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Dominici FP, Gironacci MM, Narvaez Pardo JA. Therapeutic opportunities in targeting the protective arm of the renin-angiotensin system to improve insulin sensitivity: a mechanistic review. Hypertens Res 2024; 47:3397-3408. [PMID: 39363004 DOI: 10.1038/s41440-024-01909-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 08/04/2024] [Accepted: 09/02/2024] [Indexed: 10/05/2024]
Abstract
In recent years, the knowledge of the physiological and pathophysiological roles of the renin-angiotensin system (RAS) in glucose metabolism has advanced significantly. It is now well-established that blockade of the angiotensin AT1 receptor (AT1R) improves insulin sensitivity. Activation of the AT2 receptor (AT2R) and the MAS receptor are significant contributors to this beneficial effect. Elevated availability of angiotensin (Ang) II) for interaction with the AT2R and increased Ang-(1-7) formation during AT1R blockade mediate these effects. The ongoing development of selective AT2R agonists, such as compound 21 and the novel Ang III peptidomimetics, has significantly advanced the exploration of the role of AT2R in metabolism and its potential as a therapeutic target. These agents show promise, particularly when RAS inhibition is contraindicated. Additionally, other RAS peptides, including Ang IV, des-Asp-Ang I, Ang-(1-9), and alamandine, hold therapeutic capability for addressing metabolic disturbances linked to type 2 diabetes. The possibility of AT2R heteromerization with either AT1R or MAS receptor offers an exciting area for future research, particularly concerning therapeutic strategies to improve glycemic control. This review focuses on therapeutic opportunities to improve insulin sensitivity, taking advantage of the protective arm of the RAS.
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Affiliation(s)
- Fernando P Dominici
- Departamento de Química Biológica and IQUIFIB (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
| | - Mariela M Gironacci
- Departamento de Química Biológica and IQUIFIB (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jorge A Narvaez Pardo
- Departamento de Química Biológica and IQUIFIB (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
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Michaels TM, Essop MF, Joseph DE. Potential Effects of Hyperglycemia on SARS-CoV-2 Entry Mechanisms in Pancreatic Beta Cells. Viruses 2024; 16:1243. [PMID: 39205219 PMCID: PMC11358987 DOI: 10.3390/v16081243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 07/29/2024] [Accepted: 07/30/2024] [Indexed: 09/04/2024] Open
Abstract
The COVID-19 pandemic has revealed a bidirectional relationship between SARS-CoV-2 infection and diabetes mellitus. Existing evidence strongly suggests hyperglycemia as an independent risk factor for severe COVID-19, resulting in increased morbidity and mortality. Conversely, recent studies have reported new-onset diabetes following SARS-CoV-2 infection, hinting at a potential direct viral attack on pancreatic beta cells. In this review, we explore how hyperglycemia, a hallmark of diabetes, might influence SARS-CoV-2 entry and accessory proteins in pancreatic β-cells. We examine how the virus may enter and manipulate such cells, focusing on the role of the spike protein and its interaction with host receptors. Additionally, we analyze potential effects on endosomal processing and accessory proteins involved in viral infection. Our analysis suggests a complex interplay between hyperglycemia and SARS-CoV-2 in pancreatic β-cells. Understanding these mechanisms may help unlock urgent therapeutic strategies to mitigate the detrimental effects of COVID-19 in diabetic patients and unveil if the virus itself can trigger diabetes onset.
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Affiliation(s)
- Tara M. Michaels
- Centre for Cardio-Metabolic Research in Africa, Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch 7600, South Africa;
| | - M. Faadiel Essop
- Centre for Cardio-Metabolic Research in Africa, Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7505, South Africa;
| | - Danzil E. Joseph
- Centre for Cardio-Metabolic Research in Africa, Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch 7600, South Africa;
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3
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Galis P, Bartosova L, Farkasova V, Bartekova M, Ferenczyova K, Rajtik T. Update on clinical and experimental management of diabetic cardiomyopathy: addressing current and future therapy. Front Endocrinol (Lausanne) 2024; 15:1451100. [PMID: 39140033 PMCID: PMC11319149 DOI: 10.3389/fendo.2024.1451100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 07/12/2024] [Indexed: 08/15/2024] Open
Abstract
Diabetic cardiomyopathy (DCM) is a severe secondary complication of type 2 diabetes mellitus (T2DM) that is diagnosed as a heart disease occurring in the absence of any previous cardiovascular pathology in diabetic patients. Although it is still lacking an exact definition as it combines aspects of both pathologies - T2DM and heart failure, more evidence comes forward that declares DCM as one complex disease that should be treated separately. It is the ambiguous pathological phenotype, symptoms or biomarkers that makes DCM hard to diagnose and screen for its early onset. This re-view provides an updated look on the novel advances in DCM diagnosis and treatment in the experimental and clinical settings. Management of patients with DCM proposes a challenge by itself and we aim to help navigate and advice clinicians with early screening and pharmacotherapy of DCM.
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Affiliation(s)
- Peter Galis
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Bratislava, Slovakia
| | - Linda Bartosova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Bratislava, Slovakia
| | - Veronika Farkasova
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Monika Bartekova
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
- Institute of Physiology, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia
| | - Kristina Ferenczyova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Bratislava, Slovakia
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Tomas Rajtik
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Bratislava, Slovakia
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
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Pan M, Yu M, Zheng S, Luo L, Zhang J, Wu J. Genetic variations in ACE2 gene associated with metabolic syndrome in southern China: a case-control study. Sci Rep 2024; 14:10505. [PMID: 38714718 PMCID: PMC11076479 DOI: 10.1038/s41598-024-61254-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 05/03/2024] [Indexed: 05/10/2024] Open
Abstract
Metabolic syndrome (MetS) is closely related to cardiovascular and cerebrovascular diseases, and genetic predisposition is one of the main triggers for its development. To identify the susceptibility genes for MetS, we investigated the relationship between angiotensin-converting enzyme 2 (ACE2) single nucleotide polymorphisms (SNPs) and MetS in southern China. In total, 339 MetS patients and 398 non-MetS hospitalized patients were recruited. Four ACE2 polymorphisms (rs2074192, rs2106809, rs879922, and rs4646155) were genotyped using the polymerase chain reaction-ligase detection method and tested for their potential association with MetS and its related components. ACE2 rs2074192 and rs2106809 minor alleles conferred 2.485-fold and 3.313-fold greater risks of MetS in women. ACE2 rs2074192 and rs2106809 variants were risk factors for obesity, diabetes, and low-high-density lipoprotein cholesterolemia. However, in men, the ACE2 rs2074192 minor allele was associated with an approximately 0.525-fold reduction in MetS prevalence. Further comparing the components of MetS, ACE2 rs2074192 and rs2106809 variants reduced the risk of obesity and high triglyceride levels. In conclusion, ACE2 rs2074192 and rs2106809 SNPs were independently associated with MetS in a southern Chinese population and showed gender heterogeneity, which can be partially explained by obesity. Thus, these SNPs may be utilized as predictive biomarkers and molecular targets for MetS. A limitation of this study is that environmental and lifestyle differences, as well as genetic heterogeneity among different populations, were not considered in the analysis.
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Affiliation(s)
- Min Pan
- Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Fujian Hypertension Research Institute, Fuzhou, 350005, Fujian, People's Republic of China
| | - Mingzhong Yu
- Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Fujian Hypertension Research Institute, Fuzhou, 350005, Fujian, People's Republic of China
| | - Suli Zheng
- Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Fujian Hypertension Research Institute, Fuzhou, 350005, Fujian, People's Republic of China
| | - Li Luo
- Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China
- Fujian Hypertension Research Institute, Fuzhou, 350005, Fujian, People's Republic of China
| | - Jie Zhang
- Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China.
- Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China.
- Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China.
- Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China.
- Fujian Hypertension Research Institute, Fuzhou, 350005, Fujian, People's Republic of China.
| | - Jianmin Wu
- Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China.
- Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China.
- Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China.
- Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, People's Republic of China.
- Fujian Hypertension Research Institute, Fuzhou, 350005, Fujian, People's Republic of China.
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Meng H, Liao Z, Ji Y, Wang D, Han Y, Huang C, Hu X, Chen J, Zhang H, Li Z, Wang C, Sun H, Sun J, Chen L, Yin J, Zhao J, Xu T, Liu H. FGF7 enhances the expression of ACE2 in human islet organoids aggravating SARS-CoV-2 infection. Signal Transduct Target Ther 2024; 9:104. [PMID: 38654010 PMCID: PMC11039711 DOI: 10.1038/s41392-024-01790-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 03/04/2024] [Accepted: 03/10/2024] [Indexed: 04/25/2024] Open
Abstract
The angiotensin-converting enzyme 2 (ACE2) is a primary cell surface viral binding receptor for SARS-CoV-2, so finding new regulatory molecules to modulate ACE2 expression levels is a promising strategy against COVID-19. In the current study, we utilized islet organoids derived from human embryonic stem cells (hESCs), animal models and COVID-19 patients to discover that fibroblast growth factor 7 (FGF7) enhances ACE2 expression within the islets, facilitating SARS-CoV-2 infection and resulting in impaired insulin secretion. Using hESC-derived islet organoids, we demonstrated that FGF7 interacts with FGF receptor 2 (FGFR2) and FGFR1 to upregulate ACE2 expression predominantly in β cells. This upregulation increases both insulin secretion and susceptibility of β cells to SARS-CoV-2 infection. Inhibiting FGFR counteracts the FGF7-induced ACE2 upregulation, subsequently reducing viral infection and replication in the islets. Furthermore, retrospective clinical data revealed that diabetic patients with severe COVID-19 symptoms exhibited elevated serum FGF7 levels compared to those with mild symptoms. Finally, animal experiments indicated that SARS-CoV-2 infection increased pancreatic FGF7 levels, resulting in a reduction of insulin concentrations in situ. Taken together, our research offers a potential regulatory strategy for ACE2 by controlling FGF7, thereby protecting islets from SARS-CoV-2 infection and preventing the progression of diabetes in the context of COVID-19.
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Affiliation(s)
- Hao Meng
- School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, 511495, Guangdong, China
- Guangzhou National Laboratory, Guangzhou, 510320, Guangdong, China
| | - Zhiying Liao
- School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, 511495, Guangdong, China
- Guangzhou National Laboratory, Guangzhou, 510320, Guangdong, China
| | - Yanting Ji
- Guangzhou National Laboratory, Guangzhou, 510320, Guangdong, China
| | - Dong Wang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
| | - Yang Han
- Center for Translational Medicine, Wuhan Jinyintan Hospital, Wuhan, 430023, Hubei, China
| | - Chaolin Huang
- Center for Translational Medicine, Wuhan Jinyintan Hospital, Wuhan, 430023, Hubei, China
| | - Xujuan Hu
- Center for Translational Medicine, Wuhan Jinyintan Hospital, Wuhan, 430023, Hubei, China
| | - Jingyi Chen
- Guangzhou National Laboratory, Guangzhou, 510320, Guangdong, China
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - Hengrui Zhang
- Guangzhou National Laboratory, Guangzhou, 510320, Guangdong, China
| | - Zonghong Li
- Guangzhou National Laboratory, Guangzhou, 510320, Guangdong, China
| | - Changliang Wang
- Guangzhou National Laboratory, Guangzhou, 510320, Guangdong, China
| | - Hui Sun
- Guangzhou National Laboratory, Guangzhou, 510320, Guangdong, China
| | - Jiaqi Sun
- Guangzhou National Laboratory, Guangzhou, 510320, Guangdong, China
| | - Lihua Chen
- Guangzhou National Laboratory, Guangzhou, 510320, Guangdong, China
| | - Jiaxiang Yin
- Guangzhou National Laboratory, Guangzhou, 510320, Guangdong, China
| | - Jincun Zhao
- Guangzhou National Laboratory, Guangzhou, 510320, Guangdong, China.
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China.
| | - Tao Xu
- School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, 511495, Guangdong, China.
- Guangzhou National Laboratory, Guangzhou, 510320, Guangdong, China.
| | - Huisheng Liu
- School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, 511495, Guangdong, China.
- Guangzhou National Laboratory, Guangzhou, 510320, Guangdong, China.
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou, 510006, Guangdong, China.
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Shukla AK, Awasthi K, Usman K, Banerjee M. Role of renin-angiotensin system/angiotensin converting enzyme-2 mechanism and enhanced COVID-19 susceptibility in type 2 diabetes mellitus. World J Diabetes 2024; 15:606-622. [PMID: 38680697 PMCID: PMC11045416 DOI: 10.4239/wjd.v15.i4.606] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 01/22/2024] [Accepted: 02/27/2024] [Indexed: 04/11/2024] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a disease that caused a global pandemic and is caused by infection of severe acute respiratory syndrome coronavirus 2 virus. It has affected over 768 million people worldwide, resulting in approximately 6900000 deaths. High-risk groups, identified by the Centers for Disease Control and Prevention, include individuals with conditions like type 2 diabetes mellitus (T2DM), obesity, chronic lung disease, serious heart conditions, and chronic kidney disease. Research indicates that those with T2DM face a heightened susceptibility to COVID-19 and increased mortality compared to non-diabetic individuals. Examining the renin-angiotensin system (RAS), a vital regulator of blood pressure and pulmonary stability, reveals the significance of the angiotensin-converting enzyme (ACE) and ACE2 enzymes. ACE converts angiotensin-I to the vasoconstrictor angiotensin-II, while ACE2 counters this by converting angiotensin-II to angiotensin 1-7, a vasodilator. Reduced ACE2 expression, common in diabetes, intensifies RAS activity, contributing to conditions like inflammation and fibrosis. Although ACE inhibitors and angiotensin receptor blockers can be therapeutically beneficial by increasing ACE2 levels, concerns arise regarding the potential elevation of ACE2 receptors on cell membranes, potentially facilitating COVID-19 entry. This review explored the role of the RAS/ACE2 mechanism in amplifying severe acute respiratory syndrome coronavirus 2 infection and associated complications in T2DM. Potential treatment strategies, including recombinant human ACE2 therapy, broad-spectrum antiviral drugs, and epigenetic signature detection, are discussed as promising avenues in the battle against this pandemic.
