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Faruque L, Yau K, Cherney DZI. Glucagon-like peptide-1 receptor agonists to improve cardiorenal outcomes: data from FLOW and beyond. Curr Opin Nephrol Hypertens 2025; 34:232-240. [PMID: 40047207 DOI: 10.1097/mnh.0000000000001066] [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: 03/27/2025]
Abstract
PURPOSE OF REVIEW Glucagon-like peptide-1 receptor agonists (GLP1RA), initially approved for glycemic control in type 2 diabetes mellitus (T2DM), have emerged as agents for weight loss, cardiovascular and kidney protection. This review summarizes the evidence supporting the benefits of these therapies on cardiorenal outcomes. RECENT FINDINGS Clinical trials have consistently demonstrated reductions in major adverse cardiovascular events with GLP1RA treatments. Recently, the FLOW trial revealed that semaglutide reduced the composite outcome of kidney failure, at least 50% decline in estimated glomerular filtration rate, kidney or cardiovascular mortality by 24% in patients with T2DM, thereby establishing GLP1RA as a pillar of therapy in this population. New evidence suggests favorable effects on kidney endpoints in nondiabetic individuals with overweight or obesity. Dedicated trials have also provided evidence for reduction in the risk for heart failure hospitalization and improvement in symptoms in individuals with heart failure with preserved ejection fraction. Subgroup analyses have suggested that GLP1RAs confer additive cardiorenal benefits irrespective of background medication use. SUMMARY There is increasing evidence that GLP1RA reduces the risk for cardiovascular events, chronic kidney disease progression, and heart failure hospitalizations. Further data on the effect of dual and triple GLP1-based therapies on cardiorenal outcomes is required.
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Affiliation(s)
- Labib Faruque
- Department of Medicine, Division of Nephrology, University Health Network
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Kevin Yau
- Department of Medicine, Division of Nephrology, University Health Network
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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2
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Gliozzi M, Coppoletta AR, Cardamone A, Carresi C, Mollace R, Musolino V, Mollace V. Modulation of GLP-1 signalling as an innovative strategy counteracting the onset of heart failure: Potential for natural compound supplementation. Pharmacol Res 2025; 216:107744. [PMID: 40268125 DOI: 10.1016/j.phrs.2025.107744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 04/14/2025] [Accepted: 04/20/2025] [Indexed: 04/25/2025]
Abstract
The clinical continuum of heart failure (HF) is commonly divided into four stages (A, B, C and D), but despite the identification of its staging, to date, the management of the early phases remains an unmet need. In fact, the incomplete knowledge of the molecular mechanisms associated with the comorbidities leading to HF onset represents an obstacle to a targeted therapy. Recently, stages A and B have been further typified and, starting from this novel characterization, the aim of our review was to propose an alternative criterion to appropriately use GLP-1 RA in association with plant-derived polyphenolic extracts. This alternative approach is based on the selection of the main molecular mechanisms underlying the early and asymptomatic HF onset that might be further prevented or antagonized through the administration of natural extracts.
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Affiliation(s)
- Micaela Gliozzi
- Pharmacology Laboratory, CIS IRC-FSH, Department of Health Sciences - University Magna Græcia of Catanzaro, Catanzaro 88100, Italy.
| | - Anna Rita Coppoletta
- Pharmacology Laboratory, CIS IRC-FSH, Department of Health Sciences - University Magna Græcia of Catanzaro, Catanzaro 88100, Italy
| | - Antonio Cardamone
- Physiology Laboratory, CIS IRC-FSH, Department of Health Sciences - University Magna Græcia of Catanzaro, Catanzaro 88100, Italy.
| | - Cristina Carresi
- Veterinary Pharmacology Laboratory, CIS IRC-FSH, Department of Health Sciences - University Magna Græcia of Catanzaro, Catanzaro 88100, Italy
| | - Rocco Mollace
- Department of Experimental Medicine, Tor Vergata University, Rome 00133, Italy; Cardiology Unit, Humanitas Gavazzeni, Bergamo 24125, Italy
| | - Vincenzo Musolino
- Laboratory of Pharmaceutical Biology, CIS IRC-FSH, Department of Health Sciences - University "Magna Græcia" of Catanzaro, Catanzaro 88100, Italy
| | - Vincenzo Mollace
- Pharmacology Laboratory, CIS IRC-FSH, Department of Health Sciences - University Magna Græcia of Catanzaro, Catanzaro 88100, Italy
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3
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Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, Zhang C, Gao J. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduct Target Ther 2024; 9:234. [PMID: 39289339 PMCID: PMC11408715 DOI: 10.1038/s41392-024-01931-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 06/17/2024] [Accepted: 07/16/2024] [Indexed: 09/19/2024] Open
Abstract
The glucagon-like peptide-1 (GLP-1) receptor, known as GLP-1R, is a vital component of the G protein-coupled receptor (GPCR) family and is found primarily on the surfaces of various cell types within the human body. This receptor specifically interacts with GLP-1, a key hormone that plays an integral role in regulating blood glucose levels, lipid metabolism, and several other crucial biological functions. In recent years, GLP-1 medications have become a focal point in the medical community due to their innovative treatment mechanisms, significant therapeutic efficacy, and broad development prospects. This article thoroughly traces the developmental milestones of GLP-1 drugs, from their initial discovery to their clinical application, detailing the evolution of diverse GLP-1 medications along with their distinct pharmacological properties. Additionally, this paper explores the potential applications of GLP-1 receptor agonists (GLP-1RAs) in fields such as neuroprotection, anti-infection measures, the reduction of various types of inflammation, and the enhancement of cardiovascular function. It provides an in-depth assessment of the effectiveness of GLP-1RAs across multiple body systems-including the nervous, cardiovascular, musculoskeletal, and digestive systems. This includes integrating the latest clinical trial data and delving into potential signaling pathways and pharmacological mechanisms. The primary goal of this article is to emphasize the extensive benefits of using GLP-1RAs in treating a broad spectrum of diseases, such as obesity, cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases, musculoskeletal inflammation, and various forms of cancer. The ongoing development of new indications for GLP-1 drugs offers promising prospects for further expanding therapeutic interventions, showcasing their significant potential in the medical field.
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Affiliation(s)
- Zhikai Zheng
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yao Zong
- Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia
| | - Yiyang Ma
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yucheng Tian
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yidan Pang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Changqing Zhang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
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Jarade C, Zolotarova T, Moiz A, Eisenberg MJ. GLP-1-based therapies for the treatment of resistant hypertension in individuals with overweight or obesity: a review. EClinicalMedicine 2024; 75:102789. [PMID: 39246720 PMCID: PMC11377134 DOI: 10.1016/j.eclinm.2024.102789] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 07/26/2024] [Accepted: 07/29/2024] [Indexed: 09/10/2024] Open
Abstract
Despite the availability of a wide range of antihypertensive agents, a significant proportion of individuals with resistant hypertension (RHTN) struggle to achieve blood pressure (BP) control. Obesity ranks among the most significant modifiable risk factors for RHTN, with 56-91% of patients with RHTN classified as overweight or obese. Glucagon-like peptide-1 receptor agonist (GLP-1 RAs) are a class of anti-obesity medications that have recently demonstrated efficacy in reducing BP and improving cardiovascular (CV) outcomes in individuals with overweight or obesity. Among the available GLP-1-based therapies, liraglutide, semaglutide, and tirzepatide have been approved for chronic weight management in this population. Tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist, has the greatest effect on weight loss and BP reduction compared to GLP-1 RAs alone. To our knowledge, no trials have directly evaluated the effect of GLP-1 RAs or dual GLP-1/GIP receptor agonists on RHTN management. In this review article, we propose that targeting weight loss through GLP-1-based therapies should be explored as a treatment option for individuals with RHTN who are overweight or obese.
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Affiliation(s)
- Candace Jarade
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada
| | - Tetiana Zolotarova
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada
| | - Areesha Moiz
- Graduate Program in Clinical and Translational Research, McGill University, Montreal, QC, Canada
| | - Mark J Eisenberg
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada
- Graduate Program in Clinical and Translational Research, McGill University, Montreal, QC, Canada
- Departments of Medicine and of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada
- Division of Cardiology, Jewish General Hospital, McGill University, Montreal, QC, Canada
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Zong Y, Wang X, Zhang Y, Tan N, Zhang Y, Li L, Liu L. Sitagliptin Ameliorates Creb5/lncRNA ENSMUST00000213271-Mediated Vascular Endothelial Dysfunction in Obese Mice. Cardiovasc Drugs Ther 2024; 38:679-691. [PMID: 36738369 DOI: 10.1007/s10557-023-07436-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/24/2023] [Indexed: 02/05/2023]
Abstract
PURPOSE Obesity is mediated by the changes in dyslipidemia, oxidative stress, and inflammation, leading to vascular endothelial dysfunction. Glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 inhibitors prevent the development of endothelial dysfunction. However, the underlying mechanism still remains largely unclear. Long non-coding RNAs (lncRNAs), one class of non-coding small RNAs, have been shown to exert a regulatory impact on the endothelial function in obesity. This study aimed to investigate whether the elevation of GLP-1 by a DPP-4 inhibitor sitagliptin improved vascular endothelial function by modulating lncRNAs in obese mice and to clarify the underlying molecular mechanism. METHODS Male C57BL/6J mice were fed a high-fat diet for 4 months to induce obesity and some obese mice were treated with sitagliptin for the last 1 month. Levels of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and glucagon-like peptide-1 (GLP-1) in plasma were detected by ELISA. LncRNA expression profile was analyzed via microarray. Aortic relaxations were examined by myograph. Protein expressions and phosphorylations were determined using western blot. The differentially expressed lncRNAs were validated using qRT-PCR. RESULTS Obese mice exhibited increased levels of TC and LDL, decreased concentrations of HDL and GLP-1 in plasma, and impaired aortic endothelium-dependent relaxations; such effects could be reversed by sitagliptin. Moreover, the altered expression profile of lncRNAs in the obese mouse aortae could be modulated by sitagliptin. Consistent with microarray analysis, qRT-PCR also revealed that lncRNA ENSMUST00000213271 was up-regulated in obese mouse aortae and aortic endothelial cells (ECs), which could be down-regulated by sitagliptin. Creb5 silencing reduced lncRNA ENSMUST00000213271 in obese mouse ECs. Knockdown of either Creb5 or lncRNA ENSMUST00000213271 restored the activation of AMPK/eNOS in obese mouse ECs. Furthermore, sitagliptin also suppressed Creb5 and lncRNA ENSMUST00000213271 and increased the phosphorylations of AMPK and eNOS in obese mice. CONCLUSION Creb5/lncRNA ENSMUST00000213271 mediated vascular endothelial dysfunction through inhibiting AMPK/eNOS cascade in obesity. Elevation of GLP-1 by sitagliptin possibly improved endothelial function by suppressing Creb5/lncRNA ENSMUST00000213271 and subsequently restoring AMPK/eNOS activation in obese mice. This study will provide new evidence for the benefits of GLP-1 against vasculopathy in obesity.
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MESH Headings
- Animals
- Sitagliptin Phosphate/pharmacology
- Male
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- RNA, Long Noncoding/drug effects
- Mice, Inbred C57BL
- Obesity/drug therapy
- Obesity/metabolism
- Dipeptidyl-Peptidase IV Inhibitors/pharmacology
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/physiopathology
- Glucagon-Like Peptide 1/metabolism
- Diet, High-Fat
- Cyclic AMP Response Element-Binding Protein/metabolism
- Disease Models, Animal
- Vasodilation/drug effects
- Mice
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Mice, Obese
- Signal Transduction/drug effects
- Phosphorylation
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Affiliation(s)
- Yi Zong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Xiaorui Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yi Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Na Tan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yan Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Li Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Limei Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
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6
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Sardar MB, Nadeem ZA, Babar M. Tirzepatide: A novel cardiovascular protective agent in type 2 diabetes mellitus and obesity. Curr Probl Cardiol 2024; 49:102489. [PMID: 38417475 DOI: 10.1016/j.cpcardiol.2024.102489] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 02/24/2024] [Indexed: 03/01/2024]
Abstract
Cardiovascular disease (CVD) remains a major global health concern, and obesity and diabetes mellitus have been found to be important risk factors. Tirzepatide a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP1) receptor agonist has been shown to have cardioprotective effects. Noteworthy benefits of Tirzepatide include decreased cardiovascular risk factors in people with Type 2 diabetes mellitus (T2DM). In the SURPASS-4 trial, tirzepatide significant decreased blood pressure, body weight, and HbA1c. Furthermore, the SURMOUNT-1 trial demonstrated the effectiveness of tirzepatide in reducing cardiometabolic risk factors in people with obesity without T2DM. Together, the dual receptor agonism improves lipid profiles, increases insulin secretion, reduces inflammation, and promotes endothelial integrity. Tirzepatide shows promise as a comprehensive therapeutic option for managing cardiovascular risk factors in patients with T2DM and obesity. While further studies are needed to assess the long-term cardiovascular benefits, current evidence supports tirzepatide's potential impact on cardiovascular health beyond its antidiabetic properties.
