Early dysregulation of cardiac-specific microRNA-208a is linked to maladaptive cardiac remodelling in diabetic myocardium

Shruti Rawal,Sean Coffey,Michael J A Williams,Ivor F Galvin,Rajesh Katare,Isabelle Van Hout,Prashanth Thevakar Nagesh,Richard W Bunton,Philip Davis

doi:10.1186/s12933-019-0814-4

Shruti Rawal, Sean Coffey + Show 7 more

Open Access

https://doi.org/10.1186/s12933-019-0814-4

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Abstract

BackgroundThe 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.MethodsReal-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.ResultsRT-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.ConclusionOur 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.

Highlights

The diabetic heart undergoes remodelling contributing to an increased incidence of heart failure in individuals with diabetes at a later stage
Results from our study has revealed the involvement of cardiac-enriched miR-208a in the progression of diabetes-mediated maladaptive cardiac remodelling and the causal relation between miR-208a and cardiac hypertrophy protein myosin heavy chain (MHC) using in vitro adult cardiomyocytes
In conclusion, we show that upregulation of α-MHC triggers the activation of miR-208a in the early stages of diabetes

Summary

Introduction

The diabetic heart undergoes remodelling contributing to an increased incidence of heart failure in individuals with diabetes at a later stage. In response to hyperglycaemic stress, the heart undergoes extensive cardiac remodelling, resulting in pathological growth of cardiomyocytes (hypertrophy) [1, 5]. This response aims to normalize wall stress and preserve contractile performance, but chronically it produces hypertrophy and may eventually lead to heart failure. It is essential to determine the miRNA which has a direct role in regulating myocardial hypertrophy and those which exhibit altered expression secondary to hypertrophic growth in the diabetic myocardium

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