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Affiliation(s)
- Ashwin Kumar Shukla
- Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India
| | - Komal Awasthi
- Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India
| | - Kauser Usman
- Department of Medicine, King Georges’ Medical University, Lucknow 226003, Uttar Pradesh, India
| | - Monisha Banerjee
- Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India
- Institute of Advanced Molecular Genetics, and Infectious Diseases (IAMGID), University of Lucknow, Lucknow 226007, Uttar Pradesh, India
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Lin X, Wang X, Feng W, Wan Y, Chai J, Li F, Xu M. The Counteracting Effects of Ang II and Ang-(1-7) on the Function andGrowth of Insulin-secreting NIT-1 Cells. Curr Diabetes Rev 2024; 20:e010124225112. [PMID: 38173074 DOI: 10.2174/0115733998276291231204115314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 10/17/2023] [Accepted: 10/23/2023] [Indexed: 01/05/2024]
Abstract
INTRODUCTION China now has the highest number of diabetes in the world. Angiotensin II (Ang II) causes insulin resistance by acting on the insulin signaling pathway of peripheral target tissues. However, its effect on islet β-cells remains unclear. The possible role of Angiotensin-( 1-7) [Ang-(1-7)] as an antagonist to the effects of Ang II and in treating diabetes needs to be elucidated. OBJECTIVES To assess the effects of Ang II and Ang-(1-7) on the function and growth of islet β cell line NIT-1, which is derived from the islets of non-obese diabetic/large T-antigen (NOD/LT) mice with insulinoma. METHODS NIT-1 cells were treated with Ang II, Ang-(1-7) and their respective receptor antagonists. The impact on cell function and growth was then evaluated. RESULTS Ang II significantly reduced insulin-stimulated IR-β-Tyr and Akt-Ser; while Ang-(1-7), saralasin (an Ang II receptor antagonist), and diphenyleneiodonium [DPI, a nicotinamide adenine dinucleotide phosphate oxidase (NOX) antagonist] reversed the inhibiting effect. Conversely, Ang II significantly increased insulin-stimulated intracellular H2O2 and P47 phox, while saralasin and DPI reverted the effect. Furthermore, Ang-(1-7) reduced the elevated concentrations of ROS and MDA while increasing the proliferation rate that was reduced by high glucose, all of which were reversed by A-779, an antagonist of the Mas receptor (MasR). CONCLUSION Angiotensin II poses a negative regulatory effect on insulin signal transduction, increases oxidative stress, and may inhibit the transcription of insulin genes stimulated by insulin in NIT-1 cells. Meanwhile, angiotensin-(1-7) blocked these effects via MasR. These results corroborate the rising potential of the renin-angiotensin system (RAS) in treating diabetes.
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Affiliation(s)
- Xiuhong Lin
- Department of Clinical Nutrition, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Xiaoyun Wang
- Department of Endocrinology, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, Fujian, People's Republic of China
| | - Weilian Feng
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Yan Wan
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Jiani Chai
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Feng Li
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Mingtong Xu
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
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Wang CW, Chuang HC, Tan TH. ACE2 in chronic disease and COVID-19: gene regulation and post-translational modification. J Biomed Sci 2023; 30:71. [PMID: 37608279 PMCID: PMC10464117 DOI: 10.1186/s12929-023-00965-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 08/15/2023] [Indexed: 08/24/2023] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2), a counter regulator of the renin-angiotensin system, provides protection against several chronic diseases. Besides chronic diseases, ACE2 is the host receptor for SARS-CoV or SARS-CoV-2 virus, mediating the first step of virus infection. ACE2 levels are regulated by transcriptional, post-transcriptional, and post-translational regulation or modification. ACE2 transcription is enhanced by transcription factors including Ikaros, HNFs, GATA6, STAT3 or SIRT1, whereas ACE2 transcription is reduced by the transcription factor Brg1-FoxM1 complex or ERRα. ACE2 levels are also regulated by histone modification or miRNA-induced destabilization. The protein kinase AMPK, CK1α, or MAP4K3 phosphorylates ACE2 protein and induces ACE2 protein levels by decreasing its ubiquitination. The ubiquitination of ACE2 is induced by the E3 ubiquitin ligase MDM2 or UBR4 and decreased by the deubiquitinase UCHL1 or USP50. ACE2 protein levels are also increased by the E3 ligase PIAS4-mediated SUMOylation or the methyltransferase PRMT5-mediated ACE2 methylation, whereas ACE2 protein levels are decreased by AP2-mediated lysosomal degradation. ACE2 is downregulated in several human chronic diseases like diabetes, hypertension, or lung injury. In contrast, SARS-CoV-2 upregulates ACE2 levels, enhancing host cell susceptibility to virus infection. Moreover, soluble ACE2 protein and exosomal ACE2 protein facilitate SARS-CoV-2 infection into host cells. In this review, we summarize the gene regulation and post-translational modification of ACE2 in chronic disease and COVID-19. Understanding the regulation and modification of ACE2 may help to develop prevention or treatment strategies for ACE2-mediated diseases.
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Affiliation(s)
- Chia-Wen Wang
- Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan, 35053 Taiwan
| | - Huai-Chia Chuang
- Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan, 35053 Taiwan
| | - Tse-Hua Tan
- Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan, 35053 Taiwan
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Sherif ZA, Gomez CR, Connors TJ, Henrich TJ, Reeves WB. Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC). eLife 2023; 12:e86002. [PMID: 36947108 DOI: 10.7554/elife.86002:] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/10/2023] [Indexed: 08/28/2024] Open
Abstract
COVID-19, with persistent and new onset of symptoms such as fatigue, post-exertional malaise, and cognitive dysfunction that last for months and impact everyday functioning, is referred to as Long COVID under the general category of post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is highly heterogenous and may be associated with multisystem tissue damage/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment. This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC. The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein-Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage specific patients.
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Affiliation(s)
- Zaki A Sherif
- Department of Biochemistry & Molecular Biology, Howard University College of Medicine, Washington, District of Columbia, United States
| | - Christian R Gomez
- Division of Lung Diseases, National Institutes of Health (NIH), National Heart, Lung and Blood Institute (NHLBI), Bethesda, United States
| | - Thomas J Connors
- Department of Pediatrics, Division of Critical Care, Columbia University Vagelos College of Physicians and Surgeons and New York - Presbyterian Morgan Stanley Children's Hospital, New York, United States
| | - Timothy J Henrich
- Division of Experimental Medicine, University of California, San Francisco, United States
| | - William Brian Reeves
- Department of Medicine, Joe R. and Teresa Lozano Long School of Medicine, University of Texas, San Antonio, United States
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10
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Sherif ZA, Gomez CR, Connors TJ, Henrich TJ, Reeves WB. Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC). eLife 2023; 12:e86002. [PMID: 36947108 PMCID: PMC10032659 DOI: 10.7554/elife.86002] [Citation(s) in RCA: 98] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/10/2023] [Indexed: 03/23/2023] Open
Abstract
COVID-19, with persistent and new onset of symptoms such as fatigue, post-exertional malaise, and cognitive dysfunction that last for months and impact everyday functioning, is referred to as Long COVID under the general category of post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is highly heterogenous and may be associated with multisystem tissue damage/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment. This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC. The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein-Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage specific patients.
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Affiliation(s)
- Zaki A Sherif
- Department of Biochemistry & Molecular Biology, Howard University College of MedicineWashington, District of ColumbiaUnited States
| | - Christian R Gomez
- Division of Lung Diseases, National Institutes of Health (NIH), National Heart, Lung and Blood Institute (NHLBI)BethesdaUnited States
| | - Thomas J Connors
- Department of Pediatrics, Division of Critical Care, Columbia University Vagelos College of Physicians and Surgeons and New York - Presbyterian Morgan Stanley Children's HospitalNew YorkUnited States
| | - Timothy J Henrich
- Division of Experimental Medicine, University of CaliforniaSan FranciscoUnited States
| | - William Brian Reeves
- Department of Medicine, Joe R. and Teresa Lozano Long School of Medicine, University of TexasSan AntonioUnited States
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11
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Gupta P, Rani V. The Surging Mechanistic Role of Angiotensin Converting Enzyme 2 in Human Pathologies: A Potential Approach for Herbal Therapeutics. Curr Drug Targets 2023; 24:1046-1054. [PMID: 37861036 DOI: 10.2174/0113894501247616231009065415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 07/27/2023] [Accepted: 09/15/2023] [Indexed: 10/21/2023]
Abstract
Advancements in biological sciences revealed the significant role of angiotensin-converting enzyme 2 (ACE2), a key cell surface receptor in various human pathologies. ACE2 is a metalloproteinase that not only functions in the regulation of Angiotensin II but also possesses some non-catalytic roles in the human body. There is considerable uncertainty regarding its protein expression, despite its presence in virtually all organs. The level of ACE2 expression and its subcellular localisation in humans may be a key determinant of susceptibility to various infections, symptoms, and outcomes of numerous diseases. Therefore, we summarize the distribution and expression pattern of ACE2 in different cell types related to all major human tissues and organs. Moreover, this review constitutes accumulated evidences of the important resources for further studies on ACE2 Inhibitory capacity via different natural compounds in order to understand its mechanism as the potential drug target in disease pathophysiology and to aid in the development of an effective therapeutic approach towards the various diseases.
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Affiliation(s)
- Priyadarshini Gupta
- Transcriptome laboratory, Centre of Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Sector-62, Noida, Uttar Pradesh, India
| | - Vibha Rani
- Transcriptome laboratory, Centre of Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Sector-62, Noida, Uttar Pradesh, India
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12
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A Closer Look at ACE2 Signaling Pathway and Processing during COVID-19 Infection: Identifying Possible Targets. Vaccines (Basel) 2022; 11:vaccines11010013. [PMID: 36679858 PMCID: PMC9867515 DOI: 10.3390/vaccines11010013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/11/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
Since the identification of its role as the functional receptor for SARS-CoV in 2003 and for SARS-CoV-2 in 2020, ACE2 has been studied in depth to understand COVID-19 susceptibility and severity. ACE2 is a widely expressed protein, and it plays a major regulatory role in the renin-angiotensin-aldosterone System (RAAS). The key to understanding susceptibility and severity may be found in ACE2 variants. Some variants have been shown to affect binding affinity with SARS-CoV-2. In this review, we discuss the role of ACE2 in COVID-19 infection, highlighting the importance of ACE2 isoforms (soluble and membrane-bound) and explore how ACE2 variants may influence an individual's susceptibility to SARS-CoV-2 infection and disease outcome.
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13
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Yu L, Li L, Liu J, Sun H, Li X, Xiao H, Alfred MO, Wang M, Wu X, Gao Y, Luo C. Recombinant Reg3α Prevents Islet β-Cell Apoptosis and Promotes β-Cell Regeneration. Int J Mol Sci 2022; 23:ijms231810584. [PMID: 36142497 PMCID: PMC9504149 DOI: 10.3390/ijms231810584] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/05/2022] [Accepted: 09/09/2022] [Indexed: 11/16/2022] Open
Abstract
Progressive loss and dysfunction of islet β-cells has not yet been solved in the treatment of diabetes. Regenerating protein (Reg) has been identified as a trophic factor which is demonstrated to be associated with pancreatic tissue regeneration. We previously produced recombinant Reg3α protein (rReg3α) and proved that it protects against acute pancreatitis in mice. Whether rReg3α protects islet β-cells in diabetes has been elusive. In the present study, rReg3α stimulated MIN6 cell proliferation and resisted STZ-caused cell death. The protective effect of rReg3α was also found in mouse primary islets. In BALB/c mice, rReg3α administration largely alleviated STZ-induced diabetes by the preservation of β-cell mass. The protective mechanism could be attributed to Akt/Bcl-2/-xL activation and GRP78 upregulation. Scattered insulin-expressing cells and clusters with small size, low insulin density, and exocrine distribution were observed and considered to be neogenic. In isolated acinar cells with wheat germ agglutinin (WGA) labeling, rReg3α treatment generated insulin-producing cells through Stat3/Ngn3 signaling, but these cells were not fully functional in response to glucose stimulation. Our results demonstrated that rReg3α resists STZ-induced β-cell death and promotes β-cell regeneration. rReg3α could serve as a potential drug for β-cell maintenance in anti-diabetic treatment.
