Abstract 3539: Pharmacological Stimulation of Soluble Guanylate Cyclase Prevents the Progression of Cardiac Fibrosis: Inhibitions of Myofibroblasts Transformation and Angiotensin-Converting Enzyme Synthesis
Background: Cardiac fibrosis resulting from exaggerated collagen accumulation is assumed to be a critical determinant of diastolic dysfunction. The increased cardiac production of angiotensin (Ang) II mediated via the induction of angiotensin-converting enzyme (ACE) stimulates the fibrosis, while natriuretic peptides/cGMP signaling attenuates the cardiovascular remodeling. The objective of this study was to explore the mechanism of soluble guanylate cyclase (sGC) stimulator BAY41–2272 leading to intracellular cGMP elevation on modulating the fibrotic process in pressure-overloaded rat heart.
Methods and Results: Eight-week-old male Wistar rats with hypertension induced by suprarenal aortic constriction (AC) were treated orally with 2 mg/kg/day of the sGC stimulator BAY41–2272 for 14 days (AC group, n=36; AC+BAY group, n=29). Both the systemic blood pressure (194±5 vs. 183±3 mmHg, mean±SEM) and the heart weight (4.5±0.1 vs. 4.3±0.2 mg/g body weight) remained unchanged by the treatment with BAY41–2272; however, AC-induced left ventricular (LV) accumulation of collagen in the perivascular area and myocardial interstitium was significantly (p<0.05) decreased by 30% and 46%, respectively with BAY41–2272. The reduction of collagen accumulation in the LV was accompanied by reducing the number of myofibroblasts determined by positive staining for α-smooth muscle actin (−87%, p<0.05), gene expressions of transforming growth factor (TGF)-β1 (−31%, p<0.05) and type 1 collagen (−48%, p<0.01) assessed by quantitative PCR. In addition, BAY41–2272 significantly (p<0.01) suppressed AC-induced increases of ACE mRNA (−47%) and of its enzymatic activity (6.2±0.4 vs. 2.3±0.5 mIU/mg protein), resulting in decreasing the Ang II concentration by 36% in the LV. The immunoreactivity of ACE in the overloaded heart was specifically localized in the cytoplasm of myofibroblasts distributed in the interstitium of LV. In cultured cardiac fibroblasts, BAY41–2272 (10−6 mol/L) or cGMP analogue 8-bromo cGMP (10−3 mol/L) directly inhibited the TGF-β1 induced myofibroblast transformation and ACE synthesis.
Conclusion: These results highlight the anti-fibrotic action of sGC/cGMP stimulation against the Ang II generation via myofibroblast transformation.