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C elastrol protects