title: Spironolactone decreases isoproterenol-induced ventricular fibrosis and matrix metalloproteinase-2 in rats.
abstract: Although transregulation between the sympathetic nervous system and the renin-angiotensin-aldosterone system has been reported, it remains unclear whether sympathetic hyperactivity-induced matrix metalloproteinease (MMP) expression/activity and cardiac fibrosis are mediated by the mineralocorticoid receptor system. We investigated whether isoproterenol (ISO)-induced MMP expression/activity and cardiac fibrosis are mediated by spironolactone in rats. Male Wistar Kyoto rats were divided into 3 groups: control, ISO, and ISO combined with spironolactone (SPI). ISO (2.0 mg/kg/d) and/or SPI (40 mg/kg/d) were given for 14 d. Echocardiography and hemodynamic measurements were recorded and hearts were excised. The myocyte cross-sectional and fibrotic area was evaluated via histopathological analysis. MMP-2 and collagen-I were analyzed by Western blotting and zymography. Compared with the controls, ISO significantly elevated the end-diastolic left ventricular (LV) pressure and the time constant of isovolumic relaxation and decreased the -dP/dt, while those of SPI co-treatment did not. ISO treatment induced significant increases in the fractional shortening and relative wall thickness, whereas SPI co-treatment significantly decreased relative wall thickness. Similarly, ISO significantly increased LV weight and myocyte cross-sectional and fibrotic area, which occurred concomitantly with the MMP-2 expression/activity and the expression of collagen-I. Moreover, ISO induced these features were significantly attenuated by SPI co-treatment. Our results suggest that ISO-evoked sympathetic hyperactivity induced LV fibrosis and MMP-2, which may be partially controlled via the mineralocorticoid receptor system.
authors.affiliation: Laboratory of Small Animal Internal Medicine, School of Veterinary Medicine, Kitasato University, Towada, Aomori 034–8628, Japan. hori@vmas.kitasato-u.ac.jp
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Hori
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Kanai
authors.forename: Fumio
authors.initials: F
authors.lastname: Hoshi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Itoh
authors.forename: Sei-Ichi
authors.initials: S
authors.lastname: Higuchi
mesh_terms: D000818:Animals; D005355:Fibrosis / Q000139:chemically induced* / Q000188:drug therapy; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology; D007545:Isoproterenol / Q000633:toxicity*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011921:Rats, Inbred WKY; D013148:Spironolactone / Q000494:pharmacology*
chemical_list: D013148:Spironolactone; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D007545:Isoproterenol