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Affiliation(s)
- Muhammad Bilal Sardar
- Department of Cardiology, Allama Iqbal Medical College, Allama Shabbir Ahmed Usmani Road, Lahore 54700, Pakistan.
| | - Zain Ali Nadeem
- Department of Medicine, Allama Iqbal Medical College, Lahore, Pakistan
| | - Muhammad Babar
- Department of Internal Medicine, Social Security Hospital, Faisalabad, Pakistan
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7
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Zhou Y, Suo W, Zhang X, Liang J, Zhao W, Wang Y, Li H, Ni Q. Targeting mitochondrial quality control for diabetic cardiomyopathy: Therapeutic potential of hypoglycemic drugs. Biomed Pharmacother 2023; 168:115669. [PMID: 37820568 DOI: 10.1016/j.biopha.2023.115669] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/23/2023] [Accepted: 10/06/2023] [Indexed: 10/13/2023] Open
Abstract
Diabetic cardiomyopathy is a chronic cardiovascular complication caused by diabetes that is characterized by changes in myocardial structure and function, ultimately leading to heart failure and even death. Mitochondria serve as the provider of energy to cardiomyocytes, and mitochondrial dysfunction plays a central role in the development of diabetic cardiomyopathy. In response to a series of pathological changes caused by mitochondrial dysfunction, the mitochondrial quality control system is activated. The mitochondrial quality control system (including mitochondrial biogenesis, fusion and fission, and mitophagy) is core to maintaining the normal structure of mitochondria and performing their normal physiological functions. However, mitochondrial quality control is abnormal in diabetic cardiomyopathy, resulting in insufficient mitochondrial fusion and excessive fission within the cardiomyocyte, and fragmented mitochondria are not phagocytosed in a timely manner, accumulating within the cardiomyocyte resulting in cardiomyocyte injury. Currently, there is no specific therapy or prevention for diabetic cardiomyopathy, and glycemic control remains the mainstay. In this review, we first elucidate the pathogenesis of diabetic cardiomyopathy and explore the link between pathological mitochondrial quality control and the development of diabetic cardiomyopathy. Then, we summarize how clinically used hypoglycemic agents (including sodium-glucose cotransport protein 2 inhibitions, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, metformin, and α-glucosidase inhibitors) exert cardioprotective effects to treat and prevent diabetic cardiomyopathy by targeting the mitochondrial quality control system. In addition, the mechanisms of complementary alternative therapies, such as active ingredients of traditional Chinese medicine, exercise, and lifestyle, targeting mitochondrial quality control for the treatment of diabetic cardiomyopathy are also added, which lays the foundation for the excavation of new diabetic cardioprotective drugs.
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Affiliation(s)
- Yutong Zhou
- Guang'an Men Hospital, China Academy of Chinese Medicine, Beijing 100053, China
| | - Wendong Suo
- LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Xinai Zhang
- Guang'an Men Hospital, China Academy of Chinese Medicine, Beijing 100053, China
| | - Jiaojiao Liang
- Zhengzhou Shuqing Medical College, Zhengzhou 450064, China
| | - Weizhe Zhao
- College of Traditional Chinese Medicine, Beijing University of Traditional Chinese Medicine, Beijing 100105, China
| | - Yue Wang
- Capital Medical University, Beijing 100069, China
| | - Hong Li
- LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
| | - Qing Ni
- Guang'an Men Hospital, China Academy of Chinese Medicine, Beijing 100053, China.
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8
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Wójcicka G, Pradiuch A, Fornal E, Stachniuk A, Korolczuk A, Marzec-Kotarska B, Nikolaichuk H, Czechowska G, Kozub A, Trzpil A, Góralczyk A, Bełtowski J. The effect of exenatide (a GLP-1 analogue) and sitagliptin (a DPP-4 inhibitor) on asymmetric dimethylarginine (ADMA) metabolism and selected biomarkers of cardiac fibrosis in rats with fructose-induced metabolic syndrome. Biochem Pharmacol 2023; 214:115637. [PMID: 37290595 DOI: 10.1016/j.bcp.2023.115637] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 05/31/2023] [Accepted: 05/31/2023] [Indexed: 06/10/2023]
Abstract
Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis, is a risk factor for endothelial dysfunction, a common pathophysiological denominator for both atherogenesis and cardiac fibrosis. We aimed to investigate whether the cardioprotective and antifibrotic effects of incretin drugs, exenatide and sitagliptin, may be associated with their ability to affect circulating and cardiac ADMA metabolism. Normal and fructose-fed rats were treated with sitagliptin (5.0/10 mg/kg) or exenatide (5/10 µg/kg) for 4 weeks. The following methods were used: LC-MS/MS, ELISA, Real-Time-PCR, colorimetry, IHC and H&E staining, PCA and OPLS-DA projections. Eight-week fructose feeding resulted in an increase in plasma ADMA and a decrease in NO concentration. Exenatide administration into fructose-fed rats reduced the plasma ADMA level and increased NO level. In the heart of these animals exenatide administration increased NO and PRMT1 level, reduced TGF-ß1, α-SMA levels and COL1A1 expression. In the exenatide treated rats renal DDAH activity positively correlated with plasma NO level and negatively with plasma ADMA level and cardiac α-SMA concentration. Sitagliptin treatment of fructose-fed rats increased plasma NO concentration, reduced circulating SDMA level, increased renal DDAH activity and reduced myocardial DDAH activity. Both drugs attenuated the myocardial immunoexpression of Smad2/3/P and perivascular fibrosis. In the metabolic syndrome condition both sitagliptin and exenatide positively modulated cardiac fibrotic remodeling and circulating level of endogenous NOS inhibitors but had no effects on ADMA levels in the myocardium.
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Affiliation(s)
- G Wójcicka
- Department of Pathophysiology, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090 Lublin, Poland.
| | - A Pradiuch
- Department of Pathophysiology, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090 Lublin, Poland.
| | - E Fornal
- Department of Bioanalytic, Medical University of Lublin ul. Jaczewskiego 8b, 20-090 Lublin, Poland.
| | - A Stachniuk
- Department of Bioanalytic, Medical University of Lublin ul. Jaczewskiego 8b, 20-090 Lublin, Poland.
| | - A Korolczuk
- Department of Clinical Pathology, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090 Lublin, Poland.
| | - B Marzec-Kotarska
- Department of Clinical Pathology, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090 Lublin, Poland.
| | - H Nikolaichuk
- Department of Bioanalytic, Medical University of Lublin ul. Jaczewskiego 8b, 20-090 Lublin, Poland.
| | - G Czechowska
- Department of Pharmacology, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090 Lublin, Poland.
| | - A Kozub
- Department of Bioanalytic, Medical University of Lublin ul. Jaczewskiego 8b, 20-090 Lublin, Poland.
| | - A Trzpil
- Department of Bioanalytic, Medical University of Lublin ul. Jaczewskiego 8b, 20-090 Lublin, Poland.
| | - A Góralczyk
- Department of Pathophysiology, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090 Lublin, Poland.
| | - J Bełtowski
- Department of Pathophysiology, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090 Lublin, Poland.
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9
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Ribeiro-Silva JC, Tavares CAM, Girardi ACC. The blood pressure lowering effects of glucagon-like peptide-1 receptor agonists: A mini-review of the potential mechanisms. Curr Opin Pharmacol 2023; 69:102355. [PMID: 36857807 DOI: 10.1016/j.coph.2023.102355] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 01/10/2023] [Accepted: 01/27/2023] [Indexed: 03/03/2023]
Abstract
The incretin hormone glucagon-like peptide 1 (GLP-1) is a key component of the signaling mechanisms promoting glucose homeostasis. Clinical and experimental studies demonstrated that GLP-1 receptor agonists, including GLP-1 itself, have favorable effects on blood pressure and reduce the risk of major cardiovascular events, independently of their effect on glycemic control. GLP-1 receptors are present in the hypothalamus and brainstem, the carotid body, the vasculature, and the kidneys. These organs are involved in blood pressure regulation, have their function altered in hypertension, and are positively benefited by the treatment with GLP-1 receptor agonists. Here, we discuss the potential mechanisms whereby activation of GLP-1R signaling exerts blood pressure-lowering effects beyond glycemic control.
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Affiliation(s)
- Joao Carlos Ribeiro-Silva
- Laboratório de Genética e Cardiologia Molecular, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Caio A M Tavares
- Unidade de Cardiogeriatria, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil; Academic Research Organization (ARO), Hospital Israelita Albert Einstein, São Paulo, São Paulo, Brazil
| | - Adriana C C Girardi
- Laboratório de Genética e Cardiologia Molecular, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
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10
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Jia Y, Mao C, Ma Z, Huang J, Li W, Ma X, Zhang S, Li M, Yu F, Sun Y, Chen J, Feng J, Zhou Y, Xu Q, Zhao L, Fu Y, Kong W. PHB2 Maintains the Contractile Phenotype of VSMCs by Counteracting PKM2 Splicing. Circ Res 2022; 131:807-824. [PMID: 36200440 DOI: 10.1161/circresaha.122.321005] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND Phenotypic transition of vascular smooth muscle cells (VSMCs) accounts for the pathogenesis of a variety of vascular diseases during the early stage. Recent studies indicate the metabolic reprogramming may be involved in VSMC phenotypic transition. However, the definite molecules that link energy metabolism to distinct VSMC phenotype remain elusive. METHODS A carotid artery injury model was used to study postinjury neointima formation as well as VSMC phenotypic transition in vivo. RNA-seq analysis, cell migration assay, collagen gel contraction assay, wire myography assay, immunoblotting, protein interactome analysis, co-immunoprecipitation, and mammalian 2-hybrid assay were performed to clarify the phenotype and elucidate the molecular mechanisms. RESULTS We collected cell energy-regulating genes by using Gene Ontology annotation and applied RNA-Seq analysis of transforming growth factor-β or platelet-derived growth factor BB stimulated VSMCs. Six candidate genes were overlapped from energy metabolism-related genes and genes reciprocally upregulated by transforming growth factor-β and downregulated by platelet-derived growth factor BB. Among them, prohibitin 2 has been reported to regulate mitochondrial oxidative phosphorylation. Indeed, prohibitin 2-deficient VSMCs lost the contractile phenotype as evidenced by reduced contractile proteins. Consistently, Phb2SMCKO mice were more susceptible to postinjury VSMC proliferation and neointima formation compared with Phb2flox/flox mice. Further protein interactome analysis, co-immunoprecipitation, and mammalian 2-hybrid assay revealed that prohibitin 2, through its C-terminus, directly interacts with hnRNPA1, a key modulator of pyruvate kinase M1/2 (PKM) mRNA splicing that promotes PKM2 expression and glycolysis. Prohibitin 2 deficiency facilitated PKM1/2 mRNA splicing and reversion from PKM1 to PKM2, and enhanced glycolysis in VSMCs. Blocking prohibitin 2-hnRNPA1 interaction resulted in increased PKM2 expression, enhanced glycolysis, repressed contractile marker genes expression in VSMCs, as well as aggravated postinjury neointima formation in vivo. CONCLUSIONS Prohibitin 2 maintains VSMC contractile phenotype by interacting with hnRNPA1 to counteract hnRNPA1-mediated PKM alternative splicing and glucose metabolic reprogramming.
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Affiliation(s)
- Yiting Jia
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.J., C.M., Z.M., J.H., W.L., X.M., S.Z., M.L., F.Y., J.F., Y.Z., Y.F., W.K.)
| | - Chenfeng Mao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.J., C.M., Z.M., J.H., W.L., X.M., S.Z., M.L., F.Y., J.F., Y.Z., Y.F., W.K.).,Beijing Institute of Biotechnology, Beijing, P. R. China (C.M.)
| | - Zihan Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.J., C.M., Z.M., J.H., W.L., X.M., S.Z., M.L., F.Y., J.F., Y.Z., Y.F., W.K.)
| | - Jiaqi Huang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.J., C.M., Z.M., J.H., W.L., X.M., S.Z., M.L., F.Y., J.F., Y.Z., Y.F., W.K.)
| | - Wenqiang Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.J., C.M., Z.M., J.H., W.L., X.M., S.Z., M.L., F.Y., J.F., Y.Z., Y.F., W.K.)
| | - Xiaolong Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.J., C.M., Z.M., J.H., W.L., X.M., S.Z., M.L., F.Y., J.F., Y.Z., Y.F., W.K.)
| | - Siting Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.J., C.M., Z.M., J.H., W.L., X.M., S.Z., M.L., F.Y., J.F., Y.Z., Y.F., W.K.)
| | - Meihong Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.J., C.M., Z.M., J.H., W.L., X.M., S.Z., M.L., F.Y., J.F., Y.Z., Y.F., W.K.)
| | - Fang Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.J., C.M., Z.M., J.H., W.L., X.M., S.Z., M.L., F.Y., J.F., Y.Z., Y.F., W.K.)
| | - Yingying Sun
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China (Y.S., J.C.)
| | - Jingzhou Chen
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China (Y.S., J.C.)
| | - Juan Feng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.J., C.M., Z.M., J.H., W.L., X.M., S.Z., M.L., F.Y., J.F., Y.Z., Y.F., W.K.)
| | - Yuan Zhou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.J., C.M., Z.M., J.H., W.L., X.M., S.Z., M.L., F.Y., J.F., Y.Z., Y.F., W.K.)
| | - Qingbo Xu
- Cardiovascular Division, Kings College London BHF Centre, London SE5 9NU, UK (Q.X.).,Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China (Q.X.)
| | - Ling Zhao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, P. R. China (L.Z.)
| | - Yi Fu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.J., C.M., Z.M., J.H., W.L., X.M., S.Z., M.L., F.Y., J.F., Y.Z., Y.F., W.K.)
| | - Wei Kong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.J., C.M., Z.M., J.H., W.L., X.M., S.Z., M.L., F.Y., J.F., Y.Z., Y.F., W.K.)
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11
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Chen SY, Kong XQ, Zhang KF, Luo S, Wang F, Zhang JJ. DPP4 as a Potential Candidate in Cardiovascular Disease. J Inflamm Res 2022; 15:5457-5469. [PMID: 36147690 PMCID: PMC9488155 DOI: 10.2147/jir.s380285] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 09/09/2022] [Indexed: 11/23/2022] Open
Abstract
The rising prevalence of cardiovascular disease has become a global health concern. The occurrence of cardiovascular disease is the result of long-term interaction of many risk factors, one of which is diabetes. As a novel anti-diabetic drug, DPP4 inhibitor has been proven to be cardiovascular safe in five recently completed cardiovascular outcome trials. Accumulating studies suggest that DPP4 inhibitor has potential benefits in a variety of cardiovascular diseases, including hypertension, calcified aortic valve disease, coronary atherosclerosis, and heart failure. On the one hand, in addition to improving blood glucose control, DPP4 inhibitor is involved in controlling cardiovascular risk factors. On the other hand, DPP4 inhibitor directly regulates the occurrence and progression of cardiovascular diseases through a variety of mechanisms. In this review, we summarize the recent advances of DPP4 in cardiovascular disease, aiming to discuss DPP4 inhibitor as a potential option for cardiovascular therapy.
