Abstract 1831: Phosphodiesterase-5 Inhibition Prevents Cardiac Hypertrophy, Independently of the Calcineurin Pathway
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-Aβ subunit (CnAβ−/−) 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 CnAβ −/− 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 βMHC) in CnAβ −/−TAC hearts, while it inhibited LVH by 60% and suppressed ANP and βMHC in WT-TAC hearts. SIL improved cardiac systolic and diastolic function (pressure-volume analysis) in CnAβ −/− TAC hearts much as in WT-TAC hearts. In CnAβ −/− 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 3β (GSK3β) 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 GSK3βsimilarly 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 CnAβ −/− 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.