Abstract
Cardiac hypertrophy is a well-known major risk factor for poor prognosis in patients with cardiovascular diseases. Dysregulation of intracellular Ca2+ is involved in the pathogenesis of cardiac hypertrophy. However, the precise mechanism underlying cardiac hypertrophy remains elusive. Here, we investigate whether pressure-overload induced hypertrophy can be induced by destabilization of cardiac ryanodine receptor (RyR2) through calmodulin (CaM) dissociation and subsequent Ca2+ leakage, and whether it can be genetically rescued by enhancing the binding affinity of CaM to RyR2. In the very initial phase of pressure-overload induced cardiac hypertrophy, when cardiac contractile function is preserved, reactive oxygen species (ROS)-mediated RyR2 destabilization already occurs in association with relaxation dysfunction. Further, stabilizing RyR2 by enhancing the binding affinity of CaM to RyR2 completely inhibits hypertrophic signaling and improves survival. Our study uncovers a critical missing link between RyR2 destabilization and cardiac hypertrophy.
Highlights
Cardiac hypertrophy is a well-known major risk factor for poor prognosis in patients with cardiovascular diseases
Based on the domainswitch hypothesis proposed by Ikemoto and his colleagues[6], we have shown that defective inter-domain interactions between the N-terminal domain (a.a. 1–600) and the central domain (a.a. 2000–2500) of RyR2, causes Ca2+ leakage through RyR2, inducing catecholaminergic polymorphic ventricular tachycardia (CPVT) and heart failure[7,8,9,10]
Peak systolic pressure increased to a similar extent after transverse aortic constriction (TAC) in both WT and V3599K mice, indicating that a comparable degree of pressure-overload was imposed on left ventricle (LV) (Supplementary Fig. 1b, Fig. 1c)
Summary
Cardiac hypertrophy is a well-known major risk factor for poor prognosis in patients with cardiovascular diseases. Several experimental studies have indicated that abolishment of the hypertrophic response to systolic pressure overload does not result in left ventricle (LV) decompensation, but rather in beneficial outcomes such as improved contractile function and prognosis[2,3]. We showed that domain unzipping causes a leaky Ca2+ channel via dissociation of CaM from RyR211,12, and that RyR2 function was restored by the introduction of modified CaM (+ Gly-Ser-His), which has a significantly higher binding affinity for RyR212 These findings strongly suggest that in the pathogenesis of heart failure, domain unzipping is allosterically coupled with conformational changes in the CaM binding domain (3583–3603), leading to CaM dissociation and subsequent Ca2+ leakage. Most disease mutations in the N-terminal region of
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