Heart Disease and Relaxin: New Actions for an Old Hormone

Abstract

The hormone relaxin has long been recognized for its involvement in maternal adaptation during pregnancy. However, discoveries during the past two decades on the mechanism of action of relaxin, its family of receptors, and newly described roles in attenuating ischemia/reperfusion (I/R) injury, inflammation, and arrhythmias have prompted vast interest in exploring its therapeutic potential in cardiovascular disease. These observations inspired recently concluded clinical trials in patients with acute heart failure. This review discusses our current understanding of the protective signaling pathways elicited by relaxin in the heart, and highlights important new breakthroughs about relaxin signaling that may pave the way to more carefully designed future trials.

Keywords: RXFP1; fibrosis; heart failure; myocardial infarction; relaxin.

Figure 1

Schematic outlining pathologic signaling after myocardial I/R injury over the course of adverse remodeling (red) and protective mechanisms conferred upon activation of RXFP1 by serelaxin (green) in the mammalian heart. Pathways that require further validation for mechanistic insight are also indicated (dashed). NO produced downstream of βγ subunit activation is central to protection. This involves, but is not limited to, cGMP generation and activation of Protein Kinase G (PKG): targets attributed to mitigating ROS injury and countering fibrosis. NO also counters activation of the inflammasome. RXFP1 signaling can upregulate sodium channel and connexin 43 expression, which lead to increased conduction velocity.

Figure 2

Pleotropic cardioprotective actions of relaxin: The physiological roles of relaxin involve mediating vasodilatation by interacting with smooth muscle and endothelial cells within vascular beds, and increasing cardiac inotropy and chronotropy. In the context of MI, relaxin attenuates inflammation by reducing mast cell degranulation, neutrophil extravasation (infiltrating cells) and inflammasome activity (in resident and infiltrating cells of myocardium). Relaxin also reduces platelet aggregation and counters adverse remodeling by inhibiting fibrosis and arrhythmogenesis in the post-infarcted heart.