Relaxin as a Therapeutic Target for the Cardiovascular Complications of Diabetes.

Hooi Hooi Ng,Chen Huei Leo,Laura J Parry,Rebecca H Ritchie

doi:10.3389/fphar.2018.00501

Abstract

Cardiovascular complications are the major cause of mortality in patients with diabetes. This is closely associated with both macrovascular and microvascular complications of diabetes, which lead to organ injuries in diabetic patients. Previous studies have consistently demonstrated the beneficial effects of relaxin treatment for protection of the vasculature, with evidence of antioxidant and anti-remodeling actions. Relaxin enhances nitric oxide, prostacyclin and endothelium-derived hyperpolarization (EDH)-type-mediated relaxation in various vascular beds. These effects of relaxin on the systemic vasculature, coupled with its cardiac actions, reduce pulmonary capillary wedge pressure and pulmonary artery pressure. This results in an overall decrease in systemic and pulmonary vascular resistance in heart failure patients. The anti-fibrotic actions of relaxin are well established, a desirable property in the context of diabetes. Further, relaxin ameliorates diabetic wound healing, with accelerated angiogenesis and vasculogenesis. Relaxin-mediated stimulation of vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1-α, as well as regulation of metalloproteinase expression, ameliorates cardiovascular fibrosis in diabetic mice. In the heart, relaxin is a cardioprotective molecule in several experimental animal models, exerting anti-fibrotic, anti-hypertrophy and anti-apoptotic effects in diabetic pathologies. Collectively, these studies provide a foundation to propose the therapeutic potential for relaxin as an adjunctive agent in the prevention or treatment of diabetes-induced cardiovascular complications. This review provides a comprehensive overview of the beneficial effects of relaxin, and identifies its therapeutic possibilities for alleviating diabetes-related cardiovascular injury.

Highlights

Diabetes mellitus is a major risk factor for the development of cardiovascular diseases
We suggest that relaxin likely restores diabetesinduced endothelial dysfunction by affecting the nitric oxide (NO) and prostanoid pathways, but not the endothelium-derived hyperpolarization (EDH) pathway, in both the aorta and mesenteric artery
Given that left ventricular transforming growth factor (TGF)-β gene expression was not elevated in placebo-treated type 1 diabetic mice in the above study (Ng et al, 2017), it is rational to speculate that the ability of relaxin to limit cardiac fibrosis may relate to its distinct action to restore physiological levels of TGF-β (Sassoli et al, 2013)

Summary

Introduction

Diabetes mellitus is a major risk factor for the development of cardiovascular diseases. In addition to the potent anti-fibrotic actions of relaxin in various disease animal models, relaxin has the ability to reduce oxidative stress, at least in part via protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) signaling pathways, suppressing cardiomyocytes apoptosis and hypertrophy (Moore et al, 2007).

Results

Conclusion