Pressure-independent effects of pharmacological stimulation of soluble guanylate cyclase on fibrosis in pressure-overloaded rat heart.
Cardiac fibrosis is a hallmark of cardiovascular remodeling associated with hypertension. The purpose of this study was to explore the effect and mechanism of soluble guanylate cyclase (sGC) stimulator BAY 41-2272, leading to intracellular cyclic guanosine monophosphate (cGMP) elevation, on the remodeling process induced by pressure overload. Seven-week-old male Wistar rats with hypertension induced by suprarenal aortic constriction (AC) were treated orally with 2 mg kg(-1) day(-1) of BAY 41-2272 for 14 days. BAY 41-2272 had no effects on blood pressure, but decreased AC-induced collagen accumulation in the left ventricle (LV), inhibiting the number of myofibroblasts and gene expressions of transforming growth factor-beta1 and type 1 collagen. In addition, the antifibrotic action of BAY 41-2272 was accompanied by reducing AC-induced angiotensin-converting enzyme (ACE) mRNA and its enzymatic activity, and angiotensin II concentration in LV. In cultured cardiac fibroblasts, BAY 41-2272 inhibited ACE synthesis and myofibroblast transformation, accompanied by elevating the intracellular cGMP concentration. These results suggest that sGC stimulator BAY 41-2272 might be effective to reduce fibrosis in hypertensive heart disease by attenuating angiotensin II generation through myofibroblast transformation.
Masuyama
Hiroyuki
H
Department of Internal Medicine, Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Tsuruda
Toshihiro
T
Sekita
Yoko
Y
Hatakeyama
Kinta
K
Imamura
Takuroh
T
Kato
Johji
J
Asada
Yujiro
Y
Stasch
Johannes-Peter
JP
Kitamura
Kazuo
K
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D003251:Constriction, Pathologic; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D015870:Gene Expression; D006162:Guanylate Cyclase / Q000378:metabolism*; D006321:Heart / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000648:ultrastructure; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013268:Stimulation, Chemical; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D024042:Collagen Type I; D011720:Pyrazoles; D011725:Pyridines; D053773:Transforming Growth Factor beta1; D007703:Peptidyl-Dipeptidase A; D006162:Guanylate Cyclase