Cardioprotective actions of relaxin

Abstract

Relaxin, a hormone of pregnancy, has shown broad cardioprotective effects including anti-fibrotic (reversed excess TGFβ signaling), anti-arrhythmic (Nav1.5 and INa upregulation and Cx43 phosphorylation and trafficking to intercalated disks) and anti-inflammatory properties (reduced IL-1β and IL-6). While relaxin's anti-fibrotic effects are thought to occur through the SMAD2/3/TGFβ pathway, there is a general lack of understanding of relaxin's mode of action to increase sodium current and alter connexin43 localization to suppress arrhythmias. Based on a rat model of aging, we tested the hypothesis that relaxin acts through activation of Wnt/βcatenin signaling to mediate its effects on Nav1.5 and Cx43 and to regulate collagen expression. We show for the first time that relaxin activates canonical Wnt signaling (increased nuclear βcatenin) to increase Nav1.5 in isolated cardiomyocytes. Block of canonical Wnt signaling (via Dikkopf-1) abrogated relaxin's effect on both Nav1.5 in cardiomyocytes and suppression of excess collagen from fibroblasts. Further, we show that relaxin significantly suppressed expression of Dikkopf-1 in isolated cardiomyocytes and whole LV tissue. In addition, show that relaxin suppressed the age-associated genetic upregulation in inflammatory markers in a sexdependent manner. Finally, we tested the hypothesis that relaxin would be an effective therapy in a rat model of pulmonary arterial hypertension and show that it reduced occlusion of small pulmonary arteries, myocardial and lung fibrosis and reversed the cardiac phenotype of ventricular arrhythmia or arrest. These results suggest that relaxin signals through multiple

The anti‐fibrotic actions of relaxin are mediated through AT2R‐associated protein phosphatases via RXFP1‐AT2R functional crosstalk in human cardiac myofibroblasts

“…These findings also have significant consequences as they imply that the anti‐fibrotic effects of RLX may also be indirectly mediated in part via stimulation of the protective arm of the RAS 20,21 beyond RXFP1 activation. Importantly, the stimulation of either receptor has been shown to mediate cardioprotection 8‐10,20,21 . Furthermore, it is implied that this receptor crosstalk allows AT 2 R agonists to also indirectly activate RXFP1 in myofibroblasts.…”

Adipokines and Inflammation: Focus on Cardiovascular Diseases

“…Relaxin is considered a pleiotropic hormone that exerts numerous favourable cardiovascular effects, suggesting its potential use for cardiovascular clinical purposes due to its anti-fibrotic, wound-healing, vasodilator, angiogenic, anti-hypertrophic, anti-apoptotic, anti-oxidant, and anti-inflammatory properties [ 253 ]. Relaxin highlights its anti-inflammatory role principally in conditions of MI following I/R injury.…”

Simultaneous targeting of oxidative stress and fibrosis reverses cardiomyopathy‐induced ventricular remodelling and dysfunction

“…The recombinant form of the human gene-2 relaxin hormone, serelaxin (RLX), was recently evaluated for its vasodilatory benefits in two Phase III clinical trials in patients with acute HF (Metra et al, 2019;Teerlink et al, 2013) and, based on this, has been approved as an acute HF medication in Russia. Notably though, RLX has been shown to exert rapidly occurring anti-oxidant (Dschietzig et al, 2012;Sasser et al, 2014), TGF-β1 inhibitory (Parikh et al, 2013;Samuel et al, 2004;Sassoli et al, 2013) and anti-fibrotic actions (Dschietzig, 2019;Martin et al, 2019;McVicker & Bennett, 2017;Samuel et al, 2017) in several preclinical models of heart disease, independently of aetiology or gender. The anti-oxidant (Bani-Sacchi et al, 1995;Dschietzig et al, 2012;Sasser et al, 2011Sasser et al, , 2014Segal et al, 2012) and TGF-β1 inhibitory effects of RLX (Mookerjee et al, 2009;Wang et al, 2016) involve its ability to promote NO bioavailability and NO-cGMP signalling, in addition to nitrite production (Bani-Sacchi et al, 1995;Valle Raleigh et al, 2017).…”

“…Additionally, RLX possesses anti-inflammatory, anti-hypertrophic, vasodilatory and angiogenic properties, which add to its cardioprotective actions (Dschietzig, 2019;Martin et al, 2019;McVicker & Bennett, 2017;Samuel et al, 2017).…”