Protein kinase g i? inhibits pressure overload-induced cardiac remodeling and is required for the cardioprotective effect of sildenafil in vivo.

ABSTRACT: Cyclic GMP (cGMP) signaling attenuates cardiac remodeling, but it is unclear which cGMP effectors mediate these effects and thus might serve as novel therapeutic targets. Therefore, we tested whether the cGMP downstream effector, cGMP-dependent protein kinase G I? (PKGI?), attenuates pressure overload-induced remodeling in vivo.The effect of transaortic constriction (TAC)-induced left ventricular (LV) pressure overload was examined in mice with selective mutations in the PKGI? leucine zipper interaction domain. Compared with wild-type littermate controls, in response to TAC, these Leucine Zipper Mutant (LZM) mice developed significant LV systolic and diastolic dysfunction by 48 hours (n=6 WT sham, 6 WT TAC, 5 LZM sham, 9 LZM TAC). In response to 7-day TAC, the LZM mice developed increased pathologic hypertrophy compared with controls (n=5 WT sham, 4 LZM sham, 8 WT TAC, 11 LZM TAC). In WT mice, but not in LZM mice, phosphodiesterase 5 (PDE5) inhibition with sildenafil (Sil) significantly inhibited TAC-induced cardiac hypertrophy and LV systolic dysfunction in WT mice, but this was abolished in the LZM mice (n=3 WT sham, 4 LZM sham, 3 WT TAC vehicle, 6 LZM TAC vehicle, 4 WT TAC Sil, 6 LZM TAC Sil). And in response to prolonged, 21-day TAC (n=8 WT sham, 7 LZM sham, 21 WT TAC, 15 LZM TAC), the LZM mice developed markedly accelerated mortality and congestive heart failure. TAC induced activation of JNK, which inhibits cardiac remodeling in vivo, in WT, but not in LZM, hearts, identifying a novel signaling pathway activated by PKGI? in the heart in response to LV pressure overload.These findings reveal direct roles for PKGI? in attenuating pressure overload-induced remodeling in vivo and as a required effector for the cardioprotective effects of sildenafil.

SUBMITTER: Blanton RM 

PROVIDER: S-EPMC3541610 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature