Chronic urotensin-II infusion induces diastolic dysfunction and enhances collagen production in rats

Abstract

The vasoactive peptide urotensin-II (U-II) is likely to play a key causal role in cardiac remodeling that ultimately leads to heart failure. Its contribution, specifically to the development of diastolic dysfunction and the downstream intracellular signaling, however, remains unresolved. This study interrogates the effect of chronic U-II infusion in normal rats on cardiac structure and function. The contribution of Rho kinase (ROCK) signaling to these pathophysiological changes is evaluated in cell culture studies. Chronic high-dose U-II infusion over 4 wk significantly impaired diastolic function in rats on echocardiography-derived Doppler indexes, including E-wave deceleration time (vehicle 56.7 +/- 3.3 ms, U-II 118.0 +/- 21.5 ms; P < 0.01) and mitral valve annulus peak early/late diastolic tissue velocity (vehicle 2.01 +/- 0.19 ms, U-II 1.04 +/- 0.25 ms; P < 0.01). A lower dose of U-II infusion (1 nmol.kg(-1).h(-1)) yielded comparable changes. Diastolic dysfunction was accompanied by molecular [significant increases in procollagen-alpha(1)(I) gene expression on real-time PCR] and morphological (increases in total collagen, P < 0.05, and collagen type-I protein deposition, P < 0.001) evidence of left ventricular (LV) fibrosis following high-dose U-II infusion. The ROCK inhibitor GSK-576371 (10(-7) to 10(-5) M) elicited concentration-dependent inhibition of U-II (10(-7) M)-stimulated cardiac fibroblast collagen synthesis and cardiac myocyte protein synthesis. Chronic U-II infusion causes diastolic dysfunction, caused by fibrosis of the LV. The in vitro data suggest that this may be in part occurring via a ROCK-dependent pathway.

The Efficiency of a Urotensin II Antagonist in an Experimental Lung Fibrosis Model

“…It is another effective vasoconstrictor, like ET-1. Recent studies show that U-II could play a fundamental role in cardiovascular remodeling and fibrosis, renal fibrosis, hepatic fibrosis, and in part of the fibrotic process [8,9]. Our investigation revealed that U-II levels are higher in patients with systemic sclerosis (SSc), especially in diffuse fibrotic patients, in contrast to the control group.…”

“…The mechanism of fibrosis remains elusive, and in the treatment of PF, current therapies such as immunosuppressives and steroids are not sufficient [4]. Some cytokines and chemokines, such as TGF-β, connective tissue growth factor, fibroblast growth factor, plateletderived growth factor, insulin-like growth factor (IGF), interleukins (IL-1, IL-10, IL-12, IL-17, IL-4, IL-13), interferon gamma, IGF-1, GM-CSF, tumor necrosis factor-alpha, and ET-1 have been investigated in recent studies [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. Because of the limited treatment alternatives and uncertain pathogenesis, this study was designed to investigate possible therapy alternatives of PF.…”

Urotensin II Promotes Atherosclerosis in Cholesterol-Fed Rabbits

“…The doses of UII used in the current study were based on a previous report [14] and our own experiment. We used two doses of UII: 2.7 µg/kg/h (as low dose) and 5.4 µg/kg/h (as high dose).…”

Chronic Kidney Disease-Induced Cardiac Fibrosis Is Ameliorated by Reducing Circulating Levels of a Non-Dialysable Uremic Toxin, Indoxyl Sulfate

“…Cardiac sections, stained with picrosirius red for matrix deposition, [49] were scanned (Aperio, Aperio Technologies Inc., Vista, CA) for analysis. Picrosirius red-stained matrix deposition from the whole LV myocardium, excluding perivascular fibrosis was selected for its intensity, and the proportional area was calculated using a preset algorithm for picrosirius red stain intensity.…”