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Affiliation(s)
- Si-Yu Chen
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiang-Quan Kong
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China.,Department of Cardiology, Nanjing Heart Centre, Nanjing, People's Republic of China
| | - Ke-Fan Zhang
- Department of General Surgery, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Shuai Luo
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Feng Wang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Jun-Jie Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China.,Department of Cardiology, Nanjing Heart Centre, Nanjing, People's Republic of China
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12
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Soluble Epoxide Hydrolase Inhibitor t-AUCB Ameliorates Vascular Endothelial Dysfunction by Influencing the NF-κB/miR-155-5p/eNOS/NO/IκB Cycle in Hypertensive Rats. Antioxidants (Basel) 2022; 11:antiox11071372. [PMID: 35883863 PMCID: PMC9311992 DOI: 10.3390/antiox11071372] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/09/2022] [Accepted: 07/12/2022] [Indexed: 11/16/2022] Open
Abstract
Epoxyeicosatrienoic acids (EETs), angiogenic mediators degraded by soluble epoxide hydrolase (sEH), have been shown to exert beneficial effects on the cardiovascular system. The current study assessed the impact of increased EETs with an sEH inhibitor, t-AUCB, on two-kidney-one-clip (2K1C)-induced renovascular endothelial dysfunction, associated with hypertension, in rats. The hypertensive rats exhibited increased systolic blood pressure, reduced renal blood flow, impaired endothelium-dependent relaxation and eNOS phosphorylation in the renal arteries, elevated ROS production in the endothelium of the renal arteries, and decreased EET levels in plasma, the renal arteries, and endothelial cells; however, t-AUCB reversed all the deleterious effects. Moreover, we found that the stimulation of AMPK/UCP2 scavenged ROS and restored endothelial function in the renal arteries of hypertensive rats undergoing therapy with t-AUCB. In addition, we were the first to reveal the potential role of miR-155-5p in the occurrence and development of vascular endothelial dysfunction in hypertension. Importantly, t-AUCB recovered NO bioavailability by regulating the NF-κB/miR-155-5p/eNOS/NO/IκB cycle after the activation of AMPK/UCP2 and the subsequent inhibition of ROS in hypertensive rat renal artery endothelial cells. This study will provide evidence for this additional new mechanism, underlying the benefits of EETs and the related agents against hypertensive vasculopathy.
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13
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Wu LD, Zhou N, Sun JY, Yu H, Wang RX. Effects of sitagliptin on serum lipid levels in patients with type 2 diabetes: a systematic review and meta-analysis. J Cardiovasc Med (Hagerstown) 2022; 23:308-317. [PMID: 35486682 DOI: 10.2459/jcm.0000000000001270] [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: 11/05/2022]
Abstract
AIM Lipid abnormalities often occur in patients with diabetes mellitus and the coexistence of diabetes mellitus and dyslipidaemia will increase the risk of cardiovascular diseases. However, the specific effects of sitagliptin on lipid control remain elusive in diabetic patients. The aim of this meta-analysis is to investigate the effects of sitagliptin alone or with other antidiabetic agents on serum lipid control. METHODS PubMed, Cochrane Library, Embase and the ClinicalTrials.gov website were systematically searched from 2006 (the first year that sitagliptin entered market) to 16 January 2021. Eligible studies were randomized clinical trials (RCTs) of sitagliptin including outcomes of serum total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C) or low-density lipoprotein cholesterol (LDL-C). RESULTS A total of 14 RCTs with 2654 patients were identified. Treatment with sitagliptin alone or in combination with other antidiabetic agents significantly reduced serum TC [mean difference (MD) = -5.52 95% confidence interval (95% CI), -7.88 to -3.15; P < 0.00001] and LDL-C (MD = -0.07; 95% CI, -0.14 to 0.00; P < 0.00001) in patients with type 2 diabetes. No statistical significances were found in serum triglycerides (MD = 1.53; 95% CI, -8.22 to 11.28; P = 0.76) or HDL-C (MD = 0.65; 95% CI, -1.59 to 0.29; P = 0.18). Subgroup analyses suggest that sitagliptin can significantly decrease serum LDL-C, TC and triglyceride levels compared with placebo alone, and no statistical significance was found in comparison with the serum HDLC levels. CONCLUSION Sitagliptin alone or in combination with other antidiabetic agents significantly reduces serum TC and LDL-C in patients with type 2 diabetes mellitus, while no significant difference was observed in serum triglycerides or HDL-C.
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Affiliation(s)
- Li-Da Wu
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University
| | - Nan Zhou
- Department of Nursing, Huadong Sanatorium, Wuxi
| | - Jin-Yu Sun
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University
| | - Hao Yu
- Department of Orthopedics, Tianjin Medical University General Hospital Affiliated to Tianjin Medical University, Tianjin, China
| | - Ru-Xing Wang
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University
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14
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Wang L, Cheng CK, Yi M, Lui KO, Huang Y. Targeting endothelial dysfunction and inflammation. J Mol Cell Cardiol 2022; 168:58-67. [PMID: 35460762 DOI: 10.1016/j.yjmcc.2022.04.011] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/05/2022] [Accepted: 04/14/2022] [Indexed: 12/15/2022]
Abstract
Vascular endothelium maintains vascular homeostasis through liberating a spectrum of vasoactive molecules, both protective and harmful regulators of vascular tone, structural remodeling, inflammation and atherogenesis. An intricate balance between endothelium-derived relaxing factors (nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor) and endothelium-derived contracting factors (superoxide anion, endothelin-1 and constrictive prostaglandins) tightly regulates vascular function. Disruption of such balance signifies endothelial dysfunction, a critical contributor in aging and chronic cardiometabolic disorders, such as obesity, diabetes, hypertension, dyslipidemia and atherosclerotic vascular diseases. Among many proposed cellular and molecular mechanisms causing endothelial dysfunction, oxidative stress and inflammation are often the pivotal players and they are naturally considered as useful targets for intervention in patients with cardiovascular and metabolic diseases. In this article, we provide a recent update on the therapeutic values of pharmacological agents, such as cyclooxygenase-2 inhibitors, renin-angiotensin-system inhibitors, bone morphogenic protein 4 inhibitors, peroxisome proliferator-activated receptor δ agonists, and glucagon-like peptide 1-elevating drugs, and the physiological factors, particularly hemodynamic forces, that improve endothelial function by targeting endothelial oxidative stress and inflammation.
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Affiliation(s)
- Li Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Chak Kwong Cheng
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Min Yi
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Kathy O Lui
- Department of Chemical Pathology and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
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15
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Khodir SA, Faried MA, Abd-Elhafiz HI, Sweed EM. Sitagliptin Attenuates the Cognitive Deficits in L-Methionine-Induced Vascular Dementia in Rats. BIOMED RESEARCH INTERNATIONAL 2022; 2022:7222590. [PMID: 35265716 PMCID: PMC8898801 DOI: 10.1155/2022/7222590] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 01/29/2022] [Indexed: 02/05/2023]
Abstract
Vascular dementia (VaD) is the second most prevalent type of dementia characterized by progressive cognitive deficits and is a major risk factor for the development of Alzheimer's disease and other neurodegenerative disorders. This study is aimed at determining the potential neuroprotective effect of sitagliptin (STG) on cognitive deficits in L-methionine-induced VaD in rats and the possible underlying mechanisms. 30 adult male Wistar albino rats were divided equally (n = 10) into three groups: control, VaD, and VaD + STG groups. The cognitive performance of the animals was conducted by open field, elevated plus maze, Y-maze, novel object recognition, and Morris water maze tests. Serum homocysteine, TNF-α, IL-6, IL-10, total cholesterol, and triglycerides levels were assessed together with hippocampal MDA, SOD, and BDNF. Histopathological and immunohistochemical assessments of the thoracic aorta and hippocampus (CA1 region) were also performed. Chronic L-methionine administration impaired memory and learning and induced anxiety. On the other hand, STG protected against cognitive deficits through improving oxidative stress biomarkers, inflammatory mediators, lipid profiles, and hippocampus level of BDNF as well as decreasing caspase-3 and GFAP and increasing Ki-67 immunoreactions in the hippocampus. Also, STG improved the endothelial dysfunction via upregulation of aortic eNOS immunoreaction. STG improved the cognitive deficits of L-methionine-induced VaD by its antioxidant, anti-inflammatory, antiapoptotic, and neurotrophic effects. These findings suggest that STG may be a promising future agent for protection against VaD.
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Affiliation(s)
- Suzan A. Khodir
- Medical Physiology Department, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt
| | - Manar A. Faried
- Human Anatomy and Embryology, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt
| | - Huda I. Abd-Elhafiz
- Clinical Pharmacology Department, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt
| | - Eman M. Sweed
- Clinical Pharmacology Department, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt
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16
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Huang HC, Hsu SJ, Chuang CL, Hsiung SY, Chang CC, Hou MC, Lee FY. Effects of dipeptidyl peptidase-4 inhibition on portal hypertensive and cirrhotic rats. J Chin Med Assoc 2021; 84:1092-1099. [PMID: 34670224 DOI: 10.1097/jcma.0000000000000636] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Portal hypertension is a pathophysiological abnormality with distinct vascular derangements associated with liver cirrhosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents which exert pleiotropic vascular effects, but their relevant impact on portal hypertension and liver cirrhosis remains unclear. This study aims to clarify this issue. METHODS Rats receiving partial portal vein ligation (PVL) and common bile duct ligation (BDL) served as experimental models for portal hypertension and cirrhosis, respectively. After linagliptin (a DPP-4 inhibitor) treatment, the survival rate, hemodynamics, biochemistry parameters and liver histopathology were evaluated. In addition, the collateral vascular responsiveness and severity of portal-systemic shunting were examined. mRNA and protein expression in the vasculature and liver were also examined. RESULTS Linagliptin significantly reduced portal pressure (control vs linagliptin: 12.9 ± 1.2 vs 9.1 ± 2.0 mmHg, p = 0.001) and upregulated nitric oxide synthase expression in the collateral vessel, superior mesentery artery, and liver of PVL rats. However, the portal hypotensive effect was insignificant in BDL rats. Glucose plasma levels, liver and renal biochemistry parameters were not significantly altered by linagliptin. The degree of portal-systemic shunting and collateral vascular responsiveness were also not significantly altered by linagliptin treatment. Linagliptin did not improve liver fibrosis and hepatic inflammation in BDL rats. CONCLUSION DPP-4 inhibition by linagliptin reduced portal pressure in portal hypertensive rats but not in cirrhotic rats. It may act by decreasing intrahepatic resistance via upregulation of hepatic nitric oxide synthase in portal hypertensive rats.
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Affiliation(s)
- Hui-Chun Huang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Shao-Jung Hsu
- Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chiao-Lin Chuang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Shao-Yu Hsiung
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ching-Chih Chang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ming-Chih Hou
- Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Fa-Yauh Lee
- Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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17
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Salvianolic acid B ameliorates vascular endothelial dysfunction through influencing a bone morphogenetic protein 4-ROS cycle in diabetic mice. Life Sci 2021; 286:120039. [PMID: 34637797 DOI: 10.1016/j.lfs.2021.120039] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/31/2021] [Accepted: 09/08/2021] [Indexed: 11/21/2022]
Abstract
AIM This study investigated the roles of bone morphogenetic protein-4 (BMP4) and ROS in diabetic endothelial dysfunction and explored whether Salvianolic acid B (Sal B) improved endothelial function by affecting BMP4-ROS in diabetic mice. MAIN METHODS db/db mice were orally administrated with Sal B (10 mg/kg/day) for one week while db/m + mice were injected with adenoviral vectors delivering BMP4 (3 × 108 pfu) and then received one week-Sal B treatment. ROS levels were assayed by DHE staining. Protein expression and phosphorylation were evaluated by Western blot. Aortic rings were suspended in myograph for force measurement. Flow-mediated dilatations in the second-order mesenteric arteries were determined by pressure myograph. KEY FINDINGS We first revealed the existence of a BMP4-ROS cycle in db/db mice, which stimulated p38 MAPK/JNK/caspase 3 and thus participated in endothelial dysfunction. One week-treatment or 24 h-incubation with Sal B disrupted the cycle, suppressed p38 MAPK/JNK/caspase 3 cascade, and improved endothelium-dependent relaxations (EDRs) in db/db mouse aortas. Importantly, in vivo Sal B treatment also improved flow-mediated dilatation in db/db mouse second order mesenteric arteries. Furthermore, in vivo BMP4 overexpression induced oxidative stress, stimulated p38 MAPK/JNK/caspase 3, and impaired EDRs in db/m + mouse aortas, which were all reversed by Sal B. SIGNIFICANCE The present study demonstrates that Sal B ameliorates endothelial dysfunction through breaking the BMP4-ROS cycle and subsequently inhibiting p38 MAPK/JNK/caspase 3 in diabetic mice and provides evidence for the additional new mechanism underlying the benefit of Sal B against diabetic vasculopathy.
