Direct Actions of Urotensin II on the Heart

Abstract

Abstract-Urotensin II (UII) is a somatostatin-like peptide recently identified as a potent vasoconstrictor. In this study, we examined whether UII promotes cardiac remodeling through nonhemodynamic effects on the myocardium. In a rat model of heart failure after myocardial infarction (MI), increased UII peptide and UII receptor protein expression was observed in both infarct and noninfarct regions of the left ventricle compared with sham. Moreover, post-MI remodeling was associated with a significant 75% increase in UII receptor gene expression in the heart (PϽ0.05 versus sham controls), with this increase noted in both regions of the left ventricle. In vitro, UII (10 Ϫ7 mol/L) stimulation of neonatal cardiac fibroblasts increased the level of mRNA transcripts for procollagens ␣ 1 (I), ␣ 1 (III), and fibronectin by 139Ϯ15% (PϽ0.01), 59Ϯ5% (PϽ0.05), and 141Ϯ14% (PϽ0.01), respectively, with a concomitant 23Ϯ2% increase in collagen peptide synthesis as determined by 3 H-proline incorporation (PϽ0.01). UII had no effect on cellular hypertrophy, as determined by changes in total protein content in isolated neonatal cardiomyocytes. However, expression of recombinant rat UII receptor in neonatal cardiomyocytes resulted in significant UII-dependent activation of hypertrophic signaling as demonstrated by increased total protein content (unstimulated, 122.4Ϯ4.0 g/well; rat UII, 147.6Ϯ7.0 g/well; PϽ0.01) and activation of the hypertrophic phenotype through G␣q-and Ras-dependent pathways. These results indicate that, in addition to potent hemodynamic effects, UII may be implicated in myocardial fibrogenesis through increased collagen synthesis by cardiac fibroblasts and may also be an important determinant of pathological cardiac hypertrophy in conditions characterized by UII receptor upregulation. Key Words: urotensin Ⅲ myocardial infarction Ⅲ remodeling Ⅲ collagen Ⅲ hypertrophy L eft ventricular dysfunction, regardless of the underlying etiology, is associated with activation of various neurohormonal systems that compensate for the consequent loss of ventricular function and peripheral homeostasis. These include the renin-angiotensin and endothelin systems, which act to restore the early decline in cardiac output through positive inotropic effects and peripheral vasoconstriction. Although these effects may be beneficial in the short term, prolonged activation, both local and systemic, may additionally contribute to worsening of contractile function through adverse cardiac remodeling, a process characterized by necrosis, 1 myocyte hypertrophy, 2 inflammation, 3 and the pathological accumulation of extracellular matrix material within the interstitium (fibrosis). 4 More recently, the vasoconstrictor peptide urotensin II (UII) has emerged as a likely contributor to cardiovascular physiology and pathology. UII is a somatostatin-like cyclic peptide synthesized by proteolytic cleavage from a precursor molecule, prepro-UII, and has recently been identified as a potent vasoconstrictor. 5 UII has been identified within the heart, ...

Angiotensin II and the JNK pathway mediate urotensin II expression in response to hypoxia in rat cardiomyocytes

“…Similar to AngII (Chen et al 2004) and ET-1 (Chen et al 2005), UII-induced myocyte hypertrophy may contribute to cardiac remodeling and deterioration of cardiac function. Tzanidis et al (2003) demonstrated the expression of both UII and UII-R within myocardial tissue, suggesting an important role for UII in cardiac pathophysiology. Zhou et al (2003) reported UII-dependent hypertrophy in isolated cardiomyocyte cultures.…”

“…Thus, UII may be an important determinant of cardiac dysfunction via additional nonhemodynamic effects on the myocardium, similar to angiotensin II (AngII) and ET-1 (Li et al 2005). Specifically, Tzanidis et al (2003) reported that UII stimulates collagen synthesis in cardiac fibroblasts, suggesting that UII may be involved in myocardial fibrogenesis. UII and its receptor (UII-R) are upregulated in patients with end-stage heart failure (Ng et al 2002), ischemia (Pakala 2008), chronic hypoxia (MacLean et al 2000), or post-myocardial infarct rat myocardium (Tzanidis et al 2003).…”

“…Specifically, Tzanidis et al (2003) reported that UII stimulates collagen synthesis in cardiac fibroblasts, suggesting that UII may be involved in myocardial fibrogenesis. UII and its receptor (UII-R) are upregulated in patients with end-stage heart failure (Ng et al 2002), ischemia (Pakala 2008), chronic hypoxia (MacLean et al 2000), or post-myocardial infarct rat myocardium (Tzanidis et al 2003). Upregulation of UII-R may worsen cardiac hypertrophy (Segain et al 2007) and cardiac injury under ischemia-reperfusion (Prosser et al 2008).…”

Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes

“…Ultra-thin sections obtained from the embedded blocks were examined using a TEM (H-7500; Hitachi, Tokyo, Japan). Masson staining for collagen and streptavidin-biotin-peroxidase complex (SABC) immunohistochemistry staining for type-I collagen and type-III collagen (rabbit antibodies from Santa Cruz Biotechnol- ogy, Santa Cruz, CA, USA) were undertaken after 4-μm thick sections were obtained from the paraffin-embedded cardiac samples using previously described methods [20] . Results were expressed as the mean percentage area of 10 random fields for each section.…”

PPAR-γ expression in animals subjected to volume overload and chronic Urotensin II administration

“…However, Ames et al discovered in anesthetized primates that low dose (<30 pmol/kg) administration of UTII resulted in increased cardiac output while high dose UTII (>30 pmol/kg) resulted in cardiovascular collapse due to decreased stroke volume with little change in heart rate [2]. Finally, the UTII system has been implicated in adverse remodeling and left ventricular hypertrophy as shown by increased collagen mRNA and protein expression as well as increase leucine incorporation in cell culture [12,26].…”