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Affiliation(s)
- Luting Yu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210037, China
| | - Liang Li
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
| | - Junli Liu
- MeDiC Program, The Research Institute of McGill University Health Centre, Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, QC H3A 0G4, Canada
| | - Hao Sun
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
| | - Xiang Li
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
| | - Hanyu Xiao
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
| | - Martin Omondi Alfred
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
- Institute of Primate Research, End of Karen Road, Karen, Nairobi P.O. Box 24481-00502, Kenya
| | - Min Wang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
- State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Xuri Wu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
- State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Yan Gao
- Institute of Suzhou Biobank, Suzhou Center for Disease Prevention and Control, Suzhou 215007, China
- Suzhou Institute of Advanced Study in Public Health, Gusu School, Nanjing Medical University, Suzhou 210029, China
- Correspondence: (Y.G.); (C.L.); Tel.: +86-0512-6826-2385 (Y.G.); +86-138-1388-3828 (C.L.)
| | - Chen Luo
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
- State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing 210009, China
- Correspondence: (Y.G.); (C.L.); Tel.: +86-0512-6826-2385 (Y.G.); +86-138-1388-3828 (C.L.)
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14
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Chandrashekhar Joshi S, Pozzilli P. COVID-19 induced Diabetes: A novel presentation. Diabetes Res Clin Pract 2022; 191:110034. [PMID: 35940303 PMCID: PMC9355745 DOI: 10.1016/j.diabres.2022.110034] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 08/03/2022] [Indexed: 01/08/2023]
Abstract
INTRODUCTION The COVID-19 pandemic disproportionately affected patients who had comorbid diabetes mellitus. COVID-19 patients with diabetes experience significantly higher rates of complications and mortality. COVID-induced diabetes is a novel phenomenon observed in critically ill patients. The aims of this review were to explore the literature about COVID-induced diabetes and the pathophysiological mechanisms that could lead to this novel presentation. METHODS A literature search was performed using PUBMED, Google Scholar, MEDLINE and Embase for original studies (meta-analyses, cross-sectional studies, case series, case reports) about new-onset diabetes following COVID infection, and the proposed biochemical pathways behind this presentation. It was assumed that the authors of the studies used the current diagnostic criteria for diagnosis of type 1 and type 2 diabetes. RESULTS COVID-19 causes dysregulation of glucose homeostasis leading to new-onset diabetes and hyperglycaemia. This is also seen in patients with no previous risk factors for diabetes mellitus. The atypical glycaemic parameters and increased rates of DKA suggest that COVID-induced diabetes is a novel form of diabetes. A spectrum of COVID-induced diabetes has also been noted. COVID-induced diabetes is associated with remarkably higher mortality rates and worse outcomes compared to COVID-19 patients with pre-existing diabetes. The novel presentation of COVID-induced diabetes could be due to beta cell damage and insulin resistance caused by SARS-CoV-2. CONCLUSION COVID-induced diabetes is essential to detect early, owing to its implications on prognosis. Further studies must include follow-up of these patients to better understand the trajectory of COVID-induced diabetes and the best management plan. It is also important to assess the beta cell function and insulin resistance of COVID-induced diabetes patients over time to better understand the underlying biochemical mechanisms.
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Affiliation(s)
| | - Paolo Pozzilli
- The Blizard Institute, Centre of Immunobiology, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, UK; Unit of Endocrinology and Diabetes, Campus Bio-Medico University of Rome, Italy.
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15
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Amino acid sensor GCN2 promotes SARS-CoV-2 receptor ACE2 expression in response to amino acid deprivation. Commun Biol 2022; 5:651. [PMID: 35778545 PMCID: PMC9249868 DOI: 10.1038/s42003-022-03609-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 06/21/2022] [Indexed: 12/14/2022] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2) has been identified as a primary receptor for severe acute respiratory syndrome coronaviruses 2 (SARS-CoV-2). Here, we investigated the expression regulation of ACE2 in enterocytes under amino acid deprivation conditions. In this study, we found that ACE2 expression was upregulated upon all or single essential amino acid deprivation in human colonic epithelial CCD841 cells. Furthermore, we found that knockdown of general control nonderepressible 2 (GCN2) reduced intestinal ACE2 mRNA and protein levels in vitro and in vivo. Consistently, we revealed two GCN2 inhibitors, GCN2iB and GCN2-IN-1, downregulated ACE2 protein expression in CCD841 cells. Moreover, we found that increased ACE2 expression in response to leucine deprivation was GCN2 dependent. Through RNA-sequencing analysis, we identified two transcription factors, MAFB and MAFF, positively regulated ACE2 expression under leucine deprivation in CCD841 cells. These findings demonstrate that amino acid deficiency increases ACE2 expression and thereby likely aggravates intestinal SARS-CoV-2 infection. Amino acid deprivation increases ACE2 expression in the gut, potentially aggravating SARS-CoV-2 infection.
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16
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Abstract
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, is a global pandemic impacting 254 million people in 190 countries. Comorbidities, particularly cardiovascular disease, diabetes, and hypertension, increase the risk of infection and poor outcomes. SARS-CoV-2 enters host cells through the angiotensin-converting enzyme-2 receptor, generating inflammation and cytokine storm, often resulting in multiorgan failure. The mechanisms and effects of COVID-19 on patients with high-risk diabetes are not yet completely understood. In this review, we discuss the variety of coronaviruses, structure of SARS-CoV-2, mutations in SARS-CoV-2 spike proteins, receptors associated with viral host entry, and disease progression. Furthermore, we focus on possible mechanisms of SARS-CoV-2 in diabetes, leading to inflammation and heart failure. Finally, we discuss existing therapeutic approaches, unanswered questions, and future directions.
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Affiliation(s)
- Chandrakala Aluganti Narasimhulu
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States
| | - Dinender K Singla
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States
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17
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Chrysin Attenuates Fructose-Induced Nonalcoholic Fatty Liver in Rats via Antioxidant and Anti-Inflammatory Effects: The Role of Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Receptor Axis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9479456. [PMID: 35720181 PMCID: PMC9200559 DOI: 10.1155/2022/9479456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 05/12/2022] [Indexed: 11/25/2022]
Abstract
Aim Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and if untreated, it may propagate into end-stage liver disease. The classical arm of the renin-angiotensin system (RAS) has a fundamental role in triggering oxidative stress and inflammation, which play potential roles in the pathogenesis of NAFLD. However, the nonclassical alternative axis of RAS, angiotensin- (Ang-) converting enzyme 2 (ACE2)/Ang (1-7)/Mas receptor, opposes the actions of the classical arm, mitigates the metabolic dysfunction, and improves hepatic lipid metabolism rendering it a promising protective target against NAFLD. The current study is aimed at investigating the impact of chrysin, a well-known antioxidant flavonoid, on this defensive RAS axis in NAFLD. Methods Rats were randomly distributed and treated daily for eight weeks as follows: the normal control, chrysin control (50 mg/kg, p.o), NAFLD group (received 20% fructose in drinking water), and treated groups (25 and 50 mg/kg chrysin given orally and concomitantly with fructose). Diminazene aceturate (DIZE) (15 mg/kg, s.c.) was used as a reference ACE2 activator. Key Findings. High fructose induced significant weight gain, hepatocyte degeneration with fat accumulation, and inflammatory cell infiltration (as examined by H&E staining). This was accompanied by a substantial increase in liver enzymes, glucose, circulating and hepatic triglycerides, lipid peroxides, inflammatory cytokines, and Ang II (the main component of classical RAS). At the same time, protein levels of ACE2, Ang (1-7), and Mas receptors were markedly reduced. Chrysin (25 and 50 mg/kg) significantly ameliorated these abnormalities, with a prominent effect of the dose of 50 mg/kg over DIZE and the lower dose in improving ACE2, Ang (1-7), and Mas. Significance. Chrysin is a promising efficient protective remedy against NAFLD; mechanisms include the activation of ACE2/Ang (1-7)/Mas axis.
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18
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Dai Y, Kou H, Gui S, Guo X, Liu H, Gong Z, Sun X, Wang H, Guo Y. Prenatal dexamethasone exposure induced pancreatic β-cell dysfunction and glucose intolerance of male offspring rats: Role of the epigenetic repression of ACE2. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 826:154095. [PMID: 35219660 DOI: 10.1016/j.scitotenv.2022.154095] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 02/01/2022] [Accepted: 02/19/2022] [Indexed: 06/14/2023]
Abstract
The prevalence of diabetes in children and adolescents has been rising gradually, which is relevant to adverse environment during development, especially prepartum. We aimed to explore the effects of prenatal dexamethasone exposure (PDE) on β-cell function and glucose homeostasis in juvenile offspring rats. Pregnant Wistar rats were subcutaneously administered with dexamethasone [0.1, 0.2, 0.4mg/(kg.d)] from gestational day 9 to 20. PDE impaired glucose tolerance in the male offspring rather than the females. In male offspring, PDE impaired the development and function of β-cells, accompanied with lower H3K9ac, H3K14ac and H3K27ac levels in the promoter region of angiotensin-converting enzyme 2 (ACE2) as well as suppressed ACE2 expression. Meanwhile, PDE increased expression of glucocorticoid receptor (GR) and histone deacetylase 3 (HDAC3) in fetal pancreas. Dexamethasone also inhibited ACE2 expression and insulin production in vitro. Recombinant expression of ACE2 restored insulin production inhibited by dexamethasone. In addition, dexamethasone activated GR and HDAC3, increased protein interaction of GR with HDAC3, and promoted the binding of GR-HDAC3 complex to ACE2 promoter region. Both RU486 and TSA abolished dexamethasone-induced decline of histone acetylation and ACE2 expression. In summary, suppression of ACE2 is involved in PDE induced β-cell dysfunction and glucose intolerance in juvenile male offspring rats.
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Affiliation(s)
- Yongguo Dai
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China.
| | - Hao Kou
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan 430060, Hubei Province, People's Republic of China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, Hubei Province, People's Republic of China
| | - Shuxia Gui
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China
| | - Xiaoling Guo
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China
| | - Heze Liu
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China
| | - Zheng Gong
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China
| | - Xiaoxiang Sun
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China
| | - Hui Wang
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, Hubei Province, People's Republic of China.
| | - Yu Guo
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, Hubei Province, People's Republic of China.
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19
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Ghanbari F, Yazdanpanah N, Yazdanpanah M, Richards JB, Manousaki D. Connecting Genomics and Proteomics to Identify Protein Biomarkers for Adult and Youth-Onset Type 2 Diabetes: A Two-Sample Mendelian Randomization Study. Diabetes 2022; 71:1324-1337. [PMID: 35234851 DOI: 10.2337/db21-1046] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 02/24/2022] [Indexed: 11/13/2022]
Abstract
Type 2 diabetes shows an increasing prevalence in both adults and children. Identification of biomarkers for both youth and adult-onset type 2 diabetes is crucial for development of screening tools or drug targets. In this study, using two-sample Mendelian randomization (MR), we identified 22 circulating proteins causally linked to adult type 2 diabetes and 11 proteins with suggestive evidence for association with youth-onset type 2 diabetes. Among these, colocalization analysis further supported a role in type 2 diabetes for C-type mannose receptor 2 (MR odds ratio [OR] 0.85 [95% CI 0.79-0.92] per genetically predicted SD increase in protein level), MANS domain containing 4 (MR OR 0.90 [95% CI 0.88-0.92]), sodium/potassium-transporting ATPase subunit β2 (MR OR 1.10 [95% CI 1.06-1.15]), endoplasmic reticulum oxidoreductase 1β (MR OR 1.09 [95% CI 1.05-1.14]), spermatogenesis-associated protein 20 (MR OR 1.12 [95% CI 1.06-1.18]), haptoglobin (MR OR 0.96 [95% CI 0.94-0.98]), and α1-3-N-acetylgalactosaminyltransferase and α1-3-galactosyltransferase (MR OR 1.04 [95% CI 1.03-1.05]). Our findings support a causal role in type 2 diabetes for a set of circulating proteins, which represent promising type 2 diabetes drug targets.
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Affiliation(s)
- Faegheh Ghanbari
- Research Center of the Sainte-Justine University Hospital, University of Montreal, Montreal, Quebec, Canada
| | - Nahid Yazdanpanah
- Research Center of the Sainte-Justine University Hospital, University of Montreal, Montreal, Quebec, Canada
| | - Mojgan Yazdanpanah
- Research Center of the Sainte-Justine University Hospital, University of Montreal, Montreal, Quebec, Canada
| | - J Brent Richards
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
- Department of Medicine, McGill University, Montreal, Quebec, Canada
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada
- Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada
- Department of Twin Research, King's College London, London, U.K
| | - Despoina Manousaki
- Research Center of the Sainte-Justine University Hospital, University of Montreal, Montreal, Quebec, Canada
- Departments of Pediatrics, Biochemistry and Molecular Medicine, University of Montreal, Montreal, Canada
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20
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Rajapaksha IG, Gunarathne LS, Asadi K, Laybutt R, Andrikopoulous S, Alexander IE, Watt MJ, Angus PW, Herath CB. Angiotensin Converting Enzyme-2 Therapy Improves Liver Fibrosis and Glycemic Control in Diabetic Mice With Fatty Liver. Hepatol Commun 2022; 6:1056-1072. [PMID: 34951153 PMCID: PMC9035567 DOI: 10.1002/hep4.1884] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/29/2021] [Accepted: 12/04/2021] [Indexed: 12/26/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is frequently associated with type 2 diabetes. However, there is no specific medical therapy to treat this condition. Angiotensin-converting enzyme 2 (ACE2) of the protective renin angiotensin system generates the antifibrotic peptide angiotensin-(1-7) from profibrotic angiotensin II peptide. In this study, we investigated the therapeutic potential of ACE2 in diabetic NAFLD mice fed a high-fat (20%), high-cholesterol (2%) diet for 40 weeks. Mice were given a single intraperitoneal injection of ACE2 using an adeno-associated viral vector at 30 weeks of high-fat, high-cholesterol diet (15 weeks after induction of diabetes) and sacrificed 10 weeks later. ACE2 significantly reduced liver injury and fibrosis in diabetic NAFLD mice compared with the control vector injected mice. This was accompanied by reductions in proinflammatory cytokine expressions, hepatic stellate cell activation, and collagen 1 expression. Moreover, ACE2 therapy significantly increased islet numbers, leading to an increased insulin protein content in β-cells and plasma insulin levels with subsequent reduction in plasma glucose levels compared with controls. Conclusion: We conclude that ACE2 gene therapy reduces liver fibrosis and hyperglycemia in diabetic NAFLD mice and has potential as a therapy for patients with NAFLD with diabetes.
