Abstract 3601: Deletion of H11 Kinase/Hsp22 Impairs the Activation of Survival Signaling Pathways and Precipitates Heart Failure During Pressure Overload
H11 kinase/Hsp22 (H11K) is a heat shock protein expressed mainly in the heart, which is up-regulated both in conditions of pressure overload and myocardial ischemia in animal models and in patients. Over-expression of H11K induces cardiac hypertrophy with normal function through activation of a survival pathway triggered by the bone morphogenetic receptor (BMPr) and Akt, resulting in the activation of the inducible isoform of nitric oxide synthase (iNOS). We tested the hypothesis that activation of this pathway is necessary for the normal adaptation of the heart to pressure overload, using an H11K knockout (KO) mouse model that we generated. In basal conditions (4/group), no significant differences were found between KO and wild type (WT) in terms of left ventricular (LV) size (LV end-diastolic diameter: 4.0±0.05 vs 3.9±0.2 mm in KO vs WT, respectively), myocyte cross-sectional area (298±16 vs 278±5 μm2), thickness (septal wall: 0.8±0.03 vs 0.8±0.07 mm), contractility (LV ejection fraction: 66±2 vs 72±2 %), and lung weight/tibial length (8±1 vs 7±1). Additional mice were subjected to transverse aortic banding (TAC) for 3 days to determine the activation of survival signaling pathways, or for 2 weeks to determine cardiac function and mortality. After 3 days TAC, KO mice showed significantly (P<0.05) less phosphorylation of Smad 1/5, a marker of BMPr activation (56% of WT), Akt (60% of WT), ERK 1/2 (p42: 10% of WT; p44: 12% of WT) and almost abolished expression of iNOS (7% of WT, P<0.01). After 2 weeks TAC, KO compared to WT showed significantly (P<0.05) less increase in wall thickening (septal wall: 1.05±0.08 vs 1.28±0.04 mm in KO vs WT), impaired cardiac contractility (LV ejection fraction: 41±3 vs 51±3 %), smaller cell size (376±25 vs 471±25 μm2), increased collagen accumulation (25.1±1.7 vs 15.3±2.4 % of myocardial surface), signs of heart failure (lung weight/tibial length: 22±1 vs 16±2), and doubling in mortality (53% vs 27%, P<0.01). Therefore, H11K deletion blocks the activation of a BMPr-dependent survival pathway upon initiation of pressure overload, resulting in impaired Akt, ERK 1/2 and iNOS activation, which precipitates the transition into heart failure and increases mortality.