Abstract
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.
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