approaches.
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Affiliation(s)
- Matthew M Yeh
- Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Dustin E Bosch
- Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Sayed S Daoud
- Department of Pharmaceutical Sciences, Washington State University Health Sciences, Spokane, WA 99210, United States
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29
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Ge W, Zhang W, Gao R, Li B, Zhu H, Wang J. IMM-H007 improves heart function via reducing cardiac fibrosis. Eur J Pharmacol 2019; 857:172442. [PMID: 31181209 DOI: 10.1016/j.ejphar.2019.172442] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 06/06/2019] [Accepted: 06/06/2019] [Indexed: 01/08/2023]
Abstract
Cardiac dysfunction is a pathological state characterized by damaged ability of the left ventricle (LV) to either eject or fill blood accompanied by cardiac hypertrophy and fibrosis. IMM-H007, an adenosine derivative, is an activator of AMP-Activated Protein Kinase (AMPK). AMPK can decrease the transforming growth factor-β1 (TGF-β1) expression during fibrosis. Therefore, we hypothesized that IMM-H007 contributed to cardiac dysfunction by mediating cardiac fibrosis. To test this hypothesis, we used angiotensin II (AngII)-induced cardiac remodeling model treated with IMM-H007 or vehicle. Echocardiography measurements showed that IMM-H007 significantly improved heart function indicated by increased LV ejection fraction (%LVEF) and LV fractional shortening (%LVFS). Histological staining and qRT-PCR analysis revealed that IMM-H007 markedly reduced AngII-induced cardiac fibroblast activation (α-smooth muscle actin and periostin) and matrix protein production (Collagen I and Collagen III). However, IMM-H007 did not affect AngII-induced cardiac hypertrophy. Immunoblotting analysis revealed that IMM-H007 activated AMPK, decreased the expression of TGF-β1, and inhibited the activation of Smad2 in heart tissues. In mouse primary cultured cardiac fibroblasts, pharmacological activation of AMPK by IMM-H007 significantly reduced AngII-induced TGF-β1 expression as well. Consistently, in human cardiac fibroblasts-adult ventricular (HCF-av), IMM-H007 activated AMPK and markedly suppressed AngII-induced TGF-β1 expression. These results together reveal that IMM-H007 improves heart function, and alleviates AngII-induced cardiac fibrosis by regulating AMPK-TGF-β1 signaling. These findings suggest IMM-H007 as a potential drug for treating cardiac dysfunction.
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Affiliation(s)
- Weipeng Ge
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Pathophysiology, Peking Union Medical College, Beijing, China
| | - Wei Zhang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Pathophysiology, Peking Union Medical College, Beijing, China
| | - Ran Gao
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Pathophysiology, Peking Union Medical College, Beijing, China
| | - Bolun Li
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Pathophysiology, Peking Union Medical College, Beijing, China
| | - Haibo Zhu
- State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jing Wang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Pathophysiology, Peking Union Medical College, Beijing, China.
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Li X, Liu J, Lu Q, Ren D, Sun X, Rousselle T, Tan Y, Li J. AMPK: a therapeutic target of heart failure-not only metabolism regulation. Biosci Rep 2019; 39:BSR20181767. [PMID: 30514824 PMCID: PMC6328861 DOI: 10.1042/bsr20181767] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 11/19/2018] [Accepted: 11/29/2018] [Indexed: 02/07/2023] Open
Abstract
Heart failure (HF) is a serious disease with high mortality. The incidence of this disease has continued to increase over the past decade. All cardiovascular diseases causing dysfunction of various physiological processes can result in HF. AMP-activated protein kinase (AMPK), an energy sensor, has pleiotropic cardioprotective effects and plays a critical role in the progression of HF. In this review, we highlight that AMPK can not only improve the energy supply in the failing heart by promoting ATP production, but can also regulate several important physiological processes to restore heart function. In addition, we discuss some aspects of some potential clinical drugs which have effects on AMPK activation and may have value in treating HF. More studies, especially clinical trials, should be done to evaluate manipulation of AMPK activation as a potential means of treating HF.
