Celastrol, an oral heat shock activator, ameliorates multiple animal disease models of cell death

Sudhish Sharma, Rachana Mishra, Brandon L. Walker, Savitha Deshmukh, Manuela Zampino, Jay Patel, Mani Anamalai, David L. Simpson, Ishwar S. Singh, Shalesh Kaushal, Sunjay Kaushal

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Protein homeostatic regulators have been shown to ameliorate single, loss-of-function protein diseases but not to treat broader animal disease models that may involve cell death. Diseases often trigger protein homeostatic instability that disrupts the delicate balance of normal cellular viability. Furthermore, protein homeostatic regulators have been delivered invasively and not with simple oral administration. Here, we report the potent homeostatic abilities of celastrol to promote cell survival, decrease inflammation, and maintain cellular homeostasis in three different disease models of apoptosis and inflammation involving hepatocytes and cardiomyocytes. We show that celastrol significantly recovers the left ventricular function and myocardial remodeling following models of acute myocardial infarction and doxorubicin-induced cardiomyopathy by diminishing infarct size, apoptosis, and inflammation. Celastrol prevents acute liver dysfunction and promotes hepatocyte survival after toxic doses of thioacetamide. Finally, we show that heat shock response (HSR) is necessary and sufficient for the recovery abilities of celastrol. Our observations may have dramatic clinical implications to ameliorate entire disease processes even after cellular injury initiation by using an orally delivered HSR activator.

Original languageEnglish (US)
Pages (from-to)185-201
Number of pages17
JournalCell Stress and Chaperones
Volume20
Issue number1
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • Cardiomyopathy
  • Celastrol
  • Heat shock response
  • HSPs
  • Myocardial infarct

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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    Sharma, S., Mishra, R., Walker, B. L., Deshmukh, S., Zampino, M., Patel, J., Anamalai, M., Simpson, D. L., Singh, I. S., Kaushal, S., & Kaushal, S. (2015). Celastrol, an oral heat shock activator, ameliorates multiple animal disease models of cell death. Cell Stress and Chaperones, 20(1), 185-201. https://doi.org/10.1007/s12192-014-0536-1