Novel drug development opportunity for relaxin in acute myocardial infarction: evidences from a swine model

Abstract

The hormone relaxin has been shown to cause coronary vasodilation and to prevent ischemia/reperfusion-induced cardiac injury in rodents. This study provides evidence that relaxin, used as an adjunctive drug to coronary reperfusion, reduces the functional, biochemical, and histopathological signs of myocardial injury in an in vivo swine model of heart ischemia/reperfusion, currently used to test cardiotropic drugs for myocardial infarction. Human recombinant relaxin, given at reperfusion at doses of 1.25, 2.5, and 5 microg/kg b.wt. after a 30-min ischemia, caused a dose-related reduction of key markers of myocardial damage (serum myoglobin, CK-MB, troponin T) and cardiomyocyte apoptosis (caspase 3, TUNEL assay), as well as of cardiomyocyte contractile dysfunction (myofibril hypercontraction). Compared with the controls, relaxin also increased the uptake of the viability tracer 201Thallium and improved ventricular performance (cardiac index). Relaxin likely acts by reducing oxygen free radical-induced myocardial injury (malondialdehyde, tissue calcium overload) and inflammatory leukocyte recruitment (myeloperoxidase). The present findings show that human relaxin, given as a drug to counteract reperfusion-induced cardiac injury, affords a clear-cut protection to the heart of swine with induced myocardial infarction. The findings also provide background to future clinical trials with relaxin as adjunctive therapy to catheter-based coronary angioplasty in patients with acute myocardial infarction.

Relaxin remodels fibrotic healing following myocardial infarction

“…21 The anti-apoptotic effects of relaxin in the infarcted murine heart are also consistent with its effects in a porcine model of MI, 36 and its ability to protect cardiomyocytes from apoptosis in vitro; 16 while its pro-angiogenic Relaxin remodels post-infarct fibrotic healing CS Samuel et al effects are in keeping with that observed in the pig model of MI. 14 The rationale for Glut-1 staining was based on previous studies using endothelial expression of Glut-1 as a marker of active de novo capillary formation; where 75% of Glut-1 expression in the heart was localized to the capillary endothelium.…”

Relaxin prevents the development of severe acute pancreatitis

“…The inhibition of either the nitric oxide pathway or glucocorticoid receptor stimulation significantly reduced the positive effects described previously for homogenous groups (10)(11)(12). Surprisingly for group 7 when we associated both inhibitors the severity that was developed although greater than for homogenous groups (6-7) was still less than that displayed by homogenous groups (3)(4) suggesting that there is another pathway involved in the treatment with relaxin.…”

“…It has been reported that relaxin offers protection for reperfusion-induced cardiac injury increasing coronary blood flow favoring blood supply to the ischemic myocardium while it exerts a relaxant action on smooth muscle cells [10] . It has been shown that relaxin up regulates nitric oxide synthase (NOS) II expression thus inducing nitric oxide mediated vasodilatation by a controlled activation of endogenous nitric oxide biosynthesis [11] .…”

“…We then integrated this information to rank the groups in order of "increased degree of severity" (Table 5) showing that the severe acute pancreatitis developed by homogenous groups (3-4) was signifi cantly ameliorated for homogenous groups (10)(11)(12).…”

Protection from cigarette smoke‐induced vascular injury by recombinant human relaxin‐2 (serelaxin)

“…This working hypothesis is based on the following mainstays: ( i ) blood vessels are a physiological target of RLX and their cells express the specific RLX receptor RXFP1 25; ( ii ) RLX up‐regulates NOS expression and nitric oxide production in vascular endothelial cells 26, 27, 28, 29, 30; ( iii ) RLX improves inflammation‐induced endothelial dysfunction and NOS fall 31, 32; and ( iv ) RLX reduces oxidative stress and nitric oxide failure in different animal models of vascular injury 33, 34, 35, 36, 37.…”