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.

心脏肥大是心血管疾病患者预后不良的众所周知的主要危险因素。细胞内Ca ^2+的失调与心脏肥大的发病机制有关。但是，心脏肥大的确切机制仍然难以捉摸。在这里，我们调查是否可以通过钙调蛋白（CaM）分解和随后的Ca ²⁺破坏心脏瑞丹碱受体（RyR2）的稳定性，从而诱发压力超负荷引起的肥大泄漏，以及是否可以通过增强CaM与RyR2的结合亲和力进行基因挽救。在压力超负荷引起的心脏肥大的最初阶段，当心脏收缩功能得以维持时，与松弛功能障碍相关的活性氧（ROS）介导的RyR2失稳已经发生。此外，通过增强CaM与RyR2的结合亲和力来稳定RyR2，可以完全抑制肥大信号并提高生存率。我们的研究揭示了RyR2不稳定与心脏肥大之间的关键缺失环节。