Pressure-independent effects of pharmacological stimulation of soluble guanylate cyclase on fibrosis in pressure-overloaded rat heart

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 À1 day À1 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-b1 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.

Pharmacological stimulation of soluble guanylate cyclase modulates hypoxia-inducible factor-1α in rat heart

“…The beneficial effects of stimulating sGC-cGMP on hemodynamics and remodeling in cardiovascular disorders have been demonstrated by ourselves and others (3,6,7,18,22,23). The present study extends our understanding of the important biological action for sGC-cGMP stimulation on improving the survival following the AC.…”

“…The rats were divided into the following three groups: a sham group (n ϭ 26) and two pressure-overloaded groups with (n ϭ 36) or without (n ϭ 58) BAY 41-2272 treatment. Pressure overload was induced by abdominal aortic constriction (AC) at the suprarenal level as previously described (10,23). In brief, a 22-gauge needle was placed adjacent to the abdominal aorta proximal to the renal artery and ligated tightly around the aorta and the adjacent needle.…”

“…The BAY 41-2272 compound, supplied by Bayer HealthCare, was given by gastric gavage at a dose of 2 mg/kg two times a day for 14 days. The dose of BAY 41-2272 was chosen according to our previous study (22,23), in which 2 mg/kg was the subdepressor dose. The Datascience telemetric system was used to monitor the blood pressure and heart rate of four unrestricted, conscious rats in each study group, as described (23).…”

“…The dose of BAY 41-2272 was chosen according to our previous study (22,23), in which 2 mg/kg was the subdepressor dose. The Datascience telemetric system was used to monitor the blood pressure and heart rate of four unrestricted, conscious rats in each study group, as described (23). On day 14, the survived rats were anesthetized with pentobarbital sodium and killed by drawing blood from the thoracic aorta.…”

“…Soluble guanylate cyclase (sGC) activated by nitric oxide has been shown to attenuate cardiovascular remodeling by elevating intracellular cGMP levels (6,18). We and others have previously reported that the pharmacological stimulation of sGC with BAY 41-2272 attenuated the adverse remodeling associated with systemic or pulmonary hypertension, suggesting that sGC-cGMP activation would be one of the important therapeutic targets for the treatment in the disorders (7,22,23). However, the interaction between sGC-cGMP signaling and HIF-1␣ expression during mechanical load/ischemia in the heart is unknown.…”