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Affiliation(s)
- Indu G Rajapaksha
- Department of MedicineThe University of MelbourneAustin HealthHeidelbergVICAustralia
| | - Lakmie S Gunarathne
- Department of MedicineThe University of MelbourneAustin HealthHeidelbergVICAustralia
| | | | - Ross Laybutt
- Garvan Institute of Medical ResearchSydneyNSWAustralia.,St. Vincent's Clinical SchoolUniversity of New South WalesSydneyNSWAustralia
| | - Sof Andrikopoulous
- Department of MedicineThe University of MelbourneAustin HealthHeidelbergVICAustralia
| | - Ian E Alexander
- School of MedicineUniversity of SydneyChildren's Medical Research InstituteSydneyNSWAustralia
| | - Mathew J Watt
- Department Anatomy and PhysiologyThe University of MelbourneMelbourneVICAustralia
| | - Peter W Angus
- Department of MedicineThe University of MelbourneAustin HealthHeidelbergVICAustralia.,Department GastroenterologyAustin HealthHeidelbergVICAustralia
| | - Chandana B Herath
- Department of MedicineThe University of MelbourneAustin HealthHeidelbergVICAustralia.,South Western Sydney Clinical SchoolFaculty of MedicineUniversity of New South WalesSydneyNSWAustralia.,Ingham Institute for Applied Medical ResearchLiverpoolNSWAustralia
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21
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Cook JR, Ausiello J. Functional ACE2 deficiency leading to angiotensin imbalance in the pathophysiology of COVID-19. Rev Endocr Metab Disord 2022; 23:151-170. [PMID: 34195965 PMCID: PMC8245275 DOI: 10.1007/s11154-021-09663-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/04/2021] [Indexed: 02/07/2023]
Abstract
SARS-CoV-2, the virus responsible for COVID-19, uses angiotensin converting enzyme 2 (ACE2) as its primary cell-surface receptor. ACE2 is a key enzyme in the counter-regulatory pathway of the broader renin-angiotensin system (RAS) that has been implicated in a broad array of human pathology. The RAS is composed of two competing pathways that work in opposition to each other: the "conventional" arm involving angiotensin converting enzyme (ACE) generating angiotensin-2 and the more recently identified ACE2 pathway that generates angiotensin (1-7). Following the original SARS pandemic, additional studies suggested that coronaviral binding to ACE2 resulted in downregulation of the membrane-bound enzyme. Given the similarities between the two viruses, many have posited a similar process with SARS-CoV-2. Proponents of this ACE2 deficiency model argue that downregulation of ACE2 limits its enzymatic function, thereby skewing the delicate balance between the two competing arms of the RAS. In this review we critically examine this model. The available data remain incomplete but are consistent with the possibility that the broad multisystem dysfunction of COVID-19 is due in large part to functional ACE2 deficiency leading to angiotensin imbalance with consequent immune dysregulation and endothelial cell dysfunction.
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Affiliation(s)
- Joshua R Cook
- New York-Presbyterian Hospital and the Columbia University Irving Medical Center, New York, NY, USA
| | - John Ausiello
- New York-Presbyterian Hospital and the Columbia University Irving Medical Center, New York, NY, USA.
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22
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Liu J, Li X, Wang X, Peng L, Song G, He J. Angiotensin(1-7) Improves Islet Function in Diabetes Through Reducing JNK/Caspase-3 Signaling. Horm Metab Res 2022; 54:250-258. [PMID: 35413746 DOI: 10.1055/a-1796-9286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
The aim of this study is to investigate whether Angiotensin (1-7), the physiological antagonist of Angiotensin II (AngII), has antidiabetic activity and the possible mechanism. Male Wistar rats were randomly divided into 3 groups: control group fed the normal diet, DM group fed high-fat diet and injected with STZ, and Angiotensin (1-7) group receiving injection of STZ followed by Angiotensin (1-7) treatment. Serum Ang II, fasting blood glucose, insulin, HOMA-IR, and HOMA-beta were determined in control, diabetes and Angiotensin (1-7) groups. The increased AngII and insulin resistance in diabetes group were accompanied by changes in islet histopathology. However, Angiotensin (1-7) improved the islet function and histopathology in diabetes without affecting the level of AngII. Western blot confirmed that Angiotensin (1-7) decreased the cleaved caspase 3 levels in pancreas of DM. The increased expression of JNK, Bax, and Bcl2 genes under diabetic conditions were partially reversed after Angiotensin (1-7) administration in pancreas. Immunofluorescence analysis showed that p-JNK was markedly increased in islet of DM rats, which was markedly alleviated after Angiotensin (1-7) treatment. Furthermore, Angiotensin (1-7) reversed high glucose(HG) induced mitochondrial apoptosis augments. Finally, Angiotensin (1-7) attenuated the apoptosis of INS-1 cells through reducing JNK activation in diabetes, which was blocked by anisomycin (a potent agonist of JNK). Our findings provide supporting evidence that Angiotensin (1-7) improved the islet beta-cells apoptosis by JNK-mediated mitochondrial dysfunction, which might be a novel target for the treatment and prevention of beta-cells dysfunction in DM.
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Affiliation(s)
- Jing Liu
- Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Xing Li
- Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Xiaoyan Wang
- Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Lina Peng
- Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Guoning Song
- Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Junhua He
- Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan, China
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Kosacka J, Berger C, Ceglarek U, Hoffmann A, Blüher M, Klöting N. Ramipril Reduces Acylcarnitines and Distinctly Increases Angiotensin-Converting Enzyme 2 Expression in Lungs of Rats. Metabolites 2022; 12:metabo12040293. [PMID: 35448480 PMCID: PMC9028516 DOI: 10.3390/metabo12040293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 03/22/2022] [Accepted: 03/24/2022] [Indexed: 01/08/2023] Open
Abstract
The angiotensin-converting enzyme 2 (ACE2) receptor has been identified as the entry receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is abundantly expressed in many organs. With respect to the role of circulating ACE2 and its receptor expression in the pathogenesis of the SARS-CoV-2 infection, it is still debated whether diseases such as hypertension or pharmacotherapies, including ACE inhibitors and angiotensin receptor blockers that affect ACE2 receptor expression, may modulate the severity and outcome of the coronavirus disease 2019 (COVID-19). We therefore tested the hypothesis that treatment with the ACE inhibitor Ramipril affects organ-specific ACE2 receptor mRNA and protein expression as well as the serum metabolome in BioBreeding (BB) rats. Twelve male BioBreeding rats were randomly divided into a Ramipril (10 mg/kg body weight) treatment group or a control group (N = 12; n = 6 per group) over a period of seven days. Ramipril treatment resulted in the reduction of acylcarnitines (C3–C6) out of 64 metabolites. Among the different organs studied, only in the lungs did Ramipril treatment significantly increase both Ace2 mRNA and ACE2 receptor membrane protein levels. Increased ACE2 receptor lung expression after Ramipril treatment was not associated with differences in ACE2 serum concentrations between experimental groups. Our data provide experimental in vivo evidence that the ACE inhibitor Ramipril selectively increases pulmonary ACE2 receptor mRNA and protein levels and reduces acylcarnitines.
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Affiliation(s)
- Joanna Kosacka
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Liebigstr. 20, 04103 Leipzig, Germany; (C.B.); (M.B.)
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, Liebigstr. 21, 04103 Leipzig, Germany
- Correspondence: ; Tel.: +49-341-9713405
| | - Claudia Berger
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Liebigstr. 20, 04103 Leipzig, Germany; (C.B.); (M.B.)
| | - Uta Ceglarek
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig University Medical Center, 04103 Leipzig, Germany;
| | - Anne Hoffmann
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig, Ph.-Rosenthal-Str. 27, 04103 Leipzig, Germany; (A.H.); (N.K.)
| | - Matthias Blüher
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Liebigstr. 20, 04103 Leipzig, Germany; (C.B.); (M.B.)
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig, Ph.-Rosenthal-Str. 27, 04103 Leipzig, Germany; (A.H.); (N.K.)
| | - Nora Klöting
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig, Ph.-Rosenthal-Str. 27, 04103 Leipzig, Germany; (A.H.); (N.K.)
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An insight into the mechanisms of COVID-19, SARS-CoV2 infection severity concerning β-cell survival and cardiovascular conditions in diabetic patients. Mol Cell Biochem 2022; 477:1681-1695. [PMID: 35235124 PMCID: PMC8889522 DOI: 10.1007/s11010-022-04396-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 02/16/2022] [Indexed: 01/08/2023]
Abstract
A significantly high percentage of hospitalized COVID-19 patients with diabetes mellitus (DM) had severe conditions and were admitted to ICU. In this review, we have delineated the plausible molecular mechanisms that could explain why there are increased clinical complications in patients with DM that become critically ill when infected with SARS-CoV2. RNA viruses have been classically implicated in manifestation of new onset diabetes. SARS-CoV2 infection through cytokine storm leads to elevated levels of pro-inflammatory cytokines creating an imbalance in the functioning of T helper cells affecting multiple organs. Inflammation and Th1/Th2 cell imbalance along with Th17 have been associated with DM, which can exacerbate SARS-CoV2 infection severity. ACE-2-Ang-(1-7)-Mas axis positively modulates β-cell and cardiac tissue function and survival. However, ACE-2 receptors dock SARS-CoV2, which internalize and deplete ACE-2 and activate Renin-angiotensin system (RAS) pathway. This induces inflammation promoting insulin resistance that has positive effect on RAS pathway, causes β-cell dysfunction, promotes inflammation and increases the risk of cardiovascular complications. Further, hyperglycemic state could upregulate ACE-2 receptors for viral infection thereby increasing the severity of the diabetic condition. SARS-CoV2 infection in diabetic patients with heart conditions are linked to worse outcomes. SARS-CoV2 can directly affect cardiac tissue or inflammatory response during diabetic condition and worsen the underlying heart conditions.
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Younas H, Ijaz T, Choudhry N. Investigation of angiotensin-1 converting enzyme 2 gene (G8790A) polymorphism in patients of type 2 diabetes mellitus with diabetic nephropathy in Pakistani population. PLoS One 2022; 17:e0264038. [PMID: 35176079 PMCID: PMC8853542 DOI: 10.1371/journal.pone.0264038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/31/2022] [Indexed: 11/19/2022] Open
Abstract
Background Type 2 diabetes mellitus is a multifactorial disease that escalates the risk of other associated complications such as diabetic neuropathy, retinopathy, and nephropathy. Diabetic nephropathy is a microvascular condition that leads to end-stage renal disease (ESRD). There are several genes involved in disease development and it is a challenging task to investigate all of these. Nonetheless, identifying individual gene roles can assist in evaluating the combinatorial effects with other genes. Angiotensin-1 converting enzyme 2 (ACE2), is the key regulator of blood pressure in the Renin-Angiotensin-Aldosterone System that hydrolyzes angiotensin II (vasoconstrictor) into angiotensin 1–7 (vasodilator). The association of different variants of the ACE2 with the risk of type 2 diabetes mellitus has been determined in various populations with susceptibility to other complications. This study was aimed to investigate the association of Angiotensin-1 converting enzyme 2 polymorphism, G8790A, with the increased risk of type 2 diabetes mellitus (T2DM) development with the complication of diabetic nephropathy (DN) in the Pakistani population. Methods In this case-control study, a total of 100 healthy controls and 100 patients of type 2 diabetes mellitus aged > 40 years, having disease duration ≥ 10 years were compared. The G8790A polymorphism in ACE2 was analyzed by allele-specific polymerase chain reaction (AS-PCR). The urinary albumin excretion (UAE), urinary creatinine, and albumin to creatinine ratios (ACR) were determined to assess renal function status. Pearson bivariate correlation coefficients were calculated to investigate the relationship among all the parameters. Crude and adjusted odds ratios were found to determine any risk association between ACE2 G8790A polymorphisms and disease development. The p-values < 0.05 were considered significant. Results A homogeneity was obtained regarding the distribution of data by sex, BMI, diastolic blood pressure, pulse rate and urinary creatinine levels between case and control groups. The ACR showed a significant correlation with UAE (r = 0.524, p = 0.001), urinary creatinine (r = -0.375, p = 0.001) and random blood sugar levels (r = 0.323, p = 0.005) with the complication of diabetic nephropathy in T2DM patient. Females with the AA genotype had a 10-fold increased risk for the development of type 2 Diabetes (OR = 9.5 [95% CI = 2.00–21.63] p<0.002). Males having A allele showed a significant association for susceptibility of type 2 Diabetes (OR = 3.807 [95% CI = 1.657–8.747] p<0.002). However, none of the genotypes or alleles revealed an association for diabetic nephropathy in male and female patients. Urinary ACR was also found to be positively correlated with UAE (r = 0.642 p = 0.001 & 0.524, p = 0.001) and random blood sugar levels (r = 0.302, p = 0.002 & r = 0.323, p = 0.005) in T2DM and T2DM+DN groups, respectively. Conclusion The study finding indicated that female AG/AA genotype and male A genotype of G8790A polymorphism in the ACE2 gene were associated with type 2 diabetes mellitus as a genetic risk factor but are not associated with diabetic nephropathy in the Pakistani population.
