Early Dysregulation of Cardiac-specific MicroRNA-208a is Linked to Maladaptive Cardiac Remodelling in Diabetic Myocardium

Overview

Journal Cardiovasc Diabetol

Publisher Biomed Central

Specialties Cardiology & Vascular Diseases
Endocrinology

Date 2019 Jan 31

PMID 30696455

Citations 27

Authors

Shruti Rawal

Prashanth Thevakar Nagesh

Sean Coffey

Isabelle van Hout

Ivor F Galvin

Richard W Bunton

Philip Davis

Michael J A Williams

Rajesh Katare

Affiliations

Soon will be listed here.

Abstract

Background: The diabetic heart undergoes remodelling contributing to an increased incidence of heart failure in individuals with diabetes at a later stage. The molecular regulators that drive this process in the diabetic heart are still unknown.

Methods: Real-time (RT) PCR analysis was performed to determine the expression of cardiac specific microRNA-208a in right atrial appendage (RAA) and left ventricular (LV) biopsy tissues collected from diabetic and non-diabetic patients undergoing coronary artery bypass graft surgery. To determine the time-dependent changes, cardiac tissue were collected from type 2 diabetic mice at different age groups. A western blotting analysis was conducted to determine the expression of contractile proteins α- and β-myosin heavy chain (MHC) and thyroid hormone receptor-α (TR-α), the negative regulator of β-MHC. To determine the beneficial effects of therapeutic modulation of miR-208a, high glucose treated adult mouse HL-1 cardiomyocytes were transfected with anti-miR-208a.

Results: RT-PCR analysis showed marked upregulation of miR-208a from early stages of diabetes in type 2 diabetic mouse heart, which was associated with a marked increase in the expression of pro-hypertrophic β-MHC and downregulation of TR-α. Interestingly, upregulation of miR-208a preceded the switch of α-/β-MHC isoforms and the development of diastolic and systolic dysfunction. We also observed significant upregulation of miR-208a and modulation of miR-208a associated proteins in the type 2 human diabetic heart. Therapeutic inhibition of miR-208a activity in high glucose treated HL-1 cardiomyocytes prevented the activation of β-MHC and hence the hypertrophic response.

Conclusion: Our results provide the first evidence that early modulation of miR-208a in the diabetic heart induces alterations in the downstream signaling pathway leading to cardiac remodelling and that therapeutic inhibition of miR-208a may be beneficial in preventing diabetes-induced adverse remodelling of the heart.

Citing Articles

Induction on Insulin Resistance In Vitro.

Saw E Methods Mol Biol. 2024; 2894:43-51.

PMID: 39699809 DOI: 10.1007/978-1-0716-4342-6_5.

Mini Review: the non-neuronal cardiac cholinergic system in type-2 diabetes mellitus.

Saw E, Fronius M, Katare R, Kakinuma Y Front Cardiovasc Med. 2024; 11:1425534.

PMID: 39314774 PMC: 11417620. DOI: 10.3389/fcvm.2024.1425534.

Progress and Challenges of Understanding Cardiorenal Syndrome Type 3.

Neres-Santos R, Armentano G, da Silva J, Falconi C, Carneiro-Ramos M Rev Cardiovasc Med. 2024; 24(1):8.

PMID: 39076878 PMC: 11270482. DOI: 10.31083/j.rcm2401008.

miR-369-3p ameliorates diabetes-associated atherosclerosis by regulating macrophage succinate-GPR91 signalling.

Rawal S, Randhawa V, Rizvi S, Sachan M, Wara A, Perez-Cremades D Cardiovasc Res. 2024; 120(14):1693-1712.

PMID: 38703377 PMC: 11587565. DOI: 10.1093/cvr/cvae102.

Zbtb16 increases susceptibility of atrial fibrillation in type 2 diabetic mice via Txnip-Trx2 signaling.

Wei Z, Cai X, Fei Y, Wang Q, Hu X, Li C Cell Mol Life Sci. 2024; 81(1):88.

PMID: 38349408 PMC: 10864461. DOI: 10.1007/s00018-024-05125-2.

References

Swynghedauw B . Molecular mechanisms of myocardial remodeling. Physiol Rev. 1999; 79(1):215-62. DOI: 10.1152/physrev.1999.79.1.215. View

Panguluri S, Tur J, Chapalamadugu K, Katnik C, Cuevas J, Tipparaju S . MicroRNA-301a mediated regulation of Kv4.2 in diabetes: identification of key modulators. PLoS One. 2013; 8(4):e60545. PMC: 3616003. DOI: 10.1371/journal.pone.0060545. View

Mandavia C, Aroor A, Demarco V, Sowers J . Molecular and metabolic mechanisms of cardiac dysfunction in diabetes. Life Sci. 2012; 92(11):601-8. PMC: 3594135. DOI: 10.1016/j.lfs.2012.10.028. View

