Fig. 9: Molecular mechanism of pressure-overload induced cardiac hypertrophy.

Pressure-overload first induces ROS production, which in turn induces CaM dissociation and Ca2+ leakage, thereby activating hypertrophic signaling mediated through the CaM-CaMKII and Ca²⁺-calcineurin pathway. V3599K mutation within CaM binding domain of RyR2 enhances CaM binding to RyR2, thereby inhibiting CaM dissociation and Ca²⁺ leakage despite ROS production due to pressure-overload, and thus hypertrophic signaling is not activated.