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Affiliation(s)
- Hooria Younas
- Department of Biochemistry, Kinnaird College for Women, Lahore, Punjab, Pakistan
- * E-mail:
| | - Tahira Ijaz
- Department of Biochemistry, Kinnaird College for Women, Lahore, Punjab, Pakistan
| | - Nakhshab Choudhry
- Department of Biochemistry, King Edward Medical University, Lahore, Punjab, Pakistan
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Zhang K, Bao R, Huang F, Yang K, Ding Y, Lauterboeck L, Yoshida M, Long Q, Yang Q. ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis. J Transl Med 2022; 102:69-79. [PMID: 34608240 PMCID: PMC9198815 DOI: 10.1038/s41374-021-00670-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 08/13/2021] [Accepted: 08/20/2021] [Indexed: 12/23/2022] Open
Abstract
Mitochondrial homeostasis is crucial for the function of pancreatic β-cells. ATP synthase inhibitory factor subunit 1 (IF1) is a mitochondrial protein interacting with ATP synthase to inhibit its enzyme activity. IF1 may also play a role in maintaining ATP synthase oligomerization and mitochondrial inner membrane formation. A recent study confirmed IF1 expresses in β-cells. IF1 knockdown in cultured INS-1E β-cells enhances glucose-induced insulin release. However, the role of IF1 in islet β-cells remains little known. The present study investigates islets freshly isolated from mouse lines with global IF1 knockout (IF1-/-) and overexpression (OE). The glucose-stimulated insulin secretion was increased in islets from IF1-/- mice but decreased in islets from IF1 OE mice. Transmitted Electronic Microscopic assessment of isolated islets revealed that the number of matured insulin granules (with dense core) was relatively higher in IF1-/-, but fewer in IF1 OE islets than those of controlled islets. The mitochondrial ultrastructure within β-cells of IF1 overexpressed islets was comparable with those of wild-type mice, whereas those in IF1-/- β-cells showed increased mitochondrial mass. Mitochondrial network analysis in cultured INS-1 β-cells showed a similar pattern with an increased mitochondrial network in IF1 knockdown cells. IF1 overexpressed INS-1 β-cells showed a compromised rate of mitochondrial oxidative phosphorylation with attenuated cellular ATP content. In contrast, INS-1 cells with IF1 knockdown showed markedly increased cellular respiration with improved ATP production. These results support that IF1 is a negative regulator of insulin production and secretion via inhibiting mitochondrial mass and respiration in β-cells. Therefore, inhibiting IF1 to improve β-cell function in patients can be a novel therapeutic strategy to treat diabetes.
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Affiliation(s)
- Kailiang Zhang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rong Bao
- Cardiovascular Center of Excellence and Department of Pharmacology, Louisiana State University Health Science Center New Orleans, New Orleans, LA, USA
| | - Fengyuan Huang
- Department of Nutrition Science, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kevin Yang
- Department of Nutrition Science, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Yishu Ding
- Department of Nutrition Science, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lothar Lauterboeck
- Cardiovascular Center of Excellence and Department of Pharmacology, Louisiana State University Health Science Center New Orleans, New Orleans, LA, USA
| | - Masasuke Yoshida
- Department of Molecular Bioscience, Kyoto Sangyo University, Kamigamo-Motoyama, Kyoto, Japan
| | - Qinqiang Long
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Nutrition Science, University of Alabama at Birmingham, Birmingham, AL, USA.
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
| | - Qinglin Yang
- Cardiovascular Center of Excellence and Department of Pharmacology, Louisiana State University Health Science Center New Orleans, New Orleans, LA, USA.
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Sonkar G, Singh S, Sonkar S. A systematic review approach in understanding the COVID-19 mechanism in diabetes and its progression to diabetic microvascular complications. JOURNAL OF DIABETOLOGY 2022. [DOI: 10.4103/jod.jod_87_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Qi JH, Chen PY, Cai DY, Wang Y, Wei YL, He SP, Zhou W. Exploring novel targets of sitagliptin for type 2 diabetes mellitus: Network pharmacology, molecular docking, molecular dynamics simulation, and SPR approaches. Front Endocrinol (Lausanne) 2022; 13:1096655. [PMID: 36699034 PMCID: PMC9868454 DOI: 10.3389/fendo.2022.1096655] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 12/19/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Diabetes has become a serious global public health problem. With the increasing prevalence of type 2 diabetes mellitus (T2DM), the incidence of complications of T2DM is also on the rise. Sitagliptin, as a targeted drug of DPP4, has good therapeutic effect for T2DM. It is well known that sitagliptin can specifically inhibit the activity of DPP4 to promote insulin secretion, inhibit islet β cell apoptosis and reduce blood glucose levels, while other pharmacological mechanisms are still unclear, such as improving insulin resistance, anti-inflammatory, anti-oxidative stress, and anti-fibrosis. The aim of this study was to explore novel targets and potential signaling pathways of sitagliptin for T2DM. METHODS Firstly, network pharmacology was applied to find the novel target most closely related to DPP4. Semi-flexible molecular docking was performed to confirm the binding ability between sitagliptin and the novel target, and molecular dynamics simulation (MD) was carried to verify the stability of the complex formed by sitagliptin and the novel target. Furthermore, surface-plasmon resonance (SPR) was used to explored the affinity and kinetic characteristics of sitagliptin with the novel target. Finally, the molecular mechanism of sitagliptin for T2DM was predicted by the enrichment analysis of GO function and KEGG pathway. RESULTS In this study, we found the cell surface receptor-angiotensin-converting enzyme 2 (ACE2) most closely related to DPP4. Then, we confirmed that sitagliptin had strong binding ability with ACE2 from a static perspective, and the stability of sitagliptin-ACE2 complex had better stability and longer binding time than BAR708-ACE2 in simulated aqueous solution within 50 ns. Significantly, we have demonstrated a strong affinity between sitagliptin and ACE2 on SPR biosensor, and their kinetic characteristics were "fast binding/fast dissociation". The guiding significance of clinical administration: low dose can reach saturation, but repeated administration was needed. Finally, there was certain relationship between COVID-19 and T2DM, and ACE2/Ang-(1-7)/Mas receptor (MasR) axis may be the important pathway of sitagliptin targeting ACE2 for T2DM. CONCLUSION This study used different methods to prove that ACE2 may be another novel target of sitagliptin for T2DM, which extended the application of ACE2 in improving diabetes mellitus.
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Memon B, Abdelalim EM. ACE2 function in the pancreatic islet: Implications for relationship between SARS-CoV-2 and diabetes. Acta Physiol (Oxf) 2021; 233:e13733. [PMID: 34561952 PMCID: PMC8646749 DOI: 10.1111/apha.13733] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 09/15/2021] [Accepted: 09/20/2021] [Indexed: 01/08/2023]
Abstract
The molecular link between SARS-CoV-2 infection and susceptibility is not well understood. Nonetheless, a bi-directional relationship between SARS-CoV-2 and diabetes has been proposed. The angiotensin-converting enzyme 2 (ACE2) is considered as the primary protein facilitating SARS-CoV and SARS-CoV-2 attachment and entry into the host cells. Studies suggested that ACE2 is expressed in the endocrine cells of the pancreas including beta cells, in addition to the lungs and other organs; however, its expression in the islets, particularly beta cells, has been met with some contradiction. Importantly, ACE2 plays a crucial role in glucose homoeostasis and insulin secretion by regulating beta cell physiology. Given the ability of SARS-CoV-2 to infect human pluripotent stem cell-derived pancreatic cells in vitro and the presence of SARS-CoV-2 in pancreatic samples from COVID-19 patients strongly hints that SARS-CoV-2 can invade the pancreas and directly cause pancreatic injury and diabetes. However, more studies are required to dissect the underpinning molecular mechanisms triggered in SARS-CoV-2-infected islets that lead to aggravation of diabetes. Regardless, it is important to understand the function of ACE2 in the pancreatic islets to design relevant therapeutic interventions in combatting the effects of SARS-CoV-2 on diabetes pathophysiology. Herein, we detail the function of ACE2 in pancreatic beta cells crucial for regulating insulin sensitivity, secretion, and glucose metabolism. Also, we discuss the potential role played by ACE2 in aiding SARS-COV-2 entry into the pancreas and the possibility of ACE2 cooperation with alternative entry factors as well as how that may be linked to diabetes pathogenesis.
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Affiliation(s)
- Bushra Memon
- College of Health and Life Sciences Hamad Bin Khalifa University (HBKU)Qatar Foundation Doha Qatar
- Diabetes Research Center Qatar Biomedical Research Institute (QBRI)Hamad Bin KhalifaUniversity (HBKU)Qatar Foundation (QF) Doha Qatar
| | - Essam M. Abdelalim
- College of Health and Life Sciences Hamad Bin Khalifa University (HBKU)Qatar Foundation Doha Qatar
- Diabetes Research Center Qatar Biomedical Research Institute (QBRI)Hamad Bin KhalifaUniversity (HBKU)Qatar Foundation (QF) Doha Qatar
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30
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Cauwenberghs N, Prunicki M, Sabovčik F, Perelman D, Contrepois K, Li X, Snyder MP, Nadeau KC, Kuznetsova T, Haddad F, Gardner CD. Temporal changes in soluble angiotensin-converting enzyme 2 associated with metabolic health, body composition, and proteome dynamics during a weight loss diet intervention: a randomized trial with implications for the COVID-19 pandemic. Am J Clin Nutr 2021; 114:1655-1665. [PMID: 34375388 PMCID: PMC8574695 DOI: 10.1093/ajcn/nqab243] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/29/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Angiotensin-converting enzyme 2 (ACE2) serves protective functions in metabolic, cardiovascular, renal, and pulmonary diseases and is linked to COVID-19 pathology. The correlates of temporal changes in soluble ACE2 (sACE2) remain understudied. OBJECTIVES We explored the associations of sACE2 with metabolic health and proteome dynamics during a weight loss diet intervention. METHODS We analyzed 457 healthy individuals (mean ± SD age: 39.8 ± 6.6 y) with BMI 28-40 kg/m2 in the DIETFITS (Diet Intervention Examining the Factors Interacting with Treatment Success) study. Biochemical markers of metabolic health and 236 proteins were measured by Olink CVDII, CVDIII, and Inflammation I arrays at baseline and at 6 mo during the dietary intervention. We determined clinical and routine biochemical correlates of the diet-induced change in sACE2 (ΔsACE2) using stepwise linear regression. We combined feature selection models and multivariable-adjusted linear regression to identify protein dynamics associated with ΔsACE2. RESULTS sACE2 decreased on average at 6 mo during the diet intervention. Stronger decline in sACE2 during the diet intervention was independently associated with female sex, lower HOMA-IR and LDL cholesterol at baseline, and a stronger decline in HOMA-IR, triglycerides, HDL cholesterol, and fat mass. Participants with decreasing HOMA-IR (OR: 1.97; 95% CI: 1.28, 3.03) and triglycerides (OR: 2.71; 95% CI: 1.72, 4.26) had significantly higher odds for a decrease in sACE2 during the diet intervention than those without (P ≤ 0.0073). Feature selection models linked ΔsACE2 to changes in α-1-microglobulin/bikunin precursor, E-selectin, hydroxyacid oxidase 1, kidney injury molecule 1, tyrosine-protein kinase Mer, placental growth factor, thrombomodulin, and TNF receptor superfamily member 10B. ΔsACE2 remained associated with these protein changes in multivariable-adjusted linear regression. CONCLUSIONS Decrease in sACE2 during a weight loss diet intervention was associated with improvements in metabolic health, fat mass, and markers of angiotensin peptide metabolism, hepatic and vascular injury, renal function, chronic inflammation, and oxidative stress. Our findings may improve the risk stratification, prevention, and management of cardiometabolic complications.This trial was registered at clinicaltrials.gov as NCT01826591.
