Abstract 5394: H11 Kinase/Hsp22, A Novel Mechanism in the Transition to Heart Failure
H11 kinase/Hsp22 (H11K), a heat shock protein expressed mainly in the heart, is up-regulated upon pressure overload in animal models and in patients. Cardiac-specific over-expression of H11K in a transgenic model induces cardiac hypertrophy with normal function and cardioprotection against lethal ischemia. We tested the hypothesis that H11K deletion would accelerate the transition into heart failure (HF) following chronic pressure overload. An H11K knockout (KO) mouse was generated, which survives after birth with normal Mendelian distribution. In basal conditions (4/group), no differences were found between KO and wild type (WT) in terms of left ventricular (LV) mass (LV/tibial length: 4.6±0.3 vs 4.1±0.1, NS) or LV ejection fraction (69±3% vs 70±1%, NS). After two weeks aortic banding the KO mice, compared to WT, showed a slightly greater mass (LV/tibial length: 8.2±0.3 vs 7.0±0.4, P<0.05), impaired LV function (LV ejection fraction: 45±3% vs 62±5%, P<0.05), and signs of HF (lung weight/TL: 16.2±3 vs 7.7±0.4, P<0.05; LV end-diastolic pressure: 22±4 mmHg vs 7±4 mmHg, P<0.05). 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 more than doubled (P<0.01, n=3/group) in KO (61±2.8%) compared to WT (26±2.8%). Therefore, H11K deletion does not affect basal cardiac function but it precipitates the transition into HF following pressure overload, potentially by loss of H11K cardioprotective action.
This research has received full or partial funding support from the American Heart Association, AHA National Center.