Katare R, Rawal S, Munasinghe P, Tsuchimochi H, Inagaki T, Fujii Y . Ghrelin Promotes Functional Angiogenesis in a Mouse Model of Critical Limb Ischemia Through Activation of Proangiogenic MicroRNAs. Endocrinology. 2015; 157(2):432-45. DOI: 10.1210/en.2015-1799. View

Dhalla N, Pierce G, Innes I, Beamish R . Pathogenesis of cardiac dysfunction in diabetes mellitus. Can J Cardiol. 1985; 1(4):263-81. View

Feng G, Yan Z, Li C, Hou Y . microRNA-208a in an early stage myocardial infarction rat model and the effect on cAMP-PKA signaling pathway. Mol Med Rep. 2016; 14(2):1631-5. PMC: 4940055. DOI: 10.3892/mmr.2016.5402. View

Shyu K, Wang B, Cheng W, Lo H . MicroRNA-208a Increases Myocardial Endoglin Expression and Myocardial Fibrosis in Acute Myocardial Infarction. Can J Cardiol. 2015; 31(5):679-90. DOI: 10.1016/j.cjca.2014.12.026. View

Van Rooij E, Sutherland L, Qi X, Richardson J, Hill J, Olson E . Control of stress-dependent cardiac growth and gene expression by a microRNA. Science. 2007; 316(5824):575-9. DOI: 10.1126/science.1139089. View

Callis T, Pandya K, Seok H, Tang R, Tatsuguchi M, Huang Z . MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J Clin Invest. 2009; 119(9):2772-86. PMC: 2735902. DOI: 10.1172/JCI36154. View

10.

Feng B, Chen S, George B, Feng Q, Chakrabarti S . miR133a regulates cardiomyocyte hypertrophy in diabetes. Diabetes Metab Res Rev. 2009; 26(1):40-9. DOI: 10.1002/dmrr.1054. View

11.

Rawal S, Munasinghe P, Shindikar A, Paulin J, Cameron V, Manning P . Down-regulation of proangiogenic microRNA-126 and microRNA-132 are early modulators of diabetic cardiac microangiopathy. Cardiovasc Res. 2017; 113(1):90-101. DOI: 10.1093/cvr/cvw235. View

12.

Lompre A, Nadal-Ginard B, Mahdavi V . Expression of the cardiac ventricular alpha- and beta-myosin heavy chain genes is developmentally and hormonally regulated. J Biol Chem. 1984; 259(10):6437-46. View

13.

Koshman Y, Sternlicht M, Kim T, OHara C, Koczor C, Lewis W . Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy. J Mol Cell Cardiol. 2015; 89(Pt B):214-22. PMC: 4689630. DOI: 10.1016/j.yjmcc.2015.11.003. View

14.

Munasinghe P, Riu F, Dixit P, Edamatsu M, Saxena P, Hamer N . Type-2 diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated pathway. Int J Cardiol. 2015; 202:13-20. DOI: 10.1016/j.ijcard.2015.08.111. View

15.

Van Rooij E, Sutherland L, Liu N, Williams A, McAnally J, Gerard R . A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci U S A. 2006; 103(48):18255-60. PMC: 1838739. DOI: 10.1073/pnas.0608791103. View

16.

Moore A, Shindikar A, Fomison-Nurse I, Riu F, Munasinghe P, Parshu Ram T . Rapid onset of cardiomyopathy in STZ-induced female diabetic mice involves the downregulation of pro-survival Pim-1. Cardiovasc Diabetol. 2014; 13:68. PMC: 4073808. DOI: 10.1186/1475-2840-13-68. View

17.

Katare R, Caporali A, Zentilin L, Avolio E, Sala-Newby G, Oikawa A . Intravenous gene therapy with PIM-1 via a cardiotropic viral vector halts the progression of diabetic cardiomyopathy through promotion of prosurvival signaling. Circ Res. 2011; 108(10):1238-51. DOI: 10.1161/CIRCRESAHA.110.239111. View

18.

Dixit P, Donnelly H, Edamatsu M, Galvin I, Bunton R, Katare R . Progenitor cells from atria, ventricle and peripheral blood of the same patients exhibit functional differences associated with cardiac repair. Int J Cardiol. 2016; 228:412-421. DOI: 10.1016/j.ijcard.2016.11.178. View

19.

Siedlecki A, Jin X, Muslin A . Uremic cardiac hypertrophy is reversed by rapamycin but not by lowering of blood pressure. Kidney Int. 2009; 75(8):800-8. PMC: 2764402. DOI: 10.1038/ki.2008.690. View

20.

Rawal S, Munasinghe P, Thevkar Nagesh P, Lew J, Jones G, Williams M . Down-regulation of miR-15a/b accelerates fibrotic remodelling in the Type 2 diabetic human and mouse heart. Clin Sci (Lond). 2017; 131(9):847-863. DOI: 10.1042/CS20160916. View