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18
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Love KM, Barrett EJ, Malin SK, Reusch JEB, Regensteiner JG, Liu Z. Diabetes pathogenesis and management: the endothelium comes of age. J Mol Cell Biol 2021; 13:500-512. [PMID: 33787922 PMCID: PMC8530521 DOI: 10.1093/jmcb/mjab024] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/10/2021] [Accepted: 02/25/2021] [Indexed: 12/03/2022] Open
Abstract
Endothelium, acting as a barrier, protects tissues against factors that provoke insulin resistance and type 2 diabetes and itself responds to the insult of insulin resistance inducers with altered function. Endothelial insulin resistance and vascular dysfunction occur early in the evolution of insulin resistance-related disease, can co-exist with and even contribute to the development of metabolic insulin resistance, and promote vascular complications in those affected. The impact of endothelial insulin resistance and vascular dysfunction varies depending on the blood vessel size and location, resulting in decreased arterial plasticity, increased atherosclerosis and vascular resistance, and decreased tissue perfusion. Women with insulin resistance and diabetes are disproportionately impacted by cardiovascular disease, likely related to differential sex-hormone endothelium effects. Thus, reducing endothelial insulin resistance and improving endothelial function in the conduit arteries may reduce atherosclerotic complications, in the resistance arteries lead to better blood pressure control, and in the microvasculature lead to less microvascular complications and more effective tissue perfusion. Multiple diabetes therapeutic modalities, including medications and exercise training, improve endothelial insulin action and vascular function. This action may delay the onset of type 2 diabetes and/or its complications, making the vascular endothelium an attractive therapeutic target for type 2 diabetes and potentially type 1 diabetes.
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MESH Headings
- Age Factors
- Cardiovascular Diseases/epidemiology
- Cardiovascular Diseases/ethnology
- Cardiovascular Diseases/metabolism
- Cardiovascular Diseases/physiopathology
- Comorbidity
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/epidemiology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/physiopathology
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/epidemiology
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/physiopathology
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/physiopathology
- Exercise
- Female
- Humans
- Hypoglycemic Agents/pharmacology
- Hypoglycemic Agents/therapeutic use
- Insulin Resistance
- Male
- Racial Groups
- Risk Factors
- Sex Factors
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Affiliation(s)
- Kaitlin M Love
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Eugene J Barrett
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Steven K Malin
- Department of Kinesiology and Health, Rutgers University, New Brunswick, NJ, USA
- Division of Endocrinology, Metabolism and Nutrition, Rutgers University, New Brunswick, NJ, USA
- New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, NJ, USA
- Institute of Translational Medicine and Research, Rutgers University, New Brunswick, NJ, USA
| | - Jane E B Reusch
- Center for Women’s Health Research, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA
| | - Judith G Regensteiner
- Center for Women’s Health Research, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Zhenqi Liu
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
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19
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Liu J, Zuo Q, Li Z, Chen J, Liu F. Trelagliptin ameliorates IL-1β-impaired chondrocyte function via the AMPK/SOX-9 pathway. Mol Immunol 2021; 140:70-76. [PMID: 34666245 DOI: 10.1016/j.molimm.2021.09.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 08/01/2021] [Accepted: 09/14/2021] [Indexed: 12/20/2022]
Abstract
Chondrocyte dysregulation plays a critical role in the development of osteoarthritis (OA). The pro-inflammatory cytokine interleukin-1β (IL-1β) activates chondrocytes and degrades the structural extracellular matrix (ECM). These events are the important mechanism of OA. Trelagliptin, a selective inhibitor of dipeptidyl Peptidase 4 (DPP-4) used for the treatment of type 2 diabetes mellitus (T2DM), has displayed a wide range of anti-inflammatory capacities. The effects of Trelagliptin in OA and chondrocytes have not been tested before. Here, we show that Trelagliptin mitigates IL-1β-induced production of inflammatory cytokines such as interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor-alpha (TNF-α) in human chondrocytes. Trelagliptin ameliorates IL-1β-induced oxidative stress by reducing the generation of reactive oxygen species (ROS). Particularly, the presence of Trelagliptin prevents IL-1β-induced reduction of Acan genes and the protein Aggrecan. Moreover, we show that Trelagliptin restores IL-1β-induced reduction of SOX-9 and that the knockdown of SOX-9 abolishes the protective effects of Trelagliptin. Mechanistically, we demonstrate that AMPK is required for the amelioration of Trelagliptin on SOX-9- reduction by IL-1β. Collectively, our study demonstrates that the DPP-4 inhibitor Trelagliptin has a protective effect on chondrocyte function. Trelagliptin may have the potential role to antagonize chondrocyte-derived inflammation in OA.
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Affiliation(s)
- Jiuxiang Liu
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Nanjing Medical University (Jiangsu Province Hospital), Nanjing, Jiangsu, 210029, China
| | - Qiang Zuo
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Nanjing Medical University (Jiangsu Province Hospital), Nanjing, Jiangsu, 210029, China
| | - Zhi Li
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Nanjing Medical University (Jiangsu Province Hospital), Nanjing, Jiangsu, 210029, China
| | - Jiangqi Chen
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Nanjing Medical University (Jiangsu Province Hospital), Nanjing, Jiangsu, 210029, China
| | - Feng Liu
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Nanjing Medical University (Jiangsu Province Hospital), Nanjing, Jiangsu, 210029, China.
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20
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Cheng CK, Huang Y. The gut-cardiovascular connection: new era for cardiovascular therapy. MEDICAL REVIEW (BERLIN, GERMANY) 2021; 1:23-46. [PMID: 37724079 PMCID: PMC10388818 DOI: 10.1515/mr-2021-0002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 06/02/2021] [Indexed: 09/20/2023]
Abstract
Our gut microbiome is constituted by trillions of microorganisms including bacteria, archaea and eukaryotic microbes. Nowadays, gut microbiome has been gradually recognized as a new organ system that systemically and biochemically interact with the host. Accumulating evidence suggests that the imbalanced gut microbiome contributes to the dysregulation of immune system and the disruption of cardiovascular homeostasis. Specific microbiome profiles and altered intestinal permeability are often observed in the pathophysiology of cardiovascular diseases. Gut-derived metabolites, toxins, peptides and immune cell-derived cytokines play pivotal roles in the induction of inflammation and the pathogenesis of dysfunction of heart and vasculature. Impaired crosstalk between gut microbiome and multiple organ systems, such as gut-vascular, heart-gut, gut-liver and brain-gut axes, are associated with higher cardiovascular risks. Medications and strategies that restore healthy gut microbiome might therefore represent novel therapeutic options to lower the incidence of cardiovascular and metabolic disorders.
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Affiliation(s)
- Chak Kwong Cheng
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science; The Chinese University of Hong Kong, Hong Kong SAR999077, China
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR999077, China
| | - Yu Huang
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science; The Chinese University of Hong Kong, Hong Kong SAR999077, China
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR999077, China
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21
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Cheng CK, Luo JY, Lau CW, Cho WCS, Ng CF, Ma RCW, Tian XY, Huang Y. A GLP-1 analog lowers ER stress and enhances protein folding to ameliorate homocysteine-induced endothelial dysfunction. Acta Pharmacol Sin 2021; 42:1598-1609. [PMID: 33495519 PMCID: PMC8463564 DOI: 10.1038/s41401-020-00589-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/15/2020] [Indexed: 02/02/2023]
Abstract
Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases and increases mortality in type 2 diabetic patients. HHcy induces endoplasmic reticulum (ER) stress and oxidative stress to impair endothelial function. The glucagon-like peptide 1 (GLP-1) analog exendin-4 attenuates endothelial ER stress, but the detailed vasoprotective mechanism remains elusive. The present study investigated the beneficial effects of exendin-4 against HHcy-induced endothelial dysfunction. Exendin-4 pretreatment reversed homocysteine-induced impairment of endothelium-dependent relaxations in C57BL/6 mouse aortae ex vivo. Four weeks subcutaneous injection of exendin-4 restored the impaired endothelial function in both aortae and mesenteric arteries isolated from mice with diet-induced HHcy. Exendin-4 treatment lowered superoxide anion accumulation in the mouse aortae both ex vivo and in vivo. Exendin-4 decreased the expression of ER stress markers (e.g., ATF4, spliced XBP1, and phosphorylated eIF2α) in human umbilical vein endothelial cells (HUVECs), and this change was reversed by cotreatment with compound C (CC) (AMPK inhibitor). Exendin-4 induced phosphorylation of AMPK and endothelial nitric oxide synthase in HUVECs and arteries. Exendin-4 increased the expression of endoplasmic reticulum oxidoreductase (ERO1α), an important ER chaperone in endothelial cells, and this effect was mediated by AMPK activation. Experiments using siRNA-mediated knockdown or adenoviral overexpression revealed that ERO1α mediated the inhibitory effects of exendin-4 on ER stress and superoxide anion production, thus ameliorating HHcy-induced endothelial dysfunction. The present results demonstrate that exendin-4 reduces HHcy-induced ER stress and improves endothelial function through AMPK-dependent ERO1α upregulation in endothelial cells and arteries. AMPK activation promotes the protein folding machinery in endothelial cells to suppress ER stress.
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Affiliation(s)
- Chak Kwong Cheng
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jiang-Yun Luo
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Chi Wai Lau
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - William Chi-Shing Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong SAR, China
| | - Chi Fai Ng
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ronald Ching Wan Ma
- Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, and The Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xiao Yu Tian
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China.
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Yu Huang
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China.
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
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22
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Mao C, Ma Z, Jia Y, Li W, Xie N, Zhao G, Ma B, Yu F, Sun J, Zhou Y, Cui Q, Fu Y, Kong W. Nidogen-2 Maintains the Contractile Phenotype of Vascular Smooth Muscle Cells and Prevents Neointima Formation via Bridging Jagged1-Notch3 Signaling. Circulation 2021; 144:1244-1261. [PMID: 34315224 DOI: 10.1161/circulationaha.120.053361] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: How the extracellular matrix (ECM) microenvironment modulates the contractile phenotype of vascular smooth muscle cells (VSMCs) and confers vascular homeostasis remains elusive. Methods: To explore the key ECM proteins in the maintenance of the contractile phenotype of VSMCs, we applied protein-protein interaction (PPI) network analysis to explore novel ECM proteins associated with the VSMC phenotype. By combining in vitro and in vivo genetic mice vascular injury model, we identified nidogen-2, a basement membrane (BM) glycoprotein, as a key ECM protein for maintenance of vascular smooth muscle cell identity. Results: We collected a VSMC phenotype-related gene dataset (VSMCPRG dataset) by using Gene Ontology (GO) annotation combined with a literature search. A computational analysis of protein-protein interactions between ECM protein genes and the genes from the VSMCPRG dataset revealed the candidate gene nidogen-2, a BM glycoprotein involved in regulation of the VSMC phenotype. Indeed, nidogen-2-deficient VSMCs exhibited loss of contractile phenotype in vitro, and compared with wild-type (WT) mice, nidogen-2-/- mice showed aggravated post-wire injury neointima formation of carotid arteries. Further bioinformatics analysis, co-immunoprecipitation assays and luciferase assays revealed that nidogen-2 specifically interacted with Jagged1, a conventional Notch ligand. Nidogen-2 maintained the VSMC contractile phenotype via Jagged1-Notch3 signaling but not Notch1 or Notch2 signaling. Notably, nidogen-2 enhanced Jagged1 and Notch3 interaction and subsequent Notch3 activation. Reciprocally, Jagged1 and Notch3 interaction, signaling activation, and Jagged1-triggered VSMC differentiation were significantly repressed in nidogen-2-deficient VSMCs. In accordance, the suppressive effect of Jagged1 overexpression on neointima formation was attenuated in nidogen-2-/- mice compared to wild-type mice. Conclusions: Nidogen-2 maintains the contractile phenotype of VSMCs through Jagged1-Notch3 signaling in vitro and in vivo. Nidogen-2 is required for Jagged1-Notch3 signaling.
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Affiliation(s)
- Chenfeng Mao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Zihan Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Yiting Jia
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Weihao Li
- Department of Vascular Surgery, Peking University People's Hospital, Peking University, Beijing, China
| | - Nan Xie
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Guizhen Zhao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Baihui Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Fang Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Jinpeng Sun
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yuan Zhou
- Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Qinghua Cui
- Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yi Fu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Wei Kong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
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23
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Zhang Y, Tan N, Zong Y, Li L, Zhang Y, Liu J, Wang X, Han W, Liu L. LncRNA ENSMUST00000155383 is Involved in the Improvement of DPP-4 Inhibitor MK-626 on Vascular Endothelial Function by Modulating Cacna1c-Mediated Ca 2+ Influx in Hypertensive Mice. Front Mol Biosci 2021; 8:724225. [PMID: 34368236 PMCID: PMC8343177 DOI: 10.3389/fmolb.2021.724225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 07/14/2021] [Indexed: 11/24/2022] Open
Abstract
Objective: This study investigated the protective effects of dipeptidyl peptidase-4 inhibitor MK-626 on vascular endothelial function by regulating lncRNAs in hypertensive vasculature. Methods: Angiotensin Ⅱ (Ang Ⅱ)-loaded osmotic pumps were implanted in mice with or without MK-626 administration. GLP-1 levels in plasma were measured by ELISA. Aortic rings were suspended in myograph for tension measurement. Microarray was performed to analyze lncRNA and mRNA expression profiles. Protein expression and phosphorylation were examined by Western blot. The differentially expressed (DE)-genes were validated by qRT-PCR. The intracellular Ca2+ concentration was detected by laser confocal system. Results: MK-626 elevated plasma GLP-1 level, increased eNOS phosphorylation, improved endothelium-dependent relaxations, and reduced systolic blood pressure in Ang Ⅱ-induced hypertensive mice. Microarray revealed the dysregulations of 723 lncRNAs and 742 mRNAs were reversed by MK-626 in hypertensive mouse aortae. qRT-PCR validation showed that 13 DE-lncRNAs and eight dysregulated mRNAs in both hypertensive mouse aortae and mouse aortic endothelial cells (MAECs) were rescued by MK-626. Among them, four mRNAs (Cacna1C, Itgav, Itga8, and Npnt) were co-expressed with lncRNA ENSMUST00000155383. Cacna1C protein expression was reduced in the ECs but was elevated in smooth muscle cells from Ang Ⅱ-infused mice, which were both reversed by MK-626. Knockdown of lncRNA ENSMUST00000155383 suppressed the increased Cacna1c protein and mRNA expression, elevated Ca2+ level, and enhanced eNOS phosphorylation induced by MK-626 in the hypertensive mouse ECs. Conclusion: The dysregulations of lncRNA ENSMUST00000155383-associated genes might play crucial roles in hypertension-induced endothelial dysfunction through affecting calcium pathway. MK-626 might ameliorate endothelial dysfunction by upregulating lncRNA ENSMUST00000155383, enhancing Ca2+ concentration, and subsequently restoring eNOS activity in hypertension.