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Affiliation(s)
- Xuan Li
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, U.S.A
| | - Jia Liu
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, U.S.A
- Department of Geriatrics, The First Hospital of Jilin University, Changchun 130021, China
| | - Qingguo Lu
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, U.S.A
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu 610041, China
| | - Di Ren
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, U.S.A
| | - Xiaodong Sun
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, U.S.A
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Thomas Rousselle
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, U.S.A
| | - Yi Tan
- Pediatic Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY, U.S.A
- Wendy L. Novak Diabetes Care Center, University of Louisville, Louisville, KY, U.S.A
| | - Ji Li
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, U.S.A.
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31
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Zhang N, Wei WY, Liao HH, Yang Z, Hu C, Wang SS, Deng W, Tang QZ. AdipoRon, an adiponectin receptor agonist, attenuates cardiac remodeling induced by pressure overload. J Mol Med (Berl) 2018; 96:1345-1357. [PMID: 30341569 DOI: 10.1007/s00109-018-1696-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 09/08/2018] [Accepted: 09/18/2018] [Indexed: 12/22/2022]
Abstract
AdipoRon, a small-molecule adiponectin receptor (AdipoR) agonist, has been reported to be implicated in cardiovascular diseases. However, its role in pressure-overload-induced cardiac remodeling is still elusive. To elucidate the role of AdipoRon in the pathogenesis of cardiac remodeling in vivo and vitro, in the left ventricle of human end-stage heart failure, the expression of AdipoR2 is upregulated. Meanwhile, increased expression of AdipoR2 was also observed in mice failing hearts. Oral administration of AdipoRon alleviated cardiac hypertrophy and fibrosis induced by pressure overload, as evidenced by the beneficial change of cross-sectional area of cardiomyocytes, heart weight-to-body weight ratio, gene expression of hypertrophic markers, ventricle collagen ratio, and cardiac function. The AMPKα activation mediated by AdipoRon significantly inhibited AngII-induced TGF-β1 expression and cardiac fibroblast differentiation, and these inhibitory effects were abrogated by treatment with the AMPK inhibitor Compound C. Consistent with the above results, AdipoRon abolished the ability to retard AngII-induced TGF-β1 expression in AMPKα2-/- cardiac fibroblasts. In AMPKα2-/- mice subjected to aortic banding, AdipoRon abolished the protective effect, as indicated by increased cross-sectional area, cardiac collagen ratio, and cardiac dysfunction. Our results demonstrated that AdipoR2 expression was markedly increased in the failing hearts. AdipoRon inhibited TGF-β1 expression and myofibroblast differentiation in AMPKα-dependent manner in vitro. In line with the vitro results, AMPKα2-/- mice markedly abrogated the inhibitory effects of AdipoRon in cardiac remodeling. These results indicated AdipoRon may hold promise of an effective therapy against pressure-overload-induced cardiac remodeling. KEY MESSAGES: • The increased expression of AdipoR2 is observed in human and mice failing hearts, the changeable expression of AdipoR suggests the possible role of AdipoR in cardiac remodeling. • Oral administration of AdipoRon alleviates cardiac hypertrophy and fibrosis induced by pressure overload, and AMPKα activation mediated by AdipoRon significantly inhibited AngII-induced TGF-β1 expression and cardiac fibroblast differentiation. • These findings provide new mechanistic insight and open new therapeutic pathways for heart failure.
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Affiliation(s)
- Ning Zhang
- Department of Cardiology, Affiliated Hospital of Qingdao University, Qingdao, China
- Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
| | - Wen-Ying Wei
- Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Hai-Han Liao
- Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Zheng Yang
- Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
| | - Can Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
| | - Sha-Sha Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
| | - Wei Deng
- Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China.
- Cardiovascular Research Institute of Wuhan University, Wuhan, China.
| | - Qi-Zhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China.
- Cardiovascular Research Institute of Wuhan University, Wuhan, China.
