Urotensin-II and cardiovascular diseases

Abstract

Urotensin-II (U-II) is a vasoactive factor with pleiotropic effects. U-II exerts its activity by binding to a G-protein-coupled receptor termed UT. U-II and its receptor are highly expressed in the cardiovascular system. Increased U-II plasma levels have been reported in patients with cardiovascular disease of varying etiologies. We and others have shown that U-II and UT expression is elevated in both clinical and experimental heart failure and atherosclerosis. U-II induces cardiac fibrosis by increasing fibroblast collagen synthesis. In addition, U-II induces cardiomyocyte hypertrophy and increased vascular smooth muscle cell proliferation. We have shown that U-II antagonism using a selective U-II blocker, SB-611812 reduces neointimal thickening and increases lumen diameter in a rat restenosis model of carotid artery angioplasty. These findings suggest an important role for U-II in cardiovascular dysfunction and remodeling.

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II–Related Peptide, and Their Receptor: From Structure to Function

“…The inverse relationship between UII and ejection fraction in CHF patients is supported by additional studies by Gruson et al (2006). Conversely, there have also been studies showing no difference in plasma UII in CHF patients compared with healthy controls (Dschietzig et al, 2002;Jołda-Mydłowska et al, 2006), potentially due to differences in patient populations (Bousette and Giaid, 2006). Recently, Jani et al (2013) developed a solid phase extraction technique such that both plasma UII and URP can be differentially isolated and assayed separately.…”

“…ACAT-1 is important in the formation of foam cells, which form early in atherosclerotic lesions by macrophages continuously taking up oxidized LDL via scavenger receptors. The accumulation of these macrophage-derived foam cells contributes to the necrotic fibrofatty cores seen in atherosclerotic lesions (Bousette and Giaid, 2006). The stimulating effects of UII on foam cell formation seem to involve various intracellular signaling pathways, because they were inhibited by selective UT antagonist urantide, protein kinase C inhibitor rottlerin, MEK inhibitor PD98059, Rho kinase inhibitor Y27632, c-Src protein tyrosine kinase inhibitor PP2, and G protein inactivator GDP-b-S (Watanabe et al, 2005).…”

“…Role in Heart Failure. Under physiologic conditions, UII expression is strongest in the CNS but is significantly increased in the heart in cardiovascular disease states (Bousette and Giaid, 2006;Khan et al, 2007). Both UII and UT expression increase significantly in patients with end-stage congestive heart failure (CHF), particularly in cardiomyocytes and to a lesser extent in vascular smooth muscle cells, endothelial cells, and inflammatory cells .…”

Urotensin II receptor antagonist attenuates monocrotaline-induced cardiac hypertrophy in rats

“…UII has been identified as a selective ligand of G protein-coupled receptor termed UII receptor (1,27,29). The stimulation of the UII receptors by UII activates the G␣ q -phospholipase C ␤ pathway, generating diacylglycerol (DAG) and inositol 1,3,4-trisphosphate (IP 3 ) that stimulate protein kinase C (PKC) and Ca 2ϩ release from intracellular stores, respectively (1,29,35). Human UII (hUII) is a potent vasoconstrictor in the artery, which is more potent than that of endothelin-1 (1,27).…”

“…An upregulation of the UII receptor may worsen cardiac hypertrophy (3,30) and cardiac injury under ischemia-reperfusion (43). In contrast, the beneficial effects of UII on decreasing coronary flow and cardiac contractility induced by ischemia-reperfusion have also been reported (32).…”