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Affiliation(s)
- Yi Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Na Tan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yi Zong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Li Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.,Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Yan Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.,Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Jian Liu
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Xiaorui Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Wenwen Han
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Limei Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.,Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
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24
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Montoro-Molina S, Quesada A, O'Valle F, Morales NM, de Gracia MDC, Rodríguez-Gómez I, Osuna A, Wangensteen R, Vargas F. The Long-Term Study of Urinary Biomarkers of Renal Injury in Spontaneously Hypertensive Rats. Kidney Blood Press Res 2021; 46:502-513. [PMID: 34237745 DOI: 10.1159/000516843] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 04/25/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The age-related increase in blood pressure in spontaneously hypertensive rats (SHRs) is associated to cardiac hypertrophy, heart failure, and renal injury. Here, we investigated for the first time the urinary enzymatic activities of glutamil aminopeptidase (GluAp), alanyl aminopeptidase (AlaAp), dipeptidyl peptidase-4 (DPP4), and Klotho urinary levels, proteins that are strongly expressed in the kidney, as early biomarkers of renal injury in SHRs. METHODS Male SHR and Wistar Kyoto (WKY) rats were studied from 2 to 8 months old. Systolic blood pressure (SBP), the heart rate (HR), metabolic variables, and urinary markers were measured monthly. At the end of the study, a histopathological evaluation of the kidney was performed. RESULTS Kidneys of SHR did not develop signs of relevant histopathological changes, but showed increased glomerular area and cellularity. Plasma creatinine was decreased, and creatinine clearance was augmented in SHR at the end of the study. Urinary excretion of Klotho was higher in SHR at 5 and 8 months old, whereas plasma Klotho levels were similar to WKY. GluAp, AlaAp, and DPP4 urinary activities were increased in SHR throughout the time-course study. A positive correlation between glomerular area and cellularity with creatinine clearance was observed. Urinary GluAp, AlaAp, DPP4, and Klotho showed positive correlations with SBP. CONCLUSIONS GluAp, AlaAp, DPP4, and Klotho in the urine are useful tools for the evaluation of renal damage at early stages, before the whole histopathological and biochemical manifestations of renal disease are established. Moreover, these observations may represent a novel and noninvasive diagnostic approach to assess the evolution of kidney function in hypertension and other chronic diseases.
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Affiliation(s)
| | - Andrés Quesada
- Servicio de Nefrología, Unidad Experimental, Hospital Virgen de las Nieves, Granada, Spain
| | - Francisco O'Valle
- Departamento de Anatomía Patológica e Instituto de Biomedicina Regenerativa (IBIMER), Facultad de Medicina, Granada, Spain
| | - Natividad Martín Morales
- Departamento de Anatomía Patológica e Instituto de Biomedicina Regenerativa (IBIMER), Facultad de Medicina, Granada, Spain
| | | | | | - Antonio Osuna
- Servicio de Nefrología, Unidad Experimental, Hospital Virgen de las Nieves, Granada, Spain
- Instituto de Investigación Biosanitaria GRANADA, Hospitales Universitarios de Granada, Universidad de Granada, Granada, Spain
| | | | - Félix Vargas
- Departamento de Fisiología, Facultad de Medicina, Granada, Spain
- Instituto de Investigación Biosanitaria GRANADA, Hospitales Universitarios de Granada, Universidad de Granada, Granada, Spain
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25
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Yaribeygi H, Farrokhi FR, Abdalla MA, Sathyapalan T, Banach M, Jamialahmadi T, Sahebkar A. The Effects of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptydilpeptidase-4 Inhibitors on Blood Pressure and Cardiovascular Complications in Diabetes. J Diabetes Res 2021; 2021:6518221. [PMID: 34258291 PMCID: PMC8263148 DOI: 10.1155/2021/6518221] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 06/11/2021] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) agonists are a class of newly introduced antidiabetic medications that potentially lower blood glucose by several molecular pathways. DPP-4 inhibitors are the other type of novel antidiabetic medications which act by preventing GLP-1 inactivation and thereby increasing the activity levels of GLP-1, leading to more glucose-induced insulin release from islet β-cells and suppression of glucagon release. Most patients with diabetes have concurrent hypertension and cardiovascular disorder. If antihyperglycemic agents can attenuate the risk of hypertension and cardiovascular disease, they will amplify their overall beneficial effects. There is conflicting evidence on the cardiovascular benefits of GLP-1R induction in laboratory studies and clinical trials. In this study, we have reviewed the main molecular mechanisms by which GLP-1R induction may modulate the cardiovascular function and the results of cardiovascular outcome clinical trials.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Farin Rashid Farrokhi
- Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Thozhukat Sathyapalan
- Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, UK
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, Lodz, Poland
| | - Tannaz Jamialahmadi
- Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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26
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Abstract
CONTEXT Obesity and type 2 diabetes are associated with chronic hyperinsulinemia, elevated plasma levels of dipeptidyl peptidase-4 (DPP4), and a pro-atherosclerotic milieu. EVIDENCE ACQUISITION PubMed search of the term "insulin and atherosclerosis," "hyperinsulinemia," "atherosclerosis," or "cardiovascular outcomes" cross-referenced with "DPP4." Relevant research and review articles were reviewed. EVIDENCE SYNTHESIS Hyperinsulinemia in the setting of insulin resistance promotes vascular inflammation, vascular smooth muscle cell growth, pathological cholesterol profile, hypertension, and recruitment of immune cells to the endothelium, all contributing to atherosclerosis. DPP4 has pleiotropic functions and its activity is elevated in obese humans. DPP4 mirrors hyperinsulinemia's atherogenic actions in the insulin resistant state, and genetic deletion of DPP4 protects rodents from developing insulin resistance and improves cardiovascular outcomes. DPP4 inhibition in pro-atherosclerotic preclinical models results in reduced inflammation and oxidative stress, improved endothelial function, and decreased atherosclerosis. Increased incretin levels may have contributed to but do not completely account for these benefits. Small clinical studies with DPP4 inhibitors demonstrate reduced carotid intimal thickening, improved endothelial function, and reduced arterial stiffness. To date, this has not been translated to cardiovascular risk reduction for individuals with type 2 diabetes with prior or exaggerated risk of cardiovascular disease. CONCLUSION DPP4 may represent a key link between central obesity, insulin resistance, and atherosclerosis. The gaps in knowledge in DPP4 function and discrepancy in cardiovascular outcomes observed in preclinical and large-scale randomized controlled studies with DPP4 inhibitors warrant additional research.
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Affiliation(s)
- Kaitlin M Love
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA, USA
| | - Zhenqi Liu
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA, USA
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27
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Tanaka A, Node K. Cardiovascular surrogate markers and cardiometabolic therapeutics: a viewpoint learned from clinical trials on dipeptidyl peptidase-4 inhibitors. Cardiovasc Diabetol 2021; 20:41. [PMID: 33573675 PMCID: PMC7879604 DOI: 10.1186/s12933-021-01234-5] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 01/30/2021] [Indexed: 01/14/2023] Open
Abstract
Clinical trials are often performed to investigate the effects of various types of cardiometabolic therapies on cardiovascular surrogate markers, including vascular function and biomarkers. This study platform has the potential to provide information on the suspected actions of drugs and mechanistic insights into their prognostic impact. However, despite using the same class of drugs and similar study designs we are often faced with inconsistent and even conflicting results, possibly leading to some confusion in the clinical setting. When interpreting these results, it is important to investigate what caused the differences and carefully assess the information, taking into account the research situation and the patient population investigated. Using this approach, assessment of the impact on cardiovascular surrogate markers observed in clinical studies from multiple perspectives should help to better understand the potential cardiovascular effects. In this commentary we discuss how we should interpret the effects of cardiometabolic therapeutics on vascular surrogate markers, based on viewpoints learned from the results of clinical trials on dipeptidyl peptidase-4 inhibitors. This learning strategy could also be helpful for appropriate selection of drugs for evidence-based, patient-centric, tailored medication.
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Affiliation(s)
- Atsushi Tanaka
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
| | - Koichi Node
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
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28
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Wild J, Wenzel P. Myeloid cells, tissue homeostasis, and anatomical barriers as innate immune effectors in arterial hypertension. J Mol Med (Berl) 2021; 99:315-326. [PMID: 33443617 PMCID: PMC7899956 DOI: 10.1007/s00109-020-02019-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 11/18/2020] [Indexed: 11/29/2022]
Abstract
Although essential hypertension affects a large proportion of the human population and is one of the key drivers of cardiovascular mortality worldwide, we still do not have a complete understanding of its pathophysiology. More than 50 years ago, the immune system has been identified as an important part of the pathogenesis of arterial hypertension. An exceeding variety of recent publications deals with the interplay between the numerous different components of the immune system and mechanisms of arterial hypertension and has substantially contributed to our understanding of the role of immunity and inflammation in the pathogenesis of the disease. In this review, we focus on myeloid cells and anatomical barriers as particular aspects of innate immunity in arterial hypertension. Since it represents a first line of defense protecting against pathogens and maintaining tissue homeostasis, innate immunity provides many mechanistic hinge points in the area of hypertension.
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Affiliation(s)
- Johannes Wild
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.,Center for Cardiology - Cardiology I and CTH Professorship "Vascular Inflammation", University Medical Center Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.,German Center for Cardiovascular Research (DZHK) - Partner site RheinMain, Berlin, Germany
| | - Philip Wenzel
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany. .,Center for Cardiology - Cardiology I and CTH Professorship "Vascular Inflammation", University Medical Center Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. .,German Center for Cardiovascular Research (DZHK) - Partner site RheinMain, Berlin, Germany.
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Li Y, Li R, Feng Z, Wan Q, Wu J. Linagliptin Regulates the Mitochondrial Respiratory Reserve to Alter Platelet Activation and Arterial Thrombosis. Front Pharmacol 2020; 11:585612. [PMID: 33328991 PMCID: PMC7734318 DOI: 10.3389/fphar.2020.585612] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/28/2020] [Indexed: 12/16/2022] Open
Abstract
Background: The pharmacological inhibition of dipeptidyl peptidase-4 (DPP-4) potentiates incretin action, and DPP-4 is a drug target for type 2 diabetes and reducing cardiovascular risk. However, little is known about the non-enteroendocrine pathways by which DPP-4 might contribute to ischaemic cardiovascular events. Methods: We tested the hypothesis that inhibition of DPP-4 can inhibit platelet activation and arterial thrombosis by preventing platelet mitochondrial dysfunction and release. The effects of pharmacological DPP-4 inhibition on carotid artery thrombosis, platelet aggregation, and platelet mitochondrial respiration signaling pathways were studied in mice. Results: Platelet-dependent arterial thrombosis was significantly delayed in mice treated with high dose of linagliptin, a potent DPP-4 inhibitor, and fed normal chow diet compared to vehicle-treated mice. Thrombin induced DPP-4 expression and activity, and platelets pretreated with linagliptin exhibited reduced thrombin-induced aggregation. Linagliptin blocked phosphodiesterase activity and contrained cyclic AMP reduction when thrombin stimulates platelets. Linagliptin increases the inhibition of platelet aggregation by nitric oxide. The bioenergetics profile revealed that platelets pretreated with linagliptin exhibited decreased oxygen consumption rates in response to thrombin. In transmission electron microscopy, platelets pretreated with linagliptin showed markedly reversed morphological changes in thrombin-activated platelets, including the secretion of α-granules and fewer mitochondria. Conclusion: Collectively, these findings identify distinct roles for DPP-4 in platelet function and arterial thrombosis.
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Affiliation(s)
- Yi Li
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China.,Department of Pharmacology, Laboratory for Cardiovascular Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,Department of Endocrinology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Rong Li
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China.,Department of Pharmacology, Laboratory for Cardiovascular Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Ziqian Feng
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China.,Department of Pharmacology, Laboratory for Cardiovascular Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Qin Wan
- Department of Endocrinology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jianbo Wu
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China.,Department of Pharmacology, Laboratory for Cardiovascular Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
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Abstract
Previous studies have demonstrated that individuals with type 2 diabetes mellitus (T2DM) have a two- to fourfold propensity to develop cardiovascular disease (CVD) than nondiabetic population, making CVD a major cause of death and disability among people with T2DM. The present treatment options for management of diabetes propose the earlier and more frequent use of new antidiabetic drugs that could control hyperglycaemia and reduce the risk of cardiovascular events. Findings from basic and clinical studies pointed out DPP-4 inhibitors as potentially novel pharmacological tools for cardioprotection. There is a growing body of evidence suggesting that these drugs have ability to protect the heart against acute ischaemia-reperfusion injury as well as reduce the size of infarction. Consequently, the prevention of degradation of the incretin hormones by the use of DPP-4 inhibitors represents a new strategy in the treatment of patients with T2DM and reduction of CV events in these patients. Here, we discuss the cardioprotective effects of DPP-4 inhibitors as well as proposed pathways that these hypoglycaemic agents target in the cardiovascular system.
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31
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Kim YK, Song J. Potential of Glucagon-Like Peptide 1 as a Regulator of Impaired Cholesterol Metabolism in the Brain. Adv Nutr 2020; 11:1686-1695. [PMID: 32627818 PMCID: PMC7666911 DOI: 10.1093/advances/nmaa080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 06/04/2020] [Accepted: 06/11/2020] [Indexed: 12/25/2022] Open
Abstract
Cerebral vascular diseases are the most common high-mortality diseases worldwide. Their onset and development are associated with glycemic imbalance, genetic background, alteration of atherosclerotic factors, severe inflammation, and abnormal cholesterol metabolism. Recently, the gut-brain axis has been highlighted as the key to the solution for cerebral vessel dysfunction in view of cholesterol metabolism and systemic lipid circulation. In particular, glucagon-like peptide 1 (GLP-1) is a cardinal hormone that regulates blood vessel function and cholesterol homeostasis and acts as a critical messenger between the brain and gut. GLP-1 plays a systemic regulatory role in cholesterol homeostasis and blood vessel function in various organs through blood vessels. Even though GLP-1 has potential in the treatment and prevention of cerebral vascular diseases, the importance of and relation between GLP-1 and cerebral vascular diseases are not fully understood. Herein, we review recent findings on the functions of GLP-1 in cerebral blood vessels in association with cholesterol metabolism.
