Introduction: Patients with heart failure suffer extremely high rates of mortality, with up to half dying within 5 years of diagnosis. We previously have shown that protein expression of cardiac myosin light chain kinase (cMLCK) is reduced in decompensated pressure-overload-induced heart failure mouse models, and that transgenic (TG) mice overexpressing cMLCK are protected from the transition into decompensated hypertrophic heart failure. Ischemic heart failure is more prominent in humans; however, the role of cMLCK in this disease condition is not well understood.
Hypothesis: cMLCK proteins will be reduced in post-myocardial infarction (MI) mouse models of heart failure. TG mice overexpressing cMLCK will be protected against MI-induced cardiac dysfunction.
Methods and Results: We generated mouse models of ischemic heart failure by ligation of the left anterior descending (LAD) artery. Over 90% reduction in cMLCK protein was evident by 2 weeks after LAD ligation. To examine the effects of cMLCK on post-MI heart failure, two TG lines that overexpress cMLCK and cMLCK germline-ablated mice were examined and compared to control wild-type mice. Female mice (C57BL/6 background) were examined at 2 weeks and 3 months following MI. All mice displayed a large Q-wave in lead I and aVL in ECG, and infarct area size relative to the total left ventricle area size was between 42-48% in PicroSirius red-stained tissue sections obtained 1.5 mm below the ligation. TG mice overexpressing cMLCK showed a reduction of heart weight/body weight ratio (HW/BW) at 2 weeks [control 7.83 ± 0.6 mg/g (n=8); TG1, 6.26 ± 0.3 (n=6); TG2, 5.98 ± 0.3 (n=5), p<0.05] and 3 months [control 8.17 ± 0.6 (n=9); TG1, 6.08 ± 0.45 (n=10); TG2, 6.13 ± 0.52 (n=6), p<0.05] following MI. In contrast, cMLCK-ablated mice showed an increased HW/BW 2 weeks [control 7.83 ± 0.6 (n=8); cMLCK-ablation, 10.75 ± 1.0 (n=5), p<0.05], and no cMLCK-ablated mice survived to 3 months. Echocardiogram and MRI confirmed that contractility was improved in TG mice, while it was reduced in cMLCK-ablated mice relative to the controls following LAD ligation.
Conclusion: Our data suggest that cMLCK overexpression could be a therapeutic target for treatment and prevention of heart failures induced by MI or pressure overload.