Effects of Urotensin II on Excitation-Contraction Coupling in Hypertrophic Heart Failure

Urotensin II (UII) is a potent vasoconstrictor endogenous hormone that binds to cognate G protein coupled receptors (GPCR) UT receptor. It has multiple actions on the cardiovascular system, and both the hormone and its receptor are upregulated in heart failure and may be linked to adverse remodeling. There is a marked elevation in circulating UII levels in patients suffering from heart failure, and this may lead to perturbations of Ca2+ homeostasis and adversely affect excitation-contraction coupling (E-C coupling), further contributing to the pathogenesis of heart failure. The aims of this thesis were to determine the cellular effects of UII on hypertrophy and E-C coupling in ventricular cardiomyocytes and the cellular mechanism responsible, adopting in-vitro, ex-vivo and in-vivo animal models. UII caused a significant reduction in left ventricular developed pressure in ex-vivo rat hearts and this is also observed in isolated rat ventricular cardiomyocytes, where the reduction in contraction strength is accompanied by a reduction in systolic [Ca2+]i. The reduction in systolic [Ca2+]i, appears to result from a combination of a reduction in L-type Ca2+-current density and the SR Ca2+-content. Moreover, the reduction in systolic [Ca2+]i was reflected by a reduction in action potential duration (APD30/50). This study also showed that chronic exposure of isolated rat ventricular cardiomyocytes in culture to UII, induced hypertrophy after 24 hours. The study also showed this involved the UT receptor resulting in the activation of extracellular-regulated kinases (ERK1/2), p38 mitogen-activated protein kinases and calmodulin-dependent protein kinase II (CaMKII) signalling pathways and which were shown to be involved in the induction of hypertrophy. The UT receptor was not upregulated in-vitro study, neither in a mouse model of angiotensin II induced left ventricular hypertrophy (LV- hypertrophy) and LV-dysfunction. However, there was upregulation in atria tissue. Increase in circulating UII may contribute to the development of LV-hypertrophy. The most obvious finding to emerge from this study is that the reduction in contraction will compound any LV-dysfunction in heart failure (HF). Pharmacological inhibition of the UII/UT system may prove beneficial in reducing adverse remodelling and alleviating contractile-dysfunction following heart disease.