Abstract 847: Deletion Of H11 Kinase Impairs Cardiac Cell Growth And Survival
H11 kinase (H11K) is a small heat shock protein expressed predominantly in the heart, the expression of which increases in both cardiac overload and ischemic heart disease in animal models and in patients. We generated an H11K knockout (KO) mouse to test the hypothesis whether H11K is required for cardiac cell growth and survival in response to overload or ischemic stress. The first exon of the H11K gene was flanked by LoxP sites and targeted for deletion upon crossing with a CMV-Cre mouse, providing a global KO where H11K is deleted in every cell type. PCR screening revealed the presence of homozygous KO mice at a normal Mendelian distribution. Whereas the KO mouse has lost any expression of H11K, the expression of the protein was comparable between WT and heterozygous mice. To test whether H11K participates in cardiac cell growth, both WT and KO mice were submitted to aortic banding for two weeks. After two weeks overload, the left ventricle/tibial length was 10.2±0.7 in banded WT versus 8.6±0.3 in banded KO (P<0.1, n=3/group), and 6.5±0.5 in sham animals (P<0.05 versus both banded groups). To test whether H11K participates in cardiac cell survival, both WT and KO mice were submitted to 30 min no-flow ischemia of the left anterior descending artery followed by 24 hours reperfusion and staining for the area-at-risk (AAR) and infarct size (IS). Whereas AAR was comparable between groups, the IS/AAR was 26±2.8% in WT and 61±2.8% in KO (P<0.01, n=3/group). After a protocol of ischemic preconditioning (6 episodes of 4 min ischemia/4 min reperfusion) followed by 30 min ischemia, the IS/AAR was 8.5±2.8% in WT and 23±2.8% in KO, i.e., a reduction of IS by about 70% in both groups. Therefore, H11K expression is necessary for the full development of hypertrophy in response to pressure overload and for myocyte survival following myocardial ischemia. However, H11K does not appear to be involved in the first window of preconditioning.