In:
Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 1, No. 5 ( 2012-09-26)
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 Iα ( PKG Iα), attenuates pressure overload–induced remodeling in vivo. Methods and Results The effect of transaortic constriction ( TAC )–induced left ventricular ( LV ) pressure overload was examined in mice with selective mutations in the PKG Iα leucine zipper interaction domain. Compared with wild‐type littermate controls, in response to TAC , these L eucine Z ipper M utant ( 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 ( PDE 5) 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 PKG Iα in the heart in response to LV pressure overload. Conclusions These findings reveal direct roles for PKG Iα in attenuating pressure overload–induced remodeling in vivo and as a required effector for the cardioprotective effects of sildenafil.
Type of Medium:
Online Resource
ISSN:
2047-9980
DOI:
10.1161/JAHA.112.003731
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2012
detail.hit.zdb_id:
2653953-6
