title: Celastrol, an oral heat shock activator, ameliorates multiple animal disease models of cell death.
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.
authors.affiliation: Division of Cardiac Surgery, University of Maryland Medical Center, 110 S. Paca Street, 7th Floor, Baltimore, MD, 21201, USA.
authors.forename: Sudhish
authors.initials: S
authors.lastname: Sharma
authors.forename: Rachana
authors.initials: R
authors.lastname: Mishra
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Walker
authors.forename: Savitha
authors.initials: S
authors.lastname: Deshmukh
authors.forename: Manuela
authors.initials: M
authors.lastname: Zampino
authors.forename: Jay
authors.initials: J
authors.lastname: Patel
authors.forename: Mani
authors.initials: M
authors.lastname: Anamalai
authors.forename: David
authors.initials: D
authors.lastname: Simpson
authors.forename: Ishwar S
authors.initials: IS
authors.lastname: Singh
authors.forename: Shalesh
authors.initials: S
authors.lastname: Kaushal
authors.forename: Sunjay
authors.initials: S
authors.lastname: Kaushal
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000473:pathology; D017093:Liver Failure / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D053978:Pentacyclic Triterpenes; D013853:Thioacetamide / Q000633:toxicity; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C490017:Hsf1 protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D053978:Pentacyclic Triterpenes; D014157:Transcription Factors; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; D013853:Thioacetamide; D004317:Doxorubicin; C050414:celastrol