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

  • Sci Rep. 2019 Aug 21;9(1):12149. doi: 10.1038/s41598-019-48470-0.
Ji Yoon Lee  1 ,  Jihwa Chung  1 ,  Kyoung Hwa Kim  1 ,  Shung Hyun An  1 ,  Jeong-Eun Yi  2 ,  Kyoung Ae Kwon  3 ,  Kihwan Kwon  4  5
Affiliations
  • 1. Medical Research Institute, School of Medicine, Ewha Womans University, Seoul, 158-710, Korea.
  • 2. Department of Internal Medicine, Cardiology Division, School of medicine, Ewha Womans University, Seoul, 158-710, Korea.
  • 3. Graduate School of Industrial Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.
  • 4. Medical Research Institute, School of Medicine, Ewha Womans University, Seoul, 158-710, Korea. [email protected].
  • 5. Department of Internal Medicine, Cardiology Division, School of medicine, Ewha Womans University, Seoul, 158-710, Korea. [email protected].
PMID: 31434946 DOI: 10.1038/s41598-019-48470-0
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.

Products