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Affiliation(s)
- Young-Kook Kim
- Department of Biochemistry, Chonnam National University Medical School, Hwasun, Jeollanam-do, Republic of Korea
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32
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Nedogoda SV, Barykina IN, Salasyuk AS, Sanina TN, Smirnova VO, Popova EA. The effect of various classes of glucose-lowering medications on the blood vessel elasticity in patients with type 2 diabetes. ACTA ACUST UNITED AC 2020. [DOI: 10.15829/1560-4071-2020-3766] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Aim. To study the effect of various classes of glucose-lowering agents (dipeptidyl peptidase-4 (DPP-4) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors) on the vascular stiffness in patients with type 2 diabetes (T2D) and high cardiovascular risk.Material and methods. The open-label, prospective 24-week study included 120 patients with T2D and high cardiovascular risk. We evaluated the effect of modern glucose-lowering medications, empagliflozin at a dose of 25 mg/day (SGLT-2 inhibitor) and sitagliptin at a dose of 100 mg/day (DPP-4 inhibitor), on vascular elasticity, central hemodynamic and laboratory parameters.Results. After 24-week therapy, the target glycated hemoglobin level reached 71% and 80% of patients in the sitagliptin and empagliflozin groups, respectively. In both groups, vascular stiffness and central hemodynamic parameters were improved. However, significant changes were recorded only in the empagliflozin (carotid-femoral pulse wave velocity decreased by 14,4%, augmentation index — by 6%, central pulse pressure — by 7,8%) (p<0,05). Use of sitagliptin was associated with significant improvements in the lipid profile (total cholesterol decreased by 9,5%, triglycerides — by 21%, low density lipoproteins — by 15,1%; high density lipoproteins increased by 15,7%) (p<0,05). In the empagliflozin group, anthropometric parameters were improved (body mass index decreased by 9,1%, waist circumference — by 4,1%) (p<0,05). Patients in both groups had a significant decrease in HOMA-IR index and highly sensitive C-reactive protein: by 34% and 51,6% in the empagliflozin group and by 31,8% and 22,1% in the sitagliptin group, respectively (p<0,05).Conclusion. The use of empagliflozin is more associated with arterial stiffness decrease in T2D patients with high cardiovascular risk compared with sitagliptin.
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Jensen EP, Møller S, Hviid AV, Veedfald S, Holst JJ, Pedersen J, Ørskov C, Sorensen CM. GLP-1-induced renal vasodilation in rodents depends exclusively on the known GLP-1 receptor and is lost in prehypertensive rats. Am J Physiol Renal Physiol 2020; 318:F1409-F1417. [PMID: 32390511 DOI: 10.1152/ajprenal.00579.2019] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin hormone known to stimulate postprandial insulin release. However, GLP-1 also exerts extrapancreatic effects, including renal effects. Some of these renal effects are attenuated in hypertensive rats, where renal expression of GLP-1 receptors is reduced. Here, we assessed the expression and vascular function of GLP-1 receptors in kidneys from young prehypertensive rats. We also examined GLP-1-induced vasodilation in the renal vasculature in wild-type (WT) and GLP-1 receptor knockout mice using wire and pressure myography and the isolated perfused juxtamedullary nephron preparation. We investigated whether GLP-1 and the metabolite GLP-1(9-36)amide had renal vascular effects independent of the known GLP-1 receptor. We hypothesized that hypertension decreased expression of renal GLP-1 receptors. We also hypothesized that GLP-1-induced renal vasodilatation depended on expression of the known GLP-1 receptor. In contrast to normotensive rats, no immunohistochemical staining or vasodilatory function of GLP-1 receptors was found in kidneys from prehypertensive rats. In WT mice, GLP-1 induced renal vasodilation and reduced the renal autoregulatory response. The GLP-1 receptor antagonist exendin 9-39 inhibited relaxation, and GLP-1(9-36)amide had no vasodilatory effect. In GLP-1 receptor knockout mice, no relaxation induced by GLP-1 or GLP-1(9-36)amide was found, the autoregulatory response in afferent arterioles was normal, and no GLP-1-induced reduction of autoregulation was found. We conclude that in prehypertensive kidneys, expression and function of GLP-1 receptors is lost. The renal vasodilatory effect of GLP-1 is mediated exclusively by the known GLP-1 receptor. GLP-1(9-36)amide has no renal vasodilatory effect. GLP-1 attenuates renal autoregulation by reducing the myogenic response.
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Affiliation(s)
- Elisa P Jensen
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sophie Møller
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Aleksander Vauvert Hviid
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Simon Veedfald
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens Pedersen
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Cathrine Ørskov
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Charlotte M Sorensen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Yoshitomi H, Zhou J, Nishigaki T, Li W, Liu T, Wu L, Gao M. Morinda citrifolia (Noni) fruit juice promotes vascular endothelium function in hypertension via glucagon-like peptide-1 receptor-CaMKKβ-AMPK-eNOS pathway. Phytother Res 2020; 34:2341-2350. [PMID: 32298014 DOI: 10.1002/ptr.6685] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 03/12/2020] [Accepted: 03/16/2020] [Indexed: 12/15/2022]
Abstract
Morinda citrifolia (Noni) is extensively used in herbal remedies to prevent and treat various diseases, including hypertension. The purpose of this study was to investigate the vascular effects of noni fruit juice and characterize the upstream signaling pathways. We measured the systolic blood pressure, diastolic blood pressure, 24-hr urinary nitric oxide (NO) metabolite excretion, bodyweight (BW), and urine examination in SHR.Cg-Leprcp/NDmcr (SHR/cp) rats after 6 weeks noni juice (15 ml/kg) treatment. Noni juice significantly decreased blood pressure and 24-hr urinary NO metabolite without change of BW or urine volume. Furthermore, the noni juice extract (NJE) promoted endothelial vasorelaxation in rat aorta rings and NO product through an increase in phosphorylation of endothelial nitric oxide synthase (eNOS) in human umbilical vein endothelial cells (HUVECs). NJE might act on a glucagon like peptide-1 receptor (GLP-1R) via Ca2+ /calmodulin-dependent protein kinase kinase β (CaMKKβ)-AMPK signaling with pretreatment of their inhibitors or antagonist in HUVECs. Deacetylasperulosidic acid (DAA) was an active compound in noni juice to improve NO release through same pathway in HUVECs. These results suggested that noni is a novel dietary plant that probably regulates GLP-1R-induced CaMKKβ-AMPK-eNOS pathway to improve endothelium-dependent relaxation, thus reduce the blood pressure probably via one of its responsible ingredient DAA.
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Affiliation(s)
- Hisae Yoshitomi
- School of Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Hyogo, Japan
| | - Jingxin Zhou
- Department of Nephrology and Endocrinology, Dongzhimen Hospital Affilated to Beijing University of Chinese Medicine, Tongzhou, Beijing, People's Republic of China
| | | | - Wei Li
- Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan
| | - Tonghua Liu
- Beijing University of Chinese Medicine, Chaoyang, Beijing, People's Republic of China
| | - Lili Wu
- Beijing University of Chinese Medicine, Chaoyang, Beijing, People's Republic of China
| | - Ming Gao
- School of Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Hyogo, Japan.,Department of Cell Life Analytics, Institute for Biosciences, Mukogawa Women's University, Nishinomiya, Hyogo, Japan
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Hviid AVR, Sørensen CM. Glucagon-like peptide-1 receptors in the kidney: impact on renal autoregulation. Am J Physiol Renal Physiol 2020; 318:F443-F454. [DOI: 10.1152/ajprenal.00280.2019] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) and strategies based on this blood sugar-reducing and appetite-suppressing hormone are used to treat obesity and type 2 diabetes. However, the GLP-1 receptor (GLP-1R) is also present in the kidney, where it influences renal function. The effect of GLP-1 on the kidney varies between humans and rodents. The effect of GLP-1 on kidney function also seems to vary depending on its concentration and the physiological or pathological state of the kidney. In studies with rodents or humans, acute infusion of pharmacological doses of GLP-1 stimulates natriuresis and diuresis. However, the effect on the renal vasculature is less clear. In rodents, GLP-1 infusion increases renal plasma flow and glomerular filtration rate, suggesting renal vasodilation. In humans, only a subset of the study participants exhibits increased renal plasma flow and glomerular filtration rate. Differential status of kidney function and changes in renal vascular resistance of the preglomerular arterioles may account for the different responses of the human study participants. Because renal function in patients with type 2 diabetes is already at risk or compromised, understanding the effects of GLP-1R activation on kidney function in these patients is particularly important. This review examines the distribution of GLP-1R in the kidney and the effects elicited by GLP-1 or GLP-1R agonists. By integrating results from acute and chronic studies in healthy individuals and patients with type 2 diabetes along with those from rodent studies, we provide insight into how GLP-1R activation affects renal function and autoregulation.
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Affiliation(s)
- Aleksander Vauvert R. Hviid
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Charlotte M. Sørensen
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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36
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Younes ST, Maeda KJ, Sasser J, Ryan MJ. The glucagon-like peptide 1 receptor agonist liraglutide attenuates placental ischemia-induced hypertension. Am J Physiol Heart Circ Physiol 2020; 318:H72-H77. [PMID: 31729903 PMCID: PMC6985807 DOI: 10.1152/ajpheart.00486.2019] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 11/04/2019] [Accepted: 11/06/2019] [Indexed: 11/22/2022]
Abstract
Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic perturbations of nitric oxide function, reflective of generalized endothelial dysfunction. Therapies that target the nitric oxide pathway have shown promise in both clinical and preclinical studies of preeclampsia. The glucagon-like peptide 1 agonists have been shown to increase nitric oxide and lower blood pressure in patients with diabetes, in part, through activation of nitric oxide synthase (NOS). Therefore, we hypothesized that a direct acting glucagon-like peptide 1 receptor agonist would improve stigmata of the preeclampsia syndrome. Using the reduced uterine perfusion pressure rat model, we found that treatment with liraglutide significantly lowered blood pressure, improved renal function, and upregulated NOS3 protein expression in the mesenteric arterial bed. However, there were adverse effects on pup growth that were likely related to diminished food intake in the dams. Collectively, these data support the premise that the use of drugs that improve NOS abundance, including the glucagon-like peptide 1 agonists, is a rational therapeutic approach to the treatment of preeclampsia, but suggest cautious and careful study of their safety before potential clinical use in humans.NEW & NOTEWORTHY Drugs that target the glucagon-like peptide-1 pathway such as liraglutide are already used clinically, and it has been shown to promote endothelial nitric oxide synthase (NOS3) expression. We demonstrate that liraglutide, a glucagon-like peptide 1 receptor (GLP-1R) agonist, lowers blood pressure, improves renal function, and upregulates NOS3 in a rat model of placental ischemia. These data suggest that drugs that target the nitric oxide system, including GLP-1R agonists, are a potential therapeutic option for preeclampsia.
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Affiliation(s)
- Subhi Talal Younes
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
| | - Kenji J Maeda
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Jennifer Sasser
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Michael J Ryan
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
- G.V. Sonny Montgomery Veterans Affairs Medical Center, University of Mississippi Medical Center, Jackson, Mississippi
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The Effects of DPP4 Inhibitors on Lipid Status and Blood Pressure in Rats with Diabetes Mellitus Type 2. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2019. [DOI: 10.2478/sjecr-2019-0037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Abstract
The aim of the present study was to examine, evaluate and compare the effects of administered dipeptidyl peptidase-4 (DPP4) inhibitors saxagliptin and sitagliptin on lipid status parameters and blood pressure in rats with streptozotocine induced diabetes mellitus type 2. Forty-eight Wistar albino rats were divided randomly into 4 groups: 1. group I: control healthy group; 2. group II: rats with diabetes mellitus type 2; 3. group III: rats with diabetes mellitus type 2+ treated with 0.6 mg/kg of sitagliptin; 4. group IV: rats with diabetes mellitus type 2 treated with 0.45 mg/kg of saxagliptin. The rats from experimental groups were fed with a high-fat diet for 4 weeks and after 6–8 h of starvation received one dose of streptozotocin (STZ) intraperitoneally (25 mg/kg body weight) to induce type 2 diabetes mellitus (T2DM). Animals with fasting glucose above 7 mmol/L and insulin over 6 mmol/L were included in the study as rats with T2DM. Upon completion of the experiments, the blood was collected from the anesthetized animals and serum triglyceride (TG), total cholesterol (TCH), high density lipoprotein (HDL), and low density lipoprotein (LDL) were measured using spectrophotometry and commercial kits. At the beginning of the study and the day before sacrificing animals, the blood pressure and heart rate were measured by a tail-cuff noninvasive method. DPP4 inhibitors, as glucagon-like peptide-1 (GLP-1) agonists, were associated with modest reductions in DBP, LDL-C, TCH, and TGL and significant improvement in HDL, SBP and HR.
