Extracorporeal shock waves protect cardiomyocytes from doxorubicin-induced cardiomyopathy by upregulating survivin via the integrin-ILK-Akt-Sp1/p53 axis

Abstract

Doxorubicin (DOX) is a widely used anti-cancer drug; however, it has limited application due to cardiotoxicity. Extracorporeal shock waves (ESW) have been suggested to treat inflammatory and ischemic diseases, but the concrete effect of ESW in DOX-induced cardiomyopathy remain obscure. After H9c2 cells were subjected to ESW (0.04 mJ/cm2), they were treated with 1 μM DOX. As a result, ESW protected cardiomyocytes from DOX-induced cell death. H9c2 cells treated with DOX downregulated p-Akt and survivin expression, whereas the ESW treatment recovered both, suggesting its anti-apoptotic effect. ESW activated integrin αvβ3 and αvβ5, cardiomyocyte mechanosensors, followed by upregulation of ILK, p-Akt and survivin levels. Further, Sp1 and p53 were determined as key transcriptional factors mediating survivin expression via Akt phosphorylation by ESW. In in vivo acute DOX-induced cardiomyopathy model, the echocardiographic results showed that group subjected to ESW recovered from acute DOX-induced cardiomyopathy; left ventricular function was improved. The immunohistochemical staining results showed increased survivin and Bcl2 expression in ESW + DOX group compared to those in the DOX-injected group. In conclusion, non-invasive shockwaves protect cardiomyocytes from DOX-induced cardiomyopathy by upregulating survivin via integrin-ILK-Akt-Sp1/p53 pathway. In vivo study proposed ESW as a new kind of specific and safe therapy against acute DOX-induced cardiomyopathy.