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Affiliation(s)
- Nicholas Cauwenberghs
- Stanford Cardiovascular Institute, Department of Medicine, Stanford University, Stanford, CA, USA
- Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
| | - Mary Prunicki
- Sean N Parker Center for Allergy and Asthma Research, Stanford University, Stanford, CA, USA
- Department of Medicine, Stanford University, Stanford, CA, USA
| | - František Sabovčik
- Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
| | - Dalia Perelman
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Kévin Contrepois
- Stanford Cardiovascular Institute, Department of Medicine, Stanford University, Stanford, CA, USA
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Xiao Li
- Department of Biochemistry, The Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
- Department of Computer and Data Sciences, Case Western Reserve University, Cleveland, OH, USA
| | - Michael P Snyder
- Stanford Cardiovascular Institute, Department of Medicine, Stanford University, Stanford, CA, USA
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA
| | - Kari C Nadeau
- Sean N Parker Center for Allergy and Asthma Research, Stanford University, Stanford, CA, USA
- Department of Medicine, Stanford University, Stanford, CA, USA
| | - Tatiana Kuznetsova
- Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
| | - Francois Haddad
- Stanford Cardiovascular Institute, Department of Medicine, Stanford University, Stanford, CA, USA
| | - Christopher D Gardner
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA
- Stanford Prevention Research Center, Department of Medicine, Stanford University, Stanford, CA, USA
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Elfaki I, Mir R, Duhier FMA, Alotaibi MA, Alalawy AI, Barnawi J, Babakr AT, Mir MM, Altayeb F, Mirghani H, Frah EAM. Clinical Implications of MiR128, Angiotensin I Converting Enzyme and Vascular Endothelial Growth Factor Gene Abnormalities and Their Association with T2D. Curr Issues Mol Biol 2021; 43:1859-1875. [PMID: 34889890 PMCID: PMC8928978 DOI: 10.3390/cimb43030130] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/25/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023] Open
Abstract
Type 2 DM (T2D) results from the interaction of the genetic and environmental risk factors. Vascular endothelial growth factor (VEGF), angiotensin I-converting enzyme (ACE), and MicroRNAs (MiRNAs) are involved in important physiological processes. Gene variations in VEGF, ACE and MiRNA genes are associated with diseases. In this study we investigated the associations of the VEGF-2578 C/A (rs699947), VEGF-2549 insertion/deletion (I/D), and ACE I/D rs4646994 and Mir128a (rs11888095) gene variations with T2D using the amplification refractory mutation system PCR (ARMS-PCR) and mutation specific PCR (MSP). We screened 122 T2D cases and 126 healthy controls (HCs) for the rs699947, and 133 T2D cases and 133 HCs for the VEGF I/D polymorphism. For the ACE I/D we screened 152 cases and 150 HCs, and we screened 129 cases and 112 HCs for the Mir128a (rs11888095). The results showed that the CA genotype of the VEGF rs699947 and D allele of the VEGF I/D polymorphisms were associated with T2D with OR =2.01, p-value = 0.011, and OR = 2.42, p-value = 0.010, respectively. The result indicated the D allele of the ACE ID was protective against T2D with OR = 0.10, p-value = 0.0001, whereas the TC genotype and the T allele of the Mir128a (rs11888095) were associated with increased risk to T2D with OR = 3.16, p-value = 0.0001, and OR = 1.68, p-value = 0.01, respectively. We conclude that the VEGF (rs699947), VEGF I/D and Mir128a (rs11888095) are potential risk loci for T2D, and that the D allele of the ACE ID polymorphism may be protective against T2D. These results help in identification and stratification for the individuals that at risk for T2D. However, future well-designed studies in different populations and with larger sample sizes are required. Moreover, studies to examine the effects of these polymorphisms on VEGF and ACE proteins are recommended.
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Affiliation(s)
- Imadeldin Elfaki
- Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Rashid Mir
- Prince and Fahd Bin Sultan Research Chair, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.M.); (F.M.A.D.); (J.B.); (F.A.)
| | - Faisel M. Abu Duhier
- Prince and Fahd Bin Sultan Research Chair, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.M.); (F.M.A.D.); (J.B.); (F.A.)
| | - Maeidh A. Alotaibi
- King Faisal Medical Complex Laboratory, Ministry of Health, Taif 26521, Saudi Arabia;
| | - Adel Ibrahim Alalawy
- Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Jameel Barnawi
- Prince and Fahd Bin Sultan Research Chair, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.M.); (F.M.A.D.); (J.B.); (F.A.)
| | - Abdullatif Taha Babakr
- Department of Medical Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah 57039, Saudi Arabia;
| | - Mohammad Muzaffar Mir
- Department of Basic Medical Sciences, College of Medicine, University of Bisha, Bisha 61992, Saudi Arabia;
| | - Faris Altayeb
- Prince and Fahd Bin Sultan Research Chair, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.M.); (F.M.A.D.); (J.B.); (F.A.)
| | - Hyder Mirghani
- Internal Medicine and Endocrine, Medical Department, Faculty of Medicine, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Ehab A. M. Frah
- Department of Statistics, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia;
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Sabri S, Bourron O, Phan F, Nguyen LS. Interactions between diabetes and COVID-19: A narrative review. World J Diabetes 2021; 12:1674-1692. [PMID: 34754370 PMCID: PMC8554367 DOI: 10.4239/wjd.v12.i10.1674] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/29/2021] [Accepted: 08/31/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes, whether due to pancreatic beta cells insufficiency or peripheral resistance to insulin, has been suggested as a risk factor of developing severe acute respiratory disease coronavirus-2 (SARS-CoV-2) infections. Indeed, diabetes has been associated with a higher risk of infections and higher risk of developing severe forms of coronavirus disease 2019 (COVID-19) related pneumonia. Diabetic patients often present associated comorbidities such as obesity, hypertension and cardiovascular diseases, and complications of diabetes, including chronic kidney disease, vasculopathy and relative immune dysfunction, all of which make them more susceptible to infectious complications. Moreover, they often present low-grade inflammation with increased circulating interleukin levels, endothelial susceptibility to inflammation and dysfunction, and finally, hyperglycemia, which increases this risk. Additionally, corticosteroids, which count among the few medications which showed benefit on survival and mechanical ventilation requirement in COVID-19 pneumonia in large randomized controlled trials, are associated to new onsets of diabetes, and metabolic disorders in patients with previous history of diabetes. Finally, SARS-CoV-2 via the alternate effects of the renin-angiotensin system, mediated by the angiotensin-converting-enzyme 2, was also associated with insulin resistance in key tissues involved in glucose homeostasis, such as liver, skeletal muscles, and adipose tissue; and also, with impaired insulin secretion by pancreatic β-cells. In this work, we reviewed all elements which may help understand how diabetes affects patients with COVID-19, how treatments affect outcomes in patients with COVID-19, how they may cause new onsets of diabetes, and finally review how SARS-CoV-2 may inherently be a risk factor of developing diabetes, through immune-mediated diabetogenic mechanisms.
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Affiliation(s)
- Sophia Sabri
- Intensive Care Medicine, CMC Ambroise Paré, Neuilly-Sur-Seine 92200, France
| | - Olivier Bourron
- Sorbonne Université Médecine; Assistance publique Hôpitaux de Paris (APHP), Service de Diabétologie, Hôpital Pitié-Salpêtrière; INSERM UMRS_1138, Centre de recherche des Cordeliers; Institute of CArdiometabolisme and Nutrition (ICAN), Paris 75013, France
| | - Franck Phan
- Sorbonne Université Médecine; Assistance publique Hôpitaux de Paris (APHP), Service de Diabétologie, Hôpital Pitié-Salpêtrière; INSERM UMRS_1138, Centre de recherche des Cordeliers; Institute of CArdiometabolisme and Nutrition (ICAN), Paris 75013, France
| | - Lee S Nguyen
- Research and Innovation, RICAP, CMC Ambroise Paré, Neuilly-Sur-Seine 92200, France
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Abstract
The current COVID-19 pandemic, which continues to spread across the globe, is caused by severe acute respiratory syndrome coronavirus (SARS-Cov-2). Soon after the pandemic emerged in China, it became clear that the receptor-binding domain (RBD) of angiotensin-converting enzyme 2 (ACE2) serves as the primary cell surface receptor for SARS-Cov-2. Subsequent work has shown that diabetes and hyperglycemia are major risk factors for morbidity and mortality in COVID-19 patients. However, data on the pattern of expression of ACE2 on human pancreatic β cells remain contradictory. Additionally, there is no consensus on whether the virus can directly infect and damage pancreatic islets and hence exacerbate diabetes. In this mini-review, we highlight the role of ACE2 receptor and summarize the current state of knowledge regarding its expression/co-localization in human pancreatic endocrine cells. We also discuss recent data on the permissiveness of human pancreatic β cells to SARS-Cov-2 infection.
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Affiliation(s)
- Waseem El-Huneidi
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates (UAE)
| | - Mawieh Hamad
- Department of Basic sciences, Sharjah Institute for Medical Research, Sharjah, University of Sharjah, United Arab Emirates (UAE)
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, SharjahUAE
| | - Jalal Taneera
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates (UAE)
- Department of Basic sciences, Sharjah Institute for Medical Research, Sharjah, University of Sharjah, United Arab Emirates (UAE)
- CONTACT Dr. Jalal Taneera Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272 United Arab Emirates (UAE) Tel: +97165057743
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Azu OO, Olojede SO, Lawal SK, Oseni SO, Rennie CO, Offo U, Naidu ECS. Novel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection: Microbiologic perspectives and anatomic considerations for sanctuary sites. J Infect Public Health 2021; 14:1237-1246. [PMID: 34455307 PMCID: PMC8378066 DOI: 10.1016/j.jiph.2021.08.015] [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: 06/17/2021] [Revised: 07/31/2021] [Accepted: 08/15/2021] [Indexed: 11/25/2022] Open
Abstract
Introduction A significant chunk of global life – the economy, sports, aviation, academic, and entertainment activities – has significantly been affected by the ravaging outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) with devastating consequences on morbidity and mortality in many countries of the world. Methods This review utilized search engines such as google scholar, PubMed, ResearchGate, and web of science to retrieve articles and information using keywords like “Coronavirus”, “SARS-CoV-2”, “COVID-19”, “Origin of coronavirus and SARS-CoV-2”, “microbiology of coronavirus”, “microbiology of SARS-CoV-2”, COVID-19”, “Coronavirus reservoir sites”, “Anatomic sanctuary sites and SARS-CoV-2”, biological barriers and coronavirus”, biological barrier and SARS-CoV-2”. Results While this pandemic has caught the global scientific community at its lowest level of preparedness, it has inadvertently created a unified and wholesome approach towards developing potential vaccine (s) candidates by escalating clinical trial protocols in many countries of Europe, China and the United States. Interestingly, viral pathobiology continues to be an evolving aspect that potentially shows that the management of the current outbreak may largely depend on the discovery of a vaccine as the administration of known antiviral drugs are proving to offer some respite. Unfortunately, discontinuation and longtime administration of these drugs have been implicated in endocrine, reproductive and neurological disorders owing to the development of pathological lesions at anatomical sanctuary sites such as the brain and testis, as well as the presence of complex biological barriers that permit the entry of viruses but selective to the entrance of chemical substances and drugs. Conclusion This review focuses on the microbiologic perspectives and importance of anatomical sanctuary sites in the possible viral rebound or reinfection into the system and their implications in viral re-entry and development of reproductive and neurological disorders in COVID-19 patients.
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Affiliation(s)
- Onyemaechi O Azu
- Department of Anatomy, School of Medicine, University of Namibia, Private Bag, Windhoek, 13301, Namibia.
| | - Samuel O Olojede
- Discipline of Clinical Anatomy, School of Laboratory Medicine & Medical Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, 719 Umbilo Road, Durban, South Africa
| | - Sodiq K Lawal
- Discipline of Clinical Anatomy, School of Laboratory Medicine & Medical Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, 719 Umbilo Road, Durban, South Africa
| | - Saheed O Oseni
- Department of Biological Sciences, Florida Atlantic University, Davie, FL 33314, USA
| | - Carmen O Rennie
- Discipline of Clinical Anatomy, School of Laboratory Medicine & Medical Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, 719 Umbilo Road, Durban, South Africa
| | - Ugochukwu Offo
- Department of Pre-Clinical Sciences, University of Limpopo, South Africa
| | - Edwin C S Naidu
- Discipline of Clinical Anatomy, School of Laboratory Medicine & Medical Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, 719 Umbilo Road, Durban, South Africa
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Epigenetic modifications of the renin-angiotensin system in cardiometabolic diseases. Clin Sci (Lond) 2021; 135:127-142. [PMID: 33416084 DOI: 10.1042/cs20201287] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/01/2020] [Accepted: 12/14/2020] [Indexed: 12/13/2022]
Abstract
Cardiometabolic diseases (CMDs) are among the most prevalent and the highest mortality diseases. Single disease etiology such as gene mutation, polymorphisms, or environmental exposure has failed to explain the origin of CMD. This can be evident in the discrepancies in disease susceptibility among individuals exposed to the same environmental insult or who acquire the same genetic variation. Epigenetics is the intertwining of genetic and environmental factors that results in diversity in the disease course, severity, and prognosis among individuals. Environmental exposures modify the epigenome and thus provide a link for translating environmental impact on changes in gene expression and precipitation to pathological conditions. Renin-angiotensin system (RAS) is comprising genes responsible for the regulation of cardiovascular, metabolic, and glycemic functions. Epigenetic modifications of RAS genes can lead to overactivity of the system, increased sympathetic activity and autonomic dysfunction ultimately contributing to the development of CMD. In this review, we describe the three common epigenetic modulations targeting RAS components and their impact on the susceptibility to cardiometabolic dysfunction. Additionally, we highlight the therapeutic efforts of targeting these epigenetic imprints to the RAS and its effects.
