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.
Department of Internal Medicine, Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Hiroyuki
H
Masuyama
Toshihiro
T
Tsuruda
Yoko
Y
Sekita
Kinta
K
Hatakeyama
Takuroh
T
Imamura
Johji
J
Kato
Yujiro
Y
Asada
Johannes-Peter
JP
Stasch
Kazuo
K
Kitamura
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