Abstract 17350: Altered PDE5 Targeting in Pathologic Hearts . Switching From NO-cGMP to ANP/BNP-cGMP

Abstract

Background: cGMP degrading phosphodiesterase 5 (PDE5) resides at Z-band of adult cardiac myocyte and regulates cell physiology in a compartmentalized manner. Under physiological condition, it hydrolyzes cGMP derived from endothelial nitric oxide synthase (eNOS) but not from natriuretic peptide (NP). In hypertrophied hearts, however, PDE5 localization becomes diffuse though its expression and activity increases. We tested the hypothesis that PDE5 alters its targeting to NP-cGMP from eNOS -cGMP via diffusing its localization in pathological hearts where NP is up-regulated and eNOS is dys-regulated. Methods and Results: While acute administration of PDE5 inhibitor (sildenafil, 100µg/kg/min for 5min) does not affect ANP(10µg) -stimulated myocardial cGMP level in control mouse hearts, it significantly increased ANP-cGMP in hearts exposed to 1wk pressure overload (TAC). We further tested this hypothesis by examining the impact of PDE5 over-expression on TAC response of eNOS null hearts (eNOS KO). eNOS KO animals were crossed with cardiac myocyte specific PDE5 over-expressor (PDE5-TG), and animals were subject to 1week TAC at 2 months of age. eNOS KO alone showed ameliorated hypertrophic response, associated with reduced myocardial superoxide level, while PDE5 TG alone revealed exacerbated response, as reported. Importantly, PDE5 over-expressed eNOS KO hearts (PDE5TG-eNOSKO) revealed significantly exacerbated cardiac remodeling (chamber dilation and increase in heart weight) and impaired cardiac function compared to eNOS KO hearts, though myocardial superoxide level remained low. Cardiac fetal gene expression (ANP), calcineurin activity (RCAN-1 expression) and transient receptor potential cation channel 6(TRPC6) expression were all significantly higher in PDE5TG-eNOSKO than eNOS KO. Conclusion: These results suggest that increased NP-cGMP in cardiac hypertrophy/failure might be targeted by PDE5 via altered localization of the enzyme. Myocyte PDE5 regulation of NP-cGMP plays a pivotal role in the pathogenesis of remodeling independently of myocardial superoxide level. Sildenafil may enhance ANP/BNP activated cGMP pathway in heart failure patients to exert its cardiac protective effect.