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Alves BEO, de Alencar AKN, Gamba LER, Trachez MM, da Silva JS, Araújo JSC, Montagnoli TL, Mendes LVP, Pimentel-Coelho PM, do M N Cunha V, Mendez-Otero R, Oliveira GMM, Lima LM, Barreiro EJ, Sudo RT, Zapata-Sudo G. Reduction of cardiac and renal dysfunction by new inhibitor of DPP4 in diabetic rats. Pharmacol Rep 2019; 71:1190-1200. [PMID: 31669883 DOI: 10.1016/j.pharep.2019.07.005] [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: 02/16/2019] [Revised: 07/04/2019] [Accepted: 07/19/2019] [Indexed: 11/29/2022]
Abstract
BACKGROUND Increased mortality due to type 2 diabetes mellitus (T2DM) has been associated with renal and/or cardiovascular dysfunction. Dipeptidyl dipeptidase-4 inhibitors (iDPP-4s) may exert cardioprotective effects through their pleiotropic actions via glucagon-like peptide 1-dependent mechanisms. In this study, the pharmacological profile of a new iDPP-4 (LASSBio-2124) was investigated in rats with cardiac and renal dysfunction induced by T2DM. METHODS T2DM was induced in rats by 2 weeks of a high-fat diet followed by intravenous injection of streptozotocin. Metabolic disturbance and cardiac, vascular, and renal dysfunction were analyzed in the experimental groups. RESULTS Sitagliptin and LASSBio-2124 administration after T2DM induction reduced elevated glucose levels to 319.8 ± 13.2 and 279.7 ± 17.8 mg/dL, respectively (p < 0.05). LASSBio-2124 also lowered the cholesterol and triglyceride levels from 76.8 ± 8.0 to 42.7 ± 3.2 mg/dL and from 229.7 ± 25.4 to 100.7 ± 17.1 mg/dL, in diabetic rats. Sitagliptin and LASSBio-2124 reversed the reduction of the plasma insulin level. LASSBio-2124 recovered the increased urinary flow in diabetic animals and reduced 24-h proteinuria from 23.7 ± 1.5 to 13.3 ± 2.8 mg (p < 0.05). It also reduced systolic and diastolic left-ventricular dysfunction in hearts from diabetic rats. CONCLUSION The effects of LASSBio-2124 were superior to those of sitagliptin in the cardiovascular systems of T2DM rats. This new prototype showed promise for the avoidance of comorbidities in a T2DM experimental model, and thus may constitute an innovative therapeutic agent for the treatment of these conditions in the clinical field in future.
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Affiliation(s)
- Bryelle E O Alves
- Instituto do Coração Edson Saad, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Allan K N de Alencar
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luis E R Gamba
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Margarete M Trachez
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Jaqueline S da Silva
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Josenildo S C Araújo
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Tadeu L Montagnoli
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luiza V P Mendes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Pedro M Pimentel-Coelho
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Valéria do M N Cunha
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Rosalia Mendez-Otero
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Gláucia M M Oliveira
- Instituto do Coração Edson Saad, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Lídia M Lima
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Eliezer J Barreiro
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Roberto T Sudo
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Gisele Zapata-Sudo
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
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Shen Y, Dai Y, Wang XQ, Zhang RY, Lu L, Ding FH, Shen WF. Searching for optimal blood pressure targets in type 2 diabetic patients with coronary artery disease. Cardiovasc Diabetol 2019; 18:160. [PMID: 31733658 PMCID: PMC6858977 DOI: 10.1186/s12933-019-0959-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 10/31/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Controversies exist regarding the optimal blood pressure (BP) level that is safe and provides cardiovascular protection in patients with type 2 diabetes mellitus (T2DM) and coexistent coronary artery disease. Several new glucose-lowering agents have been found to lower BP as well, making the interaction between BP and T2DM even more complex. METHODS With the reference to recent literature, this review article describes the potential mechanisms of increased risk of hypertension in T2DM and outlines the possible optimal BP levels based upon recommendations on the management of hypertension by the current guidelines, in combination with our research findings, for type 2 diabetic patients with coronary artery disease. RESULTS The development of hypertension in T2DM involves multiple processes, including enhanced sympathetic output, inappropriate activation of renin-angiotensin- aldosterone system, endothelial dysfunction induced through insulin resistance, and abnormal sodium handling by the kidney. Both AGE-RAGE axis and adipokine dysregulation activate intracellular signaling pathways, increase oxidative stress, and aggravate vascular inflammation. Pancreatic β-cell specific microRNAs are implicated in gene expression and diabetic complications. Non-pharmacological intervention with lifestyle changes improves BP control, and anti-hypertensive medications with ACEI/ARB, calcium antagonists, β-blockers, diuretics and new hypoglycemic agent SGLT2 inhibitors are effective to decrease mortality and prevent major adverse cardiovascular events. For hypertensive patients with T2DM and stable coronary artery disease, control of BP < 130/80 mmHg but not < 120/70 mmHg is reasonable, whereas for those with chronic total occlusion or acute coronary syndromes, an ideal BP target may be somewhat higher (< 140/90 mmHg). Caution is advised with aggressive lowering of diastolic BP to a critical threshold (< 60 mmHg). CONCLUSIONS Hypertension and T2DM share certain similar aspects of pathophysiology, and BP control should be individualized to minimize adverse events and maximize benefits especially for patients with T2DM and coronary artery disease.
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Affiliation(s)
- Ying Shen
- Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Yang Dai
- Institute of Cardiovascular Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Xiao Qun Wang
- Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Rui Yan Zhang
- Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Lin Lu
- Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.,Institute of Cardiovascular Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Feng Hua Ding
- Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
| | - Wei Feng Shen
- Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China. .,Institute of Cardiovascular Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
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Taguchi K, Bessho N, Kaneko N, Okudaira K, Matsumoto T, Kobayashi T. Glucagon-like peptide-1 increased the vascular relaxation response via AMPK/Akt signaling in diabetic mice aortas. Eur J Pharmacol 2019; 865:172776. [PMID: 31697935 DOI: 10.1016/j.ejphar.2019.172776] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 10/28/2019] [Accepted: 11/01/2019] [Indexed: 12/25/2022]
Abstract
The incretin glucagon-like peptide-1 (GLP-1) elicits direct favorable effects on the cardiovascular system. This study aimed to evaluate the acute effects of GLP-1 on improving aortic endothelial dysfunction in diabetic mice. Additionally, we examined whether GLP-1 elucidated the underlying mechanisms. Using the diabetic mouse models induced by nicotinamide and streptozotocin, we investigated the functional changes in the aorta caused by GLP-1. Organ baths were performed for vascular reactivity in isolated aortic rings, and western blotting was used for protein analysis. The diabetic aortas showed enhanced GLP-1-induced relaxation response and nitric oxide (NO) production. However, the pretreatment of GLP-1 did not significantly change the endothelial-dependent relaxation response to acetylcholine and -independent relaxation response to sodium nitroprusside. On the other hand, the GLP-1-induced relaxation response and NO production were abolished by the endothelial NO synthase inhibitor, GLP-1 receptor antagonist, Akt inhibitor, and AMP-activated protein kinase (AMPK) inhibitor. Finally, in diabetic mice, considerable increases in phosphorylation of Akt and AMPK were found in aortas stimulated with GLP-1, both of which were decreased by pretreatment with the AMPK inhibitor. GLP-1 significantly enhanced endothelial-dependent relaxation in diabetic aortas. The effect may be mediated through activation of the AMPK/Akt pathway via a GLP-1 receptor-dependent mechanism.
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Affiliation(s)
- Kumiko Taguchi
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Nanami Bessho
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Nozomu Kaneko
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Kanami Okudaira
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Takayuki Matsumoto
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Tsuneo Kobayashi
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, 142-8501, Japan.
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Nam DH, Park J, Park SH, Kim KS, Baek EB. Effect of gemigliptin on cardiac ischemia/reperfusion and spontaneous hypertensive rat models. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2019; 23:329-334. [PMID: 31496870 PMCID: PMC6717789 DOI: 10.4196/kjpp.2019.23.5.329] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 07/23/2019] [Accepted: 07/24/2019] [Indexed: 02/06/2023]
Abstract
Diabetes is associated with an increased risk of cardiovascular complications. Dipeptidyl peptidase-4 (DPP-IV) inhibitors are used clinically to reduce high blood glucose levels as an antidiabetic agent. However, the effect of the DPP-IV inhibitor gemigliptin on ischemia/reperfusion (I/R)-induced myocardial injury and hypertension is unknown. In this study, we assessed the effects and mechanisms of gemigliptin in rat models of myocardial I/R injury and spontaneous hypertension. Gemigliptin (20 and 100 mg/kg/d) or vehicle was administered intragastrically to Sprague-Dawley rats for 4 weeks before induction of I/R injury. Gemigliptin exerted a preventive effect on I/R injury by improving hemodynamic function and reducing infarct size compared to the vehicle control group. Moreover, administration of gemigliptin (0.03% and 0.15%) powder in food for 4 weeks reversed hypertrophy and improved diastolic function in spontaneously hypertensive rats. We report here a novel effect of the gemigliptin on I/R injury and hypertension.
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Affiliation(s)
- Dae-Hwan Nam
- Predictive Model Research Center, Korea Institute of Toxicology, Daejeon 34114, Korea.,Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA
| | - Jinsook Park
- Corporate R&D, LG Chem, Ltd., Daejeon 34122, Korea
| | - Sun-Hyun Park
- Predictive Model Research Center, Korea Institute of Toxicology, Daejeon 34114, Korea
| | - Ki-Suk Kim
- Predictive Model Research Center, Korea Institute of Toxicology, Daejeon 34114, Korea.,Department of Human and Environmental Toxicology, University of Science and Technology, Daejeon 34113, Korea
| | - Eun Bok Baek
- Corporate R&D, LG Chem, Ltd., Daejeon 34122, Korea
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Kajikawa M, Maruhashi T, Hidaka T, Matsui S, Hashimoto H, Takaeko Y, Nakano Y, Kurisu S, Kihara Y, Yusoff FM, Kishimoto S, Chayama K, Goto C, Noma K, Nakashima A, Hiro T, Hirayama A, Shiina K, Tomiyama H, Yagi S, Amano R, Yamada H, Sata M, Higashi Y. Effect of Saxagliptin on Endothelial Function in Patients with Type 2 Diabetes: A Prospective Multicenter Study. Sci Rep 2019; 9:10206. [PMID: 31308448 PMCID: PMC6629702 DOI: 10.1038/s41598-019-46726-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 07/04/2019] [Indexed: 02/06/2023] Open
Abstract
The dipeptidyl peptidase-4 inhibitor saxagliptin is a widely used antihyperglycemic agent in patients with type 2 diabetes. The purpose of this study was to evaluate the effects of saxagliptin on endothelial function in patients with type 2 diabetes. This was a prospective, multicenter, interventional study. A total of 34 patients with type 2 diabetes were enrolled at four university hospitals in Japan. Treatment of patients was initially started with saxagliptin at a dose of 5 mg daily. Assessment of endothelial function assessed by flow-mediated vasodilation (FMD) and measurement of stromal cell-derived factor-1α (SDF-1α) were conducted at baseline and at 3 months after treatment with saxagliptin. A total of 31 patients with type 2 diabetes were included in the analysis. Saxagliptin significantly increased FMD from 3.1 ± 3.1% to 4.2 ± 2.4% (P = 0.032) and significantly decreased total cholesterol from 190 ± 24 mg/dL to 181 ± 25 mg/dL (P = 0.002), glucose from 160 ± 53 mg/dL to 133 ± 25 mg/dL (P < 0.001), HbA1c from 7.5 ± 0.6% to 7.0 ± 0.6% (P < 0.001), urine albumin-to-creatinine ratio from 63.8 ± 134.2 mg/g to 40.9 ± 83.0 mg/g (P = 0.043), and total SDF-1α from 2108 ± 243 pg/mL to 1284 ± 345 pg/mL (P < 0.001). These findings suggest that saxagliptin is effective for improving endothelial function.
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Affiliation(s)
- Masato Kajikawa
- Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan
| | - Tatsuya Maruhashi
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takayuki Hidaka
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shogo Matsui
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Haruki Hashimoto
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuji Takaeko
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yukiko Nakano
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Satoshi Kurisu
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasuki Kihara
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Farina Mohamad Yusoff
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Shinji Kishimoto
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Institute of Biomedical and Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Chikara Goto
- Department of Physical Therapy, Hiroshima International University, Hiroshima, Japan
| | - Kensuke Noma
- Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Ayumu Nakashima
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Takafumi Hiro
- Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Atsushi Hirayama
- Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Kazuki Shiina
- Department of Cardiology, Tokyo Medical University, Tokyo, Japan
| | | | - Shusuke Yagi
- Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
| | - Rie Amano
- Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
| | - Hirotsugu Yamada
- Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
| | - Masataka Sata
- Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
| | - Yukihito Higashi
- Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan.
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
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Onoviran OF, Li D, Toombs Smith S, Raji MA. Effects of glucagon-like peptide 1 receptor agonists on comorbidities in older patients with diabetes mellitus. Ther Adv Chronic Dis 2019; 10:2040622319862691. [PMID: 31321014 PMCID: PMC6628533 DOI: 10.1177/2040622319862691] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 06/10/2019] [Indexed: 12/17/2022] Open
Abstract
Elderly patients with diabetes are at high risk of polypharmacy because of
multiple coexisting diseases and syndromes. Polypharmacy increases the risk of
drug–drug and drug–disease interactions in these patients, who may already have
age-related sensory and cognitive deficits; such deficits may delay timely
communication of early symptoms of adverse drug events. Several glucagon-like
peptide-1 receptor agonists (GLP-1 RAs) have been approved for diabetes:
liraglutide, exenatide, lixisenatide, dulagluatide, semaglutide, and
albiglutide. Some are also approved for treatment of obesity. The current review
of literature along with clinical case discussion provides evidence supporting
GLP-1 RAs as diabetes medications for polypharmacy reduction in older diabetes
patients because of their multiple pleiotropic effects on comorbidities (e.g.
hyperlipidemia, hypertension, and fatty liver) and syndromes (e.g. osteoporosis
and sleep apnea) that commonly co-occur with diabetes. Using one medication (in
this case, GLP-1 RAs) to address multiple conditions may help reduce costs,
medication burden, adverse drug events, and medication nonadherence.
