Mechanisms of DiseaseCongestive heart failure and expression of myocardial urotensin II
Introduction
Congestive heart failure (CHF) is the leading cause of death in the developed world. Several cytokines, vasoactive mediators, and growth factors have been implicated in the disease process. The human form of urotensin II, a cyclic peptide initially isolated from the caudal neurosecretory system of teleost fish,1 as well as its g-protein-coupled receptors (gprs), now known as UT receptor,2 have been isolated.3, 4 Human urotensin II is composed of 11 aminoacid residues with a disulfide linked cyclic octapeptide core region, which is responsible for its biological activity.4, 5 The contractile effects of urotensin II on smooth muscle cells seem to vary dependent on the species and the type of vessel, and are often more potent than that of endothelin 1.3, 6, 7 Results of experiments have shown that human urotensin II causes contraction of all non-human primate arterial vessels,3 aortocoronary vessels of rats7, 8 and dogs,7 human trabeculae,9 and human coronary, mammary, and radial arteries, saphenous, and umbilical veins.10, 11, 12 Findings of other studies, however, indicate either vasodilatory or no effect of urotensin II in vessels of human beings.13, 14 There therefore seems to be a discrepancy between in-vivo and in-vitro effects of urotensin II on blood vessels of people.
Administration of human urotensin II resulted in deterioration of cardiovascular function in anaesthetised monkeys, causing fatal circulatory collapse and severe myocardial depression (most likely an indirect effect secondary to coronary ischaemia). Indeed, bolus administration of human urotensin II induced a 300% increase in total peripheral resistance in anaesthetised monkeys, without causing systemic hypertension, and an 80% decrease in dP/dt with ST segment changes consistent with concomitant myocardial ischaemia (as would be observed as a result of constriction of coronary arteries).3, 9 The vasoconstrictor effects of human urotensin II are mediated by the binding of the peptide to specific high-affinity receptors, and seem to involve calcium mobilisation and a phospholipase c dependent increase in inositol phosphates.2, 15, 16
Myocardial expression of urotensin II and the UT receptor in the healthy or diseased heart remain to be elucidated. Findings of studies show that human urotensin II causes cardiac dysfunction in mammals, proarrhythmogenic activity in isolated human hearts,9 and increased collagen production in neonatal cardiac fibroblasts,17 suggesting that CHF might be associated with the myocardial urotensin II system. Our aim was to investigate myocardial expression of human urotensin II and its binding to the receptor in the hearts of healthy controls and in patients with CHF. We also correlated cellular expression of urotensin II with clinical characteristics of CHF.
Section snippets
Participants
We obtained tissue from the myocardium of 19 patients with end-stage heart failure (New York Heart Association functional class III-V) at surgery for heart transplantation (through the Quebec Vascular Endothelium Network Tissue Bank). Of the 19 patients, 12 had ischaemic heart disease and seven had dilated cardiomyopathy. Myocardial biopsies (3 mm) from the left ventricle of five patients with mild CHF (New York Heart Association functional class I-II), requiring deep coronary grafts, were
Results
The table shows the clinical characteristics of individuals from whom samples were taken. Patients with CHF were treated with a combination of drugs, including diuretics, digoxin, angiotensin-converting-enzyme inhibitors, nitrates, calcium channel blockers, low-dose aspirin, and antiarrhythmic drugs. Complications included hypertension (n= 10) and diabetes mellitus (n=4).
The myocardium of hearts from healthy controls showed little or no urotensin II mRNA or immunoreactivity to urotensin II
Discussion
Our results indicate that expression of urotensin II is upregulated in the hearts of patients with end-stage CHF when compared with controls. Furthermore, urotensin II expression is localised to the cardiomyocytes, endothelial cells, and vascular smooth muscle cells of the damaged heart, with greatest expression in the subendocardial region and in the surviving cardiomyocytes of infarction and border zones of patients with ischaemic heart disease. Myocardial tissue from patients with
GLOSSARY
- g-protein-coupled receptors (gprs)
- GPRs mediate cellular responses to a variety of molecules, including many drugs. More than 400 GPR have been identified. G stands for Guanosine triphosphate or GTP. When the receptors are activated they bind to G proteins, which through conformational changes and the hydyolysis of GTP then cause intracellular changes.
- phospholipase c
- Phospholipase C is a an enzyme that releases inositol trisphosphate and diacylglycerol from the plasma membrane to act as
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2020, European Journal of PharmacologyCitation Excerpt :UT gene is widely expressed in the central nervous system (CNS) and in peripheral tissues including retina, heart, vascular bed, lung, kidney, adrenal medulla, and skeletal muscle (Hunt et al., 2010; Maguire et al., 2008). Various studies have revealed the increased expression of U-II and its receptor UT in the failing hearts and renal diseases (Ng et al., 2002; Douglas et al., 2002; Bousette et al., 2006a,b; Loirand et al., 2008). Genetic deletion of UT in mice renders aortae, refractive to the contractile activity of U-II (You et al., 2012).