Elsevier

Peptides

Volume 29, Issue 5, May 2008, Pages 770-777
Peptides

Urotensin II and urotensin II-related peptide (URP) in cardiac ischemia-reperfusion injury

https://doi.org/10.1016/j.peptides.2007.08.013Get rights and content

Abstract

Circulating urotensin II (UII) concentrations and the tissue expression of its cognate receptor (UT) are elevated in patients with cardiovascular disease (CVD). The functional significance of elevated plasma UII levels in CVD is unclear. Urotensin-related peptide (URP) is a paralog of UII in that it contains the six amino acid ring structures found in UII. Although both peptides are implicated as bioactive factors capable of modulating cardiovascular status, the role of both UII and URP in ischemic injury is unknown. Accordingly, we provide here the first report describing the direct cardiac effects of UII and URP in ischemia-reperfusion injury. Isolated perfused rat hearts were subjected to no-flow global ischemia for 45 min after 30 min preconditioning with either 1 nM rUII or 10 nM URP. Both rUII- and URP-induced significant vasodilation of coronary arteries before (both P < 0.05) and after ischemia (both P < 0.05). Rat UII alone lowered contractility prior to ischemia (P = 0.053). Specific assay of perfusate revealed rUII and URP both significantly inhibited reperfusion myocardial creatine kinase (CK) release (P = 0.012 and 0.036, respectively) and atrial natriuretic peptide (ANP) secretion (P = 0.025). Antagonism of the UT receptor with 1 μM palosuran caused a significant increase in perfusion pressure (PP) prior to and post-ischemia. Furthermore, palosuran significantly inhibited reductions in both PP and myocardial damage marker release induced by both rUII and URP. In conclusion, our data suggests rUII and URP reduce cardiac ischemia-reperfusion injury by increasing flow through the coronary circulation, reducing contractility and therefore myocardial energy demand, and inhibiting reperfusion myocardial damage. Thus, UII and URP present as novel peptides with potential cardioprotective actions.

Introduction

Urotensin II (UII) is a cardiovascular peptide with an array of biological effects that are species and tissue specific [12], [30]. Thus, UII has been shown to constrict and dilate vascular tissue [3], [23], [27], increase and decrease blood pressure and contractility in vivo [1], [18], [40], [42], stimulate vascular smooth muscle cell proliferation [39], and promote cardiomyocyte hypertrophy [38], [44]. Blood levels of UII and the tissue expression of its cognate G protein-coupled receptor (UT) are both elevated in patients with congestive heart failure (CHF) and other cardiovascular diseases [13], [21], [25], [32], [33].

Recently a precursor cDNA peptide encoding the same conserved six amino acid rings as UII was isolated from rat, mouse and human tissues. This UII paralog has been named urotensin-related peptide (URP) and is a second endogenous ligand for the UT receptor [8], [35], with studies administering URP both in vitro and in vivo reporting biological actions similar to UII [8], [35]. The distribution of prepro-URP in human and rat tissue is widespread, including brain, and the cardiovascular system [35]. However, its biological effects in these systems are unclear.

Despite a number of reports documenting cardiovascular actions of UII [1], [11], [31], [42] its role in cardiac ischemia-reperfusion injury is unclear. Experimental animal models of heart failure suggest UII may have a pathological role, as antagonism of UT results in reduced mortality and improved recovery of heart function in rats [4], [38]. In contrast, patients with significantly elevated plasma UII levels have improved outcomes post-myocardial infarction, suggesting UII may play a cardioprotective role [24], [43]. Furthermore, any role for URP in cardiac ischemia-reperfusion injury is unreported. Accordingly, we provide here the first documentation of the species-specific actions of rUII and URP in cardiac ischemia-reperfusion injury and their comparative effects upon contractile and cardioendocrine function.

Section snippets

Materials

All animals used in this study were male Sprague–Dawley rats (250–400 g) obtained from the Christchurch School of Medicine, Christchurch, New Zealand. Rats had free access to standard rat chow and water and were housed under controlled temperature (21 °C), humidity (∼40%) and natural day length.

Rat urotensin II (rUII) and URP were obtained from Phoenix Pharmaceuticals (Belmont, USA). UII receptor antagonist palosuran (ACT-058362;

RUII and URP reduce PP prior to and following ischemia

Both rUII and URP significantly reduced PP during preconditioning by a maximum of 8% at 10 min (P < 0.05, Fig. 2A and B, respectively) compared with vehicle. During the first 15 min of reperfusion this vasodilation was retained in both rUII and URP preconditioned hearts with maximum reductions of 16 and 18%, respectively compared with vehicle (P < 0.05, Fig. 2A and B), before returning to vehicle levels.

Effect of UT receptor antagonism upon PP

Infusion of 1 μM palosuran alone caused a significant increase in PP (mean = 9.5 ± 1.7%, P < 0.05) during

Discussion

We provide here the first documentation that: (1) rUII and URP dilate cardiac coronary arteries both prior to and post-ischemia. (2) RUII weakly reduces left ventricular (LV) contractility post-ischemia but URP does not. (3) Both rUII and URP significantly reduce cardiac CK release upon reperfusion, whereas post-ischemia ANP release is attenuated in the isolated heart when preconditioned with rUII only. (4) Palosuran has a constrictor action in the coronary vasculature, consistent with its

Acknowledgements

Thanks are extended to the staff of Endolab, Christchurch School of Medicine for assistance with RIA and to staff of Canterbury Medical Laboratory for assistance with creatine kinase analysis. This work was supported with funding from the National Heart Foundation of New Zealand. A.M. Richards currently holds the N.H.F. Chair of cardiovascular studies, H.C.G. Prosser is the recipient of a National Heart Foundation of New Zealand Post-Graduate Fellowship, C.J. Pemberton is Sir Charles Hercus

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