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Affiliation(s)
- Olusola F Onoviran
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, USA
| | - Dongming Li
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, USA
| | - Sarah Toombs Smith
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, USA
| | - Mukaila A Raji
- Division of Geriatric Medicine, Department of Internal Medicine, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0177, USA
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Jeon J, Choi S, Ha E, Lee H, Kim T, Han S, Kim H, Kim D, Kang Y, Lee K. GLP‑1 improves palmitate‑induced insulin resistance in human skeletal muscle via SIRT1 activity. Int J Mol Med 2019; 44:1161-1171. [DOI: 10.3892/ijmm.2019.4272] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 07/01/2019] [Indexed: 11/06/2022] Open
Affiliation(s)
- Ja Jeon
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Sung‑E Choi
- Department of Physiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Eun Ha
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Han Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Tae Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul Medical Center, Seoul 02076, Republic of Korea
| | - Seung Han
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Hae Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Dae Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Yup Kang
- Department of Physiology, Ajou University School of Medicine, Suwon 16499, Republic of KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine, Seoul Medical Center, Seoul 02076, Republic of Korea
| | - Kwan‑Woo Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea
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Tsai TH, Lee CH, Cheng CI, Fang YN, Chung SY, Chen SM, Lin CJ, Wu CJ, Hang CL, Chen WY. Liraglutide Inhibits Endothelial-to-Mesenchymal Transition and Attenuates Neointima Formation after Endovascular Injury in Streptozotocin-Induced Diabetic Mice. Cells 2019; 8:cells8060589. [PMID: 31207939 PMCID: PMC6628350 DOI: 10.3390/cells8060589] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 06/06/2019] [Accepted: 06/12/2019] [Indexed: 01/08/2023] Open
Abstract
Hyperglycaemia causes endothelial dysfunction, which is the initial process in the development of diabetic vascular complications. Upon injury, endothelial cells undergo an endothelial-to-mesenchymal transition (EndMT), lose their specific marker, and gain mesenchymal phenotypes. This study investigated the effect of liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, on EndMT inhibition and neointima formation in diabetic mice induced by streptozotocin. The diabetic mice with a wire-induced vascular injury in the right carotid artery were treated with or without liraglutide for four weeks. The degree of neointima formation and re-endothelialisation was evaluated by histological assessments. Endothelial fate tracing revealed that endothelium-derived cells contribute to neointima formation through EndMT in vivo. In the diabetic mouse model, liraglutide attenuated wire injury-induced neointima formation and accelerated re-endothelialisation. In vitro, a high glucose condition (30 mmol/L) triggered morphological changes and mesenchymal marker expression in human umbilical vein endothelial cells (HUVECs), which were attenuated by liraglutide or Activin receptor-like 5 (ALK5) inhibitor SB431542. The inhibition of AMP-activated protein kinase (AMPK) signaling by Compound C diminished the liraglutide-mediated inhibitory effect on EndMT. Collectively, liraglutide was found to attenuate neointima formation in diabetic mice partially through EndMT inhibition, extending the potential therapeutic role of liraglutide.
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Affiliation(s)
- Tzu-Hsien Tsai
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
| | - Chien-Ho Lee
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
| | - Cheng-I Cheng
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
| | - Yen-Nan Fang
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
| | - Sheng-Ying Chung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
| | - Shyh-Ming Chen
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
| | - Cheng-Jei Lin
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
| | - Chiung-Jen Wu
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
| | - Chi-Ling Hang
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
| | - Wei-Yu Chen
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
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Kishimoto S, Kinoshita Y, Matsumoto T, Maruhashi T, Kajikawa M, Matsui S, Hashimoto H, Takaeko Y, Kihara Y, Chayama K, Goto C, Mohamad Yusoff F, Nakashima A, Noma K, Higashi Y. Effects of the Dipeptidyl Peptidase 4 Inhibitor Alogliptin on Blood Pressure in Hypertensive Patients with Type 2 Diabetes Mellitus. Am J Hypertens 2019; 32:695-702. [PMID: 31045223 DOI: 10.1093/ajh/hpz065] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/30/2019] [Accepted: 04/18/2019] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND The effects of dipeptidyl peptidase 4 (DPP-4) inhibitors on blood pressure in patients with diabetes mellitus (DM) are controversial. There is no information on the effect of DPP-4 inhibitors on blood pressure and arterial stiffness in hypertensive patients with DM. We evaluated the effects of alogliptin on blood pressure and arterial stiffness in hypertensive patients with type 2 diabetes mellitus (T2DM). METHODS Blood pressure and brachial-ankle pulse wave velocity (baPWV) were measured before and after 3, 6, and 12 months of treatment with alogliptin in 22 hypertensive patients with T2DM. RESULTS After 3, 6, and 12 months, alogliptin treatment decreased hemoglobin A1c from 7.0 ± 0.97% to 6.4 ± 0.61%, 6.3 ± 0.58%, and 6.3 ± 0.75% (P < 0.01, respectively), glucose from 8.6 ± 4.39 mmol/l to 7.05 ± 2.16, 7.05 ± 2.28, and 6.44 ± 1.50 mmol/l (P < 0.01, respectively), systolic blood pressure from 137 ± 18 mm Hg to 127 ± 13, 125 ± 15, and 120 ± 17 mm Hg (P < 0.01, respectively), diastolic blood pressure from 79 ± 13 mm Hg to 74 ± 8, 74 ± 10, and 70 ± 8 mm Hg (P < 0.01, respectively) and baPWV from 1,947 ± 349 cm/second to 1,774 ± 259, 1,856 ± 361, and 1,756 ± 286 cm/second (P < 0.01, respectively). A baseline baPWV value of 1,643 cm/second was the optimal cut-off value for patients who had reduced blood pressure after treatment with alogliptin (sensitivity of 83.3% and specificity of 75.0%). CONCLUSIONS Alogliptin was associated with improvements not only in glucose metabolism but also in blood pressure and arterial stiffness in hypertensive patients with T2DM. The cut-off value of baPWV may enable identification of responders of decrease in blood pressure by alogliptin in hypertensive patients with T2DM. CLINICAL TRIALS REGISTRATION Registration Number for Clinical Trial: UMIN000007722.
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Affiliation(s)
- Shinji Kishimoto
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | | | - Takeshi Matsumoto
- Department of Cardiovascular Medicine, Onomichi General Hospital, Hiroshima, Japan
| | - Tatsuya Maruhashi
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masato Kajikawa
- Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan
| | - Shogo Matsui
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Haruki Hashimoto
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuji Takaeko
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasuki Kihara
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Chikara Goto
- Department of Rehabilitation, Faculty of General Rehabilitation, Hiroshima International University, Hiroshima, Japan
| | - Farina Mohamad Yusoff
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Ayumu Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kensuke Noma
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Yukihito Higashi
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
- Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan
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Sitagliptin Protects Cardiac Function by Reducing Nitroxidative Stress and Promoting Autophagy in Zucker Diabetic Fatty (ZDF) Rats. Cardiovasc Drugs Ther 2019; 32:541-552. [PMID: 30328028 DOI: 10.1007/s10557-018-6831-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE The purpose of the study is to identify potential mechanisms involved in the cardiac protective effects of sitagliptin in Zucker diabetic fatty (ZDF) rats. METHODS AND RESULTS Male non-diabetic lean Zucker rats (Lean) and ZDF rats treated with saline (ZDF) or sitagliptin (ZDF + sita) were used in this study. The blood pressure and lipid profiles were increased significantly in ZDF rats compared with Lean rats. ZDF + sitagliptin rats had decreased systolic blood pressure compared with ZDF rats. Sitagliptin treatment decreased total cholesterol (TC), triglycerides (TGs), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels. Ejection fraction (EF) and fractional shortening (FS) were decreased in ZDF rats, which improved with sitagliptin from 59.8% ± 3.0 and 34.5% ± 3.1 to 66.9% ± 3.4 and 40.9% ± 4.2, respectively. Moreover, the nitroxidative stress level was increased while autophagy levels were decreased in ZDF rats, which was reversed by the administration of sitagliptin. Treatment with sitagliptin or FeTMPyP improved the autophagy level in high-glucose cultured H9c2 cells by increasing autolysosome numbers from 15 ± 4 to 21 ± 3 and 22 ± 3, respectively. We detected a positive correlation between DPP-4 activity and 3-nitrotyrosine levels (r = 0.3903; P < 0.01), a negative correlation between Beclin-1 levels and DPP-4 activity (r = - 0.3335; P < 0.01), and a negative correlation between 3-nitrotyrosine and Beclin-1 levels (r = - 0.3794; P < 0.01) in coronary heart disease patients. CONCLUSIONS Sitagliptin alleviates diabetes-induced cardiac injury by reducing nitroxidative stress and promoting autophagy. This study indicates a novel target pathway for the treatment of cardiovascular complications in type 2 diabetes mellitus.
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Zhang J, Chen Q, Zhong J, Liu C, Zheng B, Gong Q. DPP-4 Inhibitors as Potential Candidates for Antihypertensive Therapy: Improving Vascular Inflammation and Assisting the Action of Traditional Antihypertensive Drugs. Front Immunol 2019; 10:1050. [PMID: 31134095 PMCID: PMC6526751 DOI: 10.3389/fimmu.2019.01050] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 04/24/2019] [Indexed: 12/12/2022] Open
Abstract
Dipeptidyl peptidase-4 (DPP-4) is an important protease that is widely expressed on the surface of human cells and plays a key role in immune-regulation, inflammation, oxidative stress, cell adhesion, and apoptosis by targeting different substrates. DPP-4 inhibitors (DPP-4i) are commonly used as hypoglycemic agents. However, in addition to their hypoglycemic effect, DPP-4i have also shown potent activities in the cardiovascular system, particularly in the regulation of blood pressure (BP). Previous studies have shown that the regulatory actions of DPP-4i in controlling BP are complex and that the mechanisms involved include the functional activities of the nerves, kidneys, hormones, blood vessels, and insulin. Recent work has also shown that inflammation is closely associated with the elevation of BP, and that the inhibition of DPP-4 can reduce BP by regulating the function of the immune system, by reducing inflammatory reactions and by improving oxidative stress. In this review, we describe the potential anti-hypertensive effects of DPP-4i and discuss potential new anti-hypertensive therapies. Our analysis indicated that DPP-4i treatment has a mild anti-hypertensive effect as a monotherapy and causes a significant reduction in BP when used in combined treatments. However, the combination of DPP-4i with high-dose angiotensin converting enzyme inhibitors (ACEI) can lead to increased BP. We suggest that DPP-4i improves vascular endothelial function in hypertensive patients by suppressing inflammatory responses and by alleviating oxidative stress. In addition, DPP-4i can also regulate BP by activating the sympathetic nervous system, interfering with the renin angiotensin aldosterone system (RAAS), regulating Na/H2O metabolism, and attenuating insulin resistance (IR).
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Affiliation(s)
- Jianqiang Zhang
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
| | - Qiuyue Chen
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
| | - Jixin Zhong
- Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, United States
| | - Chaohong Liu
- Department of Microbiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Bing Zheng
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
- Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, China
| | - Quan Gong
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
- Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, China
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Lyle AN, Taylor WR. The pathophysiological basis of vascular disease. J Transl Med 2019; 99:284-289. [PMID: 30755702 DOI: 10.1038/s41374-019-0192-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 01/08/2019] [Indexed: 12/12/2022] Open
Affiliation(s)
- Alicia N Lyle
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - W Robert Taylor
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA. .,Division of Cardiology, Atlanta Veterans Affairs Medical Center, Decatur, GA, USA. .,Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA.
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Qiu DD, Liu J, Shi JS, An Y, Ge YC, Zhou ML, Jiang S. Renoprotection Provided by Dipeptidyl Peptidase-4 Inhibitors in Combination with Angiotensin Receptor Blockers in Patients with Type 2 Diabetic Nephropathy. Chin Med J (Engl) 2019; 131:2658-2665. [PMID: 30425192 PMCID: PMC6247590 DOI: 10.4103/0366-6999.245277] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Background: Treatment with the dipeptidyl peptidase-4 inhibitors (DPP4i) and angiotensin receptor blockers (ARBs) in patients with type 2 diabetic nephropathy (DN) has not been well characterized. This study aimed to assess the renoprotection of this combined treatment in DN patients. Methods: A total of 159 type 2 DN patients from 2013 to 2015 were enrolled retrospectively from a prospective DN cohort at the National Clinical Research Center of Kidney Diseases, Jinling Hospital (China). Fifty-seven patients received DPP4i and ARB treatment, and 102 patients were treated with ARBs alone. All patients were followed up for at least 12 months. Statistical analyses were performed using Stata version 12.0. Results: There were no significant differences at baseline for age, sex, body mass index, duration of diabetes, fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and estimated glomerular filtration rate (eGFR) between the two groups. Antihypertensive and antidiabetic medication use was similar in each group except calcium channel antagonists (P = 0.032). No significant changes in FBG and HbA1c were observed in the two groups after treatment. The eGFR decreased slower in the DPP4i + ARB group than in the ARB group at 12 months (Δ12 months: −2.48 ± 13.86 vs. −6.81 ± 12.52 ml·min–1·1.73m–2, P = 0.044). In addition, proteinuria was decreased further in the DPP4i + ARB group than in the ARB group after 24 months of treatment (Δ24 months: −0.18 [−1.00, 0.17] vs. 0.32 [−0.35, 0.88], P = 0.031). There were 36 patients with an eGFR decrease of more than 30% over 24 months. After adjusting for FBG, HbA1c, and other risk factors, DPP4i + ARB treatment was still associated with a reduced incidence of an eGFR decrease of 20% or 30%. Conclusions: The combined treatment of DPP4i and ARBs is superior to ARBs alone, as evidenced by the greater proteinuria reduction and lower eGFR decline. In addition, the renoprotection of DPP4i combined with ARBs was independent of glycemic control.
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Affiliation(s)
- Dan-Dan Qiu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
| | - Jing Liu
- Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
| | - Jing-Song Shi
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
| | - Yu An
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
| | - Yong-Chun Ge
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
| | - Min-Lin Zhou
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
| | - Song Jiang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
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