Abstract 1831: Phosphodiesterase-5 Inhibition Prevents Cardiac Hypertrophy, Independently of the Calcineurin Pathway

Abstract

Cyclic GMP and its downstream kinase protein kinase G (PKG) negatively regulate cardiac hypertrophy. To date the only documented target of this cascade is the serine-threonine phosphatase calcineurin (Cn), whose activation is central to the development of pathologic cardiac hypertrophy. Recently, we reported that phosphodiesterase 5 (PDE5) inhibition (sildenafil, SIL) activates myocardial PKG and prevents pressure-overload induced hypertrophy by suppressing multiple cascades including Cn. To test the centrality of Cn signaling to the in vivo anti-hypertrophic effects of SIL, we subjected mice deficient in the Cn-A β subunit (CnA β −/− ) to severe trans-aortic constriction (TAC) with or without SIL (100mg/kg/day, p.o.) for 3-wks. TAC induced less hypertrophy that was more concentric in CnA β −/− vs WT-controls (50% vs 100% increase in heart mass/tibia length, p<0.03). SIL completely blocked the hypertrophic response and fully normalized fetal gene re-expression (e.g ANP, BNP and β MHC) in CnA β −/− TAC hearts, while it inhibited LVH by 60% and suppressed ANP and β MHC in WT-TAC hearts. SIL improved cardiac systolic and diastolic function (pressure-volume analysis) in CnA β −/− TAC hearts much as in WT-TAC hearts. In CnA β −/− TAC hearts, phosphorylated calcium calmodulin kinase II (CaMK II) increased 10-fold versus only a 2-fold rise in WT-TAC, whereas Akt and glycogen synthase kinase 3 β (GSK3 β ) activation were comparable between groups. Extracellular response kinase (ERK) 1/2 was activated with TAC in WT hearts only. Importantly, SIL stimulated myocardial PKG and markedly inhibited the activation of CaMKII, Akt and GSK3 β similarly in both groups exposed to TAC. Thus, Cn is not required for the anti-hypertrophic effects of SIL. Though TAC-induced hypertrophy is less in CnA β −/− mice, SIL remains effective in suppressing the residual response by targeting alternative cascades such as CaMK II. These findings suggest that SIL acts either on multiple pathways concurrently, or at a node proximal to these pathways likely at or near the sarcolemmal membrane.