Constitutive activation of ERK1/2 signaling protects against myocardial ischemia via inhibition of mitochondrial fragmentation in the aging heart

Background: Studies have shown that the ability of the myocardium to tolerate ischemia becomes significantly compromised with age. During ischemia, several endogenous protective signals are activated to protect the heart from injury, among which extracellular-signal regulated kinase (ERK) 1/2 signaling has been established as playing a pivotal role. However, in aging hearts, the activation of ERK1/2 is compromised. Mitogen-activated protein kinase/ERK kinase (MEK) is a major regulator of ERK1/2 signaling. In the present study, we investigated whether transduction of CaMEK, a constitutively activated MEK, using adeno-associated virus serotype 9 (AAV9) could protect the aging heart against ischemia. Methods: Myocardial ischemia models were established in aging mice and senescent cardiomyocytes, and AAV9-mediated delivery of CaMEK was applied. Echocardiography, fluorescent staining, transmission electron microscopy, flow cytometry, and immunoblotting were used to explore the effects of CaMEK and their underlying mechanism. Results: AAV9-CaMEK activated ERK1/2 signaling and exerted cardioprotective effects against ischemia in aging hearts. Specifically, CaMEK transduction decreased dynamin-related protein-1 (Drp1) expression and phosphorylation at serine 616, resulting in improved mitochondrial morphology and function in aging ischemic hearts. Furthermore, CaMEK transduction exerted similar protective effects in senescent cardiomyocytes under hypoxia. Meanwhile, with the inhibition of ERK1/2 signaling in senescent cardiomyocytes under hypoxia, the opposite effects were observed, including an increase in mitochondrial fragmentation and aggravation of mitochondrial dysfunction and cell apoptosis. Conclusions: Our results suggested that AAV9-CaMEK alleviated ischemia-induced myocardium injury in the aging heart, at least in part, through inhibition of mitochondrial fragmentation. Therefore, AAV9- CaMEK is a potential intervention for prevention of ischemia-induced injury of the aging myocardium.