CaMKII inhibition in heart failure, beneficial, harmful, or both

Cheng J, Xu L, Lai D, Guilbert A, Lim HJ, Keskanokwong T, Wang Y. CaMKII inhibition in heart failure, beneficial, harmful, or both. Am J Physiol Heart Circ Physiol 302: H1454-H1465, 2012. First published January 27, 2012; doi: 10.1152/ajpheart.00812.2011.-Calmodulin- dependent protein kinase II (CaMKII) has been proposed to be a therapeutic target for heart failure (HF). However, the cardiac effect of chronic CaMKII inhibition in HF has not been well understood. We have tested alterations of Ca2+ handling, excitation-contraction coupling, and in vivo beta-adrenergic regulation in pressure-overload HF mice with CaMKII delta knockout (KO). HF was produced in wild-type (WT) and KO mice 1 wk after severe thoracic aortic banding (sTAB) with a continuous left ventricle (LV) dilation and reduction of ejection fraction for up to 3 wk postbanding. Cardiac hypertrophy was similar between WT HF and KO HF mice. However, KO HF mice manifested exacerbation of diastolic function and reduction in cardiac reserve to beta-adrenergic stimulation. Compared with WT HF, L-type calcium channel current (I-Ca) density in KO HF LV was decreased without changes in I-Ca activation and inactivation kinetics, whereas I-Ca recovery from inactivation was accelerated and Ca2+-dependent I-Ca facilitation, a positive staircase blunted in WT HF, was recovered. However, I-Ca response to isoproterenol was reduced. KO HF myocytes manifested dramatic decrease in sarcoplasmic reticulum (SR) Ca2+ leak and slowed cytostolic Ca2+ concentration decline. Sarcomere shortening was increased, but relaxation was slowed. In addition, an increase in myofilament sensitivity to Ca2+ and the slow skeletal muscle troponin I-to-cardiac troponin I ratio and interstitial fibrosis and a decrease in Na/Ca exchange function and myocyte apoptosis were observed in KO HF LV. CaMKII delta KO cannot suppress severe pressure-overload-induced HF. Although cellular contractility is improved, it reduces in vivo cardiac reserve to beta-adrenergic regulation and deteriorates diastolic function. Our findings challenge the strategy of CaMKII inhibition in HF.