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Tonyan ZN, Nasykhova YA, Danilova MM, Glotov AS. Genetics of macrovascular complications in type 2 diabetes. World J Diabetes 2021; 12:1200-1219. [PMID: 34512887 PMCID: PMC8394234 DOI: 10.4239/wjd.v12.i8.1200] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/04/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that currently affects more than 400 million worldwide and is projected to cause 552 million cases by the year 2030. Long-term vascular complications, such as coronary artery disease, myocardial infarction, stroke, are the leading causes of morbidity and mortality among diabetic patients. The recent advances in genome-wide technologies have given a powerful impetus to the study of risk markers for multifactorial diseases. To date, the role of genetic and epigenetic factors in modulating susceptibility to T2DM and its vascular complications is being successfully studied that provides the accumulation of genomic knowledge. In the future, this will provide an opportunity to reveal the pathogenetic pathways in the development of the disease and allow to predict the macrovascular complications in T2DM patients. This review is focused on the evidence of the role of genetic variants and epigenetic changes in the development of macrovascular pathology in diabetic patients.
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Affiliation(s)
- Ziravard N Tonyan
- Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Saint-Petersburg 199034, Russia
| | - Yulia A Nasykhova
- Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Saint-Petersburg 199034, Russia
- Laboratory of Biobanking and Genomic Medicine of Institute of Translation Biomedicine, St. Petersburg State University, Saint-Petersburg 199034, Russia
| | - Maria M Danilova
- Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Saint-Petersburg 199034, Russia
| | - Andrey S Glotov
- Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Saint-Petersburg 199034, Russia
- Laboratory of Biobanking and Genomic Medicine of Institute of Translation Biomedicine, St. Petersburg State University, Saint-Petersburg 199034, Russia
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Laghlam D, Jozwiak M, Nguyen LS. Renin-Angiotensin-Aldosterone System and Immunomodulation: A State-of-the-Art Review. Cells 2021; 10:cells10071767. [PMID: 34359936 PMCID: PMC8303450 DOI: 10.3390/cells10071767] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 06/30/2021] [Accepted: 07/09/2021] [Indexed: 12/11/2022] Open
Abstract
The renin–angiotensin system (RAS) has long been described in the field of cardiovascular physiology as the main player in blood pressure homeostasis. However, other effects have since been described, and include proliferation, fibrosis, and inflammation. To illustrate the immunomodulatory properties of the RAS, we chose three distinct fields in which RAS may play a critical role and be the subject of specific treatments. In oncology, RAS hyperactivation has been associated with tumor migration, survival, cell proliferation, and angiogenesis; preliminary data showed promise of the benefit of RAS blockers in patients treated for certain types of cancer. In intensive care medicine, vasoplegic shock has been associated with severe macro- and microcirculatory imbalance. A relative insufficiency in angiotensin II (AngII) was associated to lethal outcomes and synthetic AngII has been suggested as a specific treatment in these cases. Finally, in solid organ transplantation, both AngI and AngII have been associated with increased rejection events, with a regional specificity in the RAS activity. These elements emphasize the complexity of the direct and indirect interactions of RAS with immunomodulatory pathways and warrant further research in the field.
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Abstract
The link between COVID-19 infection and diabetes has been explored in several studies since the start of the pandemic, with associations between comorbid diabetes and poorer prognosis in patients infected with the virus and reports of diabetic ketoacidosis occurring with COVID-19 infection. As such, significant interest has been generated surrounding mechanisms by which the virus may exert effects on the pancreatic β cells. In this review, we consider possible routes by which SARS-CoV-2 may impact β cells. Specifically, we outline data that either support or argue against the idea of direct infection and injury of β cells by SARS-CoV-2. We also discuss β cell damage due to a "bystander" effect in which infection with the virus leads to damage to surrounding tissues that are essential for β cell survival and function, such as the pancreatic microvasculature and exocrine tissue. Studies elucidating the provocation of a cytokine storm following COVID-19 infection and potential impacts of systemic inflammation and increases in insulin resistance on β cells are also reviewed. Finally, we summarize the existing clinical data surrounding diabetes incidence since the start of the COVID-19 pandemic.
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Affiliation(s)
- Sarah Ibrahim
- Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, USA
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, USA
| | - Gabriela S.F. Monaco
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, USA
| | - Emily K. Sims
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, USA
- Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, USA
- Pediatric Endocrinology and Diabetology, Indiana University School of Medicine, Indianapolis, USA
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39
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Low plasma angiotensin-converting enzyme 2 level in diabetics increases the risk of severe COVID-19 infection. Aging (Albany NY) 2021; 13:12301-12307. [PMID: 33962399 PMCID: PMC8148475 DOI: 10.18632/aging.202967] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 04/02/2021] [Indexed: 01/25/2023]
Abstract
Patients with pre-existing chronic diseases are more susceptible to coronavirus disease 2019 (COVID-19), yet the underlying causes of increased risk are of infection remain unclear. Angiotensin-converting- enzyme 2 (ACE2), the cell surface receptor that recognizes the coronavirus spike protein has protective effects against inflammation and chronic hyperglycemia in animal models. The roles of ACE2 in severe SARS-CoV-2 infections remains ambiguous due to contradictory findings. In this study, we aimed to investigate the relationship between human plasma ACE2 levels in diabetics and the high risk of severe SARS-CoV-2 infection. First, the medical records of 245 patients with SARS-CoV-2-positive who have chronic diseases were analyzed. We also recruited 404 elderly subjects with comorbid chronic diseases such as diabetes mellitus, coronary heart disease, cerebrovascular disease, hypertension and obesity, and investigated the ACE2 plasma levels. Plasma concentrations of ACE2 were much lower (2973.83±2196.79 pg/mL) in diabetics with chronic disease than in healthy controls (4308.21±2352.42 pg/ml), and the use of hypoglycemia drugs was associated with lower circulating concentrations of ACE2 (P=1.49E-08). Diabetics with lower plasma levels of ACE2 may be susceptible to severe COVID-19. Our findings suggest that the poor prognosis in patients with diabetes infected with SARS-CoV-2 may be due to low circulating ACE2 levels.
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40
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Diabetes, inflammation, and the adiponectin paradox: Therapeutic targets in SARS-CoV-2. Drug Discov Today 2021; 26:2036-2044. [PMID: 33775925 PMCID: PMC7997138 DOI: 10.1016/j.drudis.2021.03.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 02/22/2021] [Accepted: 03/16/2021] [Indexed: 12/16/2022]
Abstract
Aging and pre-existing conditions in older patients increase severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) severity and its complications, although the causes remain unclear. Apart from acute pulmonary syndrome, Coronavirus 2019 (COVID-19) can increasingly induce chronic conditions. Importantly, SARS-CoV-2 triggers de novo type 2 diabetes mellitus (T2DM) linked to age-associated cardiovascular disease (CVD), cancers, and neurodegeneration. Mechanistically, SARS-CoV-2 induces inflammation, possibly through damage-associated molecular pattern (DAMP) signaling and ‘cytokine storm,’ causing insulin resistance and the adiponectin (APN) paradox, a phenomenon linking metabolic dysfunction to chronic disease. Accordingly, preventing the APN paradox by suppressing APN-related inflammatory signaling might prove beneficial. A better understanding could uncover novel therapies for SARS-CoV-2 and its chronic disorders.
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41
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ACE2 as therapeutic agent. Clin Sci (Lond) 2021; 134:2581-2595. [PMID: 33063820 DOI: 10.1042/cs20200570] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/28/2020] [Accepted: 10/01/2020] [Indexed: 12/11/2022]
Abstract
The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin-angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein-coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed.
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Abramczyk U, Kuzan A. What Every Diabetologist Should Know about SARS-CoV-2: State of Knowledge at the Beginning of 2021. J Clin Med 2021; 10:1022. [PMID: 33801468 PMCID: PMC7958842 DOI: 10.3390/jcm10051022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/23/2021] [Accepted: 02/24/2021] [Indexed: 02/06/2023] Open
Abstract
For almost a year, the major medical problem has been the pandemic caused by the SARS-CoV-2 virus. People with diabetes who contract COVID-19 are likely to experience more serious symptoms than patients without diabetes. This article presents new research about the epidemiology of COVID-19 in a group of patients with diabetes. It details the mortality and prognosis in such patients, as well as the relationship between COVID-19 and the diseases most often coexisting with diabetes: obesity, atherosclerosis, hypertension, and increased risk for infection. It also details how the virus infects and affects patients with hyperglycemia. The context of glycation and receptors for advanced glycation products (RAGE) seems to be of particular importance here. We also present a hypothesis related to the cause-and-effect axis-it turns out that diabetes can be both the cause of the more difficult course of COVID-19 and the result of SARS-CoV-2 infection. The last part of this article discusses the impact of antihyperglycemic drugs on the development of COVID-19 and other pharmacological implications, including which non-classical antihyperglycemic drugs seem to be effective in both the treatment of coronavirus infection and glucose homeostasis, and what strategies related to RAGE and glycation should be considered.
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Affiliation(s)
- Urszula Abramczyk
- A. Falkiewicz Specialist Hospital in Wroclaw, 52-114 Wroclaw, Poland;
| | - Aleksandra Kuzan
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland
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Pathangey G, Fadadu PP, Hospodar AR, Abbas AE. Angiotensin-converting enzyme 2 and COVID-19: patients, comorbidities, and therapies. Am J Physiol Lung Cell Mol Physiol 2021; 320:L301-L330. [PMID: 33237815 PMCID: PMC7938645 DOI: 10.1152/ajplung.00259.2020] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 11/19/2020] [Accepted: 11/24/2020] [Indexed: 02/07/2023] Open
Abstract
On March 11, 2020, the World Health Organization declared coronavirus disease 2019 (COVID-19) a pandemic, and the reality of the situation has finally caught up to the widespread reach of the disease. The presentation of the disease is highly variable, ranging from asymptomatic carriers to critical COVID-19. The availability of angiotensin-converting enzyme 2 (ACE2) receptors may reportedly increase the susceptibility and/or disease progression of COVID-19. Comorbidities and risk factors have also been noted to increase COVID-19 susceptibility. In this paper, we hereby review the evidence pertaining to ACE2's relationship to common comorbidities, risk factors, and therapies associated with the susceptibility and severity of COVID-19. We also highlight gaps of knowledge that require further investigation. The primary comorbidities of respiratory disease, cardiovascular disease, renal disease, diabetes, obesity, and hypertension had strong evidence. The secondary risk factors of age, sex, and race/genetics had limited-to-moderate evidence. The tertiary factors of ACE inhibitors and angiotensin II receptor blockers had limited-to-moderate evidence. Ibuprofen and thiazolidinediones had limited evidence.
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Affiliation(s)
- Girish Pathangey
- William Beaumont School of Medicine, Oakland University, Rochester, Michigan
| | | | | | - Amr E Abbas
- William Beaumont School of Medicine, Oakland University, Rochester, Michigan
- Department of Cardiovascular Medicine, Beaumont Hospital Royal Oak, Royal Oak, Michigan
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Shukla AK, Banerjee M. Angiotensin-Converting-Enzyme 2 and Renin-Angiotensin System Inhibitors in COVID-19: An Update. High Blood Press Cardiovasc Prev 2021; 28:129-139. [PMID: 33635533 PMCID: PMC7908946 DOI: 10.1007/s40292-021-00439-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 02/10/2021] [Indexed: 02/07/2023] Open
Abstract
Ever since its outbreak, Corona Virus Disease 2019(COVID-19) caused by SARS-CoV-2 has affected more than 26 million individuals in more than 200 countries. Although the mortality rate of COVID-19 is low, but several clinical studies showed, patients with diabetes mellitus (DM) or other major complication at high risk of COVID-19 and reported more severe disease and increased fatality. The angiotensin-converting-enzyme 2 (ACE2), a component of renin-angiotensin-system (RAS); acts on ACE/Ang-II/AT1recptor axis, and regulates pathological processes like hypertension, cardiac dysfunction, Acute Respiratory Distress Syndrome (ARDS) etc. The progression of T2DM and hypertension show decreased expression and activity of ACE2. There are several treatment strategies for controlling diabetes, hypertension, etc; like ACE2 gene therapies, endogenous ACE2 activators, human recombinant ACE2 (hrACE2), Angiotensin-II receptor blockers (ARBs) and ACE inhibitors (ACEi) medications. ACE2, the receptors for SARS-CoV2, facilitates virus entry inside host cell. Clinicians are using two classes of medications for the treatment of COVID-19; one targets the SARS-CoV-2-ACE2 interaction, while other targets human immune system. The aim of this review is to discuss the role of ACE2 in diabetes and in COVID-19 and to provide an analysis of data proposing harm and benefit of RAS inhibitor treatment in COVID-19 infection as well as showing no association whatsoever. This review also highlights some candidate vaccines which are undergoing clinical trials.
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Affiliation(s)
- Ashwin Kumar Shukla
- Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow, Uttar Pradesh, India
| | - Monisha Banerjee
- Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow, Uttar Pradesh, India.
