Abstract 27: A Novel Variant Cell Cycle-related Kinase Provides Cardioprotection Upon Pressure Overload By Promoting Autophagy

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Background: One approach to discovering novel targets for heart failure (HF) therapy is to determine which genes are down-regulated in HF. We found previously that cardiac cell cycle-related kinase (cCCRK), a novel variant of CCRK in heart, is down-regulated by 50% in failed heart vs control, and over-expression of the cCCRK decreases the susceptibility of cardiac myocytes to pro-apoptotic agents, indicating that cCCRK might be a potential target of HF. We tested here our hypothesis that cCCRK provides cardiaoprotection upon stress of pressure overload.

Methods and Results: A transgenic (TG) mouse model with cardiac-specific over-expression of cCCRK was generated. Both wild type (WT) and TG mice were submitted to aortic banding for two weeks. In basal condition, no significant differences were found between TG and WT in left ventricular (LV) /body weight (3.5±0.3 in TG vs. 3.6±0.2 in WT) and contractility (LV ejection fraction (EF): 72.7±1 in TG vs 72.7±1 % in WT). After two weeks banding, EF was significantly impaired in the WT (62±2%, P<0.05 vs sham), but maintained in the TG (71.1±2 %, P<0.05 vs WT). Lung /tibial length ratio, an index of pulmonary congestion and heart failure was lower (p<0.05) in banded heart of TG (9.9±1) vs WT (13.1±1). A cyclin-dependent kinase inhibitor p21, which is also an important regulator of autophagy, was significantly upregulated in TG by 5 folds vs WT (P<0.05). Overexpression of cCCRK in rat neonatal cardiomyocyte (RNC) stimulated autophagy in a dose-dependent manner representing by the enhanced LC3-II (autophagy marker) (P<0.05 vs β-gal). To test its effect in response to stress, glucose starvation was induced to in RNC. cCCRK induced an early response to cardiac stress via the activation of autophagy by increasing LC3-II at 0.5 hrs vs the control at 2 hrs after starvation.

Conclusions: over-expression of cCCRK in heart provides protection against pressure overload via activation of autophagy signaling pathways.

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