- Hubei Key Laboratory of Cardiology, Wuhan, China.
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32
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Xu Z, Wu J, Xin J, Feng Y, Hu G, Shen J, Li M, Zhang Y, Xiao H, Wang L. β3-adrenergic receptor activation induces TGFβ1 expression in cardiomyocytes via the PKG/JNK/c-Jun pathway. Biochem Biophys Res Commun 2018; 503:146-151. [DOI: 10.1016/j.bbrc.2018.05.200] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 05/29/2018] [Indexed: 12/22/2022]
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33
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Wang X, Huang Y, Ji Y. Spotlight on small molecules in cardiovascular diseases. Br J Pharmacol 2018; 175:1111-1113. [PMID: 29574891 PMCID: PMC5866956 DOI: 10.1111/bph.14154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
LINKED ARTICLES This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.
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Affiliation(s)
- Xin Wang
- Faculty of Life SciencesThe University of ManchesterManchesterUK
| | - Yu Huang
- Institute of Vascular BiologyChinese University of Hong KongSha TinHong Kong
| | - Yong Ji
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of PharmacyNanjing Medical UniversityNanjingChina
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34
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Chen R, Feng Y, Wu J, Song Y, Li H, Shen Q, Li D, Zhang J, Lu Z, Xiao H, Zhang Y. Metformin attenuates angiotensin II-induced TGFβ1 expression by targeting hepatocyte nuclear factor-4-α. Br J Pharmacol 2017; 175:1217-1229. [PMID: 28230250 DOI: 10.1111/bph.13753] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 01/26/2017] [Accepted: 02/13/2017] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND AND PURPOSE Metformin, a small molecule, antihyperglycaemic agent, is a well-known activator of AMP-activated protein kinase (AMPK) and protects against cardiac fibrosis. However, the underlying mechanisms remain elusive. TGFβ1 is a key cytokine mediating cardiac fibrosis. Here, we investigated the effects of metformin on TGFβ1 production induced by angiotensin II (AngII) and the underlying mechanisms. EXPERIMENTAL APPROACH Wild-type and AMPKα2-/- C57BL/6 mice were injected s.c. with metformin or saline and infused with AngII (3 mg·kg-1 ·day-1 ) for 7 days. Adult mouse cardiac fibroblasts (CFs) were isolated for in vitro experiments. KEY RESULTS In CFs, metformin inhibited AngII-induced TGFβ1 expression via AMPK activation. Analysis using bioinformatics predicted a potential hepatocyte nuclear factor 4α (HNF4α)-binding site in the promoter region of the Tgfb1 gene. Overexpressing HNF4α increased TGFβ1 expression in CFs. HNF4α siRNA attenuated AngII-induced TGFβ1 production and cardiac fibrosis in vitro and in vivo. Metformin inhibited the AngII-induced increases in HNF4α protein expression and binding to the Tgfb1 promoter in CFs. In vivo, metformin blocked the AngII-induced increase in cardiac HNF4α protein levels in wild-type mice but not in AMPKα2-/- mice. Consequently, metformin inhibited AngII-induced TGFβ1 production and cardiac fibrosis in wild-type mice but not in AMPKα2-/- mice. CONCLUSIONS AND IMPLICATIONS HNF4α mediates AngII-induced TGFβ1 transcription and cardiac fibrosis. Metformin inhibits AngII-induced HNF4α expression via AMPK activation, thus decreasing TGFβ1 transcription and cardiac fibrosis. These findings reveal a novel antifibrotic mechanism of action of metformin and identify HNF4α as a new potential therapeutic target for cardiac fibrosis. LINKED ARTICLES This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.
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Affiliation(s)
- Ruifei Chen
- Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Yenan Feng
- Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Jimin Wu
- Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Yao Song
- Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Hao Li
- Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Qiang Shen
- Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Dan Li
- Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Jianshu Zhang
- Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Zhizhen Lu
- Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Han Xiao
- Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Youyi Zhang
- Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
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