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45
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Berezin AE, Berezin AA. Shift of conventional paradigm of heart failure treatment: from angiotensin receptor neprilysin inhibitor to sodium-glucose co-transporter 2 inhibitors? Future Cardiol 2021; 17:497-506. [PMID: 33615880 DOI: 10.2217/fca-2020-0178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Current clinical guidelines for heart failure (HF) contain a brand new therapeutic strategy for HF with reduced ejection fraction (HFrEF), which is based on neurohumoral modulation through the use of angiotensin receptor neprilysin inhibitors. There is a large body of evidence for the fact that sodium-glucose co-transporter 2 inhibitors may significantly improve all-cause mortality, cardiovascular mortality and hospitalization for HF in patients with HFrEF who received renin-angiotensin system blockers including angiotensin receptor neprilysin inhibitors, β-blockers and mineralocorticoid receptor antagonists. The review discusses that sodium-glucose co-transporter 2 inhibitors have a wide spectrum of favorable molecular effects and contribute to tissue protection, improving survival in HFrEF patients.
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Affiliation(s)
- Alexander E Berezin
- Internal Medicine Department, State Medical University of Zaporozhye, 26, Mayakovsky av., Zaporozhye, UA-69035, Ukraine
| | - Alexander A Berezin
- Internal Medicine Department, Medical Academy of Post-Graduate Education, Ministry of Health of Ukraine, Zaporozhye, 69096, Ukraine
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46
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ACE2 and energy metabolism: the connection between COVID-19 and chronic metabolic disorders. Clin Sci (Lond) 2021; 135:535-554. [PMID: 33533405 DOI: 10.1042/cs20200752] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 12/13/2022]
Abstract
The renin-angiotensin system (RAS) has currently attracted increasing attention due to its potential function in regulating energy homeostasis, other than the actions on cellular growth, blood pressure, fluid, and electrolyte balance. The existence of RAS is well established in metabolic organs, including pancreas, liver, skeletal muscle, and adipose tissue, where activation of angiotensin-converting enzyme (ACE) - angiotensin II pathway contributes to the impairment of insulin secretion, glucose transport, fat distribution, and adipokines production. However, the activation of angiotensin-converting enzyme 2 (ACE2) - angiotensin (1-7) pathway, a novel branch of the RAS, plays an opposite role in the ACE pathway, which could reverse these consequences by improving local microcirculation, inflammation, stress state, structure remolding, and insulin signaling pathway. In addition, new studies indicate the protective RAS arm possesses extraordinary ability to enhance brown adipose tissue (BAT) activity and induces browning of white adipose tissue, and consequently, it leads to increased energy expenditure in the form of heat instead of ATP synthesis. Interestingly, ACE2 is the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is threating public health worldwide. The main complications of SARS-CoV-2 infected death patients include many energy metabolism-related chronic diseases, such as diabetes. The specific mechanism leading to this phenomenon is largely unknown. Here, we summarize the latest pharmacological and genetic tools on regulating ACE/ACE2 balance and highlight the beneficial effects of the ACE2 pathway axis hyperactivity on glycolipid metabolism, as well as the thermogenic modulation.
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A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection. Nat Genet 2021; 53:205-214. [PMID: 33432184 DOI: 10.1038/s41588-020-00759-x] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 12/01/2020] [Indexed: 01/29/2023]
Abstract
Angiotensin-converting enzyme 2 (ACE2) is the main entry point in airway epithelial cells for SARS-CoV-2. ACE2 binding to the SARS-CoV-2 protein spike triggers viral fusion with the cell plasma membrane, resulting in viral RNA genome delivery into the host. Despite ACE2's critical role in SARS-CoV-2 infection, full understanding of ACE2 expression, including in response to viral infection, remains unclear. ACE2 was thought to encode five transcripts and one protein of 805 amino acids. In the present study, we identify a novel short isoform of ACE2 expressed in the airway epithelium, the main site of SARS-CoV-2 infection. Short ACE2 is substantially upregulated in response to interferon stimulation and rhinovirus infection, but not SARS-CoV-2 infection. This short isoform lacks SARS-CoV-2 spike high-affinity binding sites and, altogether, our data are consistent with a model where short ACE2 is unlikely to directly contribute to host susceptibility to SARS-CoV-2 infection.
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Elemam NM, Hannawi H, Salmi IA, Naeem KB, Alokaily F, Hannawi S. Diabetes mellitus as a comorbidity in COVID-19 infection in the United Arab Emirates. Saudi Med J 2021; 42:170-180. [PMID: 33563736 PMCID: PMC7989288 DOI: 10.15537/smj.2021.2.25700] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 01/12/2021] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES To compare risk factors and clinical outcomes among COVID-19 patients with or without diabetes in the United Arab Emirates (UAE). METHODS Data of 350 COVID-19 positive patients, admitted to Al Kuwait Hospital in Dubai, UAE, from February to May 2020 was collected retrospectively, including demographic data, clinical symptoms, blood tests, as well as radiographical assessments, and clinical outcomes of COVID-19. The design of the study is a retrospective cohort study. RESULTS COVID-19 patients with diabetes belong to an older age group, had a higher percentage of male patients, exhibited more lymphopenia and neutrophilia, and higher ferritin levels. Additionally, patients with diabetes presented fever and shortness of breath (SOB), displayed more bilateral airspace consolidation and opacities in their chest x-ray and CT scans, compared to non-diabetics. A higher percentage of critical, ICU-admitted, and death of COVID-19 cases in the diabetic group was also reported. This was along with a concomitant increase in C-reactive protein, procalcitonin, and lactate dehydrogenase levels. CONCLUSIONS Diabetes is considered a comorbidity as diabetic patients showed more severe COVID-19 symptoms that led to critical clinical outcomes such as ICU admission and death.
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Affiliation(s)
- Noha M. Elemam
- From the Sharjah Institute for Medical Research, College of Medicine (Elemam), University of Sharjah, Sharjah; from the Ministry of Health and Prevention, Department of Medicine (Hannawi H, Bin Naeem, Hannawi S); from Mohammed bin Rashid University of Medicine and Health Sciences (Hannawi H), Dubai, United Arab Emirates; from Oman Medical Specialty Board (Issa Al Salmi); from The Royal Hospital (Issa Al Salmi), Muscat, Oman; and from Prince Sultan Military Medical City (Alokaily), Riyadh, Kingdom of Saudi Arabia.
| | - Haifa Hannawi
- From the Sharjah Institute for Medical Research, College of Medicine (Elemam), University of Sharjah, Sharjah; from the Ministry of Health and Prevention, Department of Medicine (Hannawi H, Bin Naeem, Hannawi S); from Mohammed bin Rashid University of Medicine and Health Sciences (Hannawi H), Dubai, United Arab Emirates; from Oman Medical Specialty Board (Issa Al Salmi); from The Royal Hospital (Issa Al Salmi), Muscat, Oman; and from Prince Sultan Military Medical City (Alokaily), Riyadh, Kingdom of Saudi Arabia.
| | - Issa Al Salmi
- From the Sharjah Institute for Medical Research, College of Medicine (Elemam), University of Sharjah, Sharjah; from the Ministry of Health and Prevention, Department of Medicine (Hannawi H, Bin Naeem, Hannawi S); from Mohammed bin Rashid University of Medicine and Health Sciences (Hannawi H), Dubai, United Arab Emirates; from Oman Medical Specialty Board (Issa Al Salmi); from The Royal Hospital (Issa Al Salmi), Muscat, Oman; and from Prince Sultan Military Medical City (Alokaily), Riyadh, Kingdom of Saudi Arabia.
| | - Kashif Bin Naeem
- From the Sharjah Institute for Medical Research, College of Medicine (Elemam), University of Sharjah, Sharjah; from the Ministry of Health and Prevention, Department of Medicine (Hannawi H, Bin Naeem, Hannawi S); from Mohammed bin Rashid University of Medicine and Health Sciences (Hannawi H), Dubai, United Arab Emirates; from Oman Medical Specialty Board (Issa Al Salmi); from The Royal Hospital (Issa Al Salmi), Muscat, Oman; and from Prince Sultan Military Medical City (Alokaily), Riyadh, Kingdom of Saudi Arabia.
| | - Fahdah Alokaily
- From the Sharjah Institute for Medical Research, College of Medicine (Elemam), University of Sharjah, Sharjah; from the Ministry of Health and Prevention, Department of Medicine (Hannawi H, Bin Naeem, Hannawi S); from Mohammed bin Rashid University of Medicine and Health Sciences (Hannawi H), Dubai, United Arab Emirates; from Oman Medical Specialty Board (Issa Al Salmi); from The Royal Hospital (Issa Al Salmi), Muscat, Oman; and from Prince Sultan Military Medical City (Alokaily), Riyadh, Kingdom of Saudi Arabia.
| | - Suad Hannawi
- From the Sharjah Institute for Medical Research, College of Medicine (Elemam), University of Sharjah, Sharjah; from the Ministry of Health and Prevention, Department of Medicine (Hannawi H, Bin Naeem, Hannawi S); from Mohammed bin Rashid University of Medicine and Health Sciences (Hannawi H), Dubai, United Arab Emirates; from Oman Medical Specialty Board (Issa Al Salmi); from The Royal Hospital (Issa Al Salmi), Muscat, Oman; and from Prince Sultan Military Medical City (Alokaily), Riyadh, Kingdom of Saudi Arabia.
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Moraes DS, Lelis DDF, Andrade JMO, Meyer L, Guimarães ALS, De Paula AMB, Farias LC, Santos SHS. Enalapril improves obesity associated liver injury ameliorating systemic metabolic markers by modulating Angiotensin Converting Enzymes ACE/ACE2 expression in high-fat feed mice. Prostaglandins Other Lipid Mediat 2021; 152:106501. [PMID: 33049402 DOI: 10.1016/j.prostaglandins.2020.106501] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 09/24/2020] [Accepted: 10/05/2020] [Indexed: 02/07/2023]
Abstract
Obesity is a chronic disease caused multiple associated factors that results in excessive body fat accumulation. The Renin-Angiotensin System (RAS) unbalance is now recognized as a key factor on regulating body energy and metabolism. AIM The aim of the present study was to evaluate the Enalapril (ACE inhibitor) effects on the metabolic function and hepatic steatosis of obese mice evaluating Angiotensin Converting Enzymes (ACEs) expression. METHODS The experiment was performed using 32 male Swiss mice (8 weeks old) equally and randomly divided into 4 groups (n = 8): standard diet (ST), standard diet plus Enalapril (ST + ENAL), hyperlipidic diet (HF) and hyperlipidic diet plus Enalapril (HF + ENAL). Weekly measurements of animal weight and feed consumption were performed. At the end of treatment period a glucose tolerance test (GTT) and insulin sensitivity test (IST) were performed. Ultrasonography was used to evaluate hepatic and epididymal fat pad. Liver samples were submitted to HE histology and gene expression analyses were performed using Real-Time PCR. RESULTS The main results showed a decrease in body weight after treatment with Enalapril, as well as a reduced size of epididymal fat pad (EFP). Hepatic echogenicity and steatosis measurement were lower in the obese groups treated with Enalapril also modulating ACE2/ACE expressions. CONCLUSIONS Enalapril use improved metabolism reducing hepatic steatosis, decreasing ACE expression and increasing ACE2 expression.
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Affiliation(s)
- Daniel Silva Moraes
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - Deborah de Farias Lelis
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - João Marcus Oliveira Andrade
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - Lara Meyer
- Department of Biomedical Sciences, McMurry University, Abilene, TX, USA
| | - André Luiz Sena Guimarães
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - Alfredo Maurício Batista De Paula
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - Lucyana Conceição Farias
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - Sérgio Henrique Sousa Santos
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil; Institute of Agricultural Sciences. Food Engineering College, Universidade Federal de Minas Gerais (UFMG), Montes Claros, Minas Gerais, Brazil.
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Abstract
COVID-19, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emerged as a global pandemic and poses a great threat to public health and society in general. SARS-CoV-2 invades cells via its spike protein, which initiates endocytosis via its binding to host
receptor angiotensin-converting enzyme 2 (ACE2) and membrane fusion after being cleaved by the serine protease, TMPRSS2. The most common clinical manifestations are fever, dry cough, fatigue and abnormalities on chest computed tomography (CT). However, some patients rapidly progress to severe
pneumonia and develop acute respiratory distress syndrome (ARDS). Furthermore, SARS-CoV-2 triggers a severe cytokine storm, which may explain the deterioration of pre-existing metabolic disorders. Interestingly, conversely, underlying metabolic-related diseases, including hypertension, diabetes,
cardiovascular disease, etc., are associated with progression and poor prognosis of COVID-19. The putative mechanisms are dysregulation of ACE2, impaired immunity especially uncontrolled hyperinflammation, hypercoagulability, etc. In this review, we summarize the crosstalk between COVID-19
and metabolic diseases and propose that in addition to controlling COVID-19, more intensive attention should be paid to the symptomatic treatment and prevention of pre-existing and foreseeable metabolic comorbidities.Significance statement: Coronavirus disease 2019 (COVID-19) has
rapidly spread worldwide and has exerted a great influence on public health and society, urging scientists to find efficient therapeutics. Metabolic disturbance involving various organs has been found in these patients, including diabetes, fatty liver, acute kidney injury (AKI), etc. In turn,
these preexisting metabolic syndromes could exacerbate COVID-19. In this review, we focus on the close interaction between COVID-19 and metabolic syndrome, as well as the potential of repurposing metabolic-related drugs and the importance of treating metabolic diseases in COVID-19 patients.
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Affiliation(s)
- Zeling Guo
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shanping Jiang
- Department of Respiratory and Critical Care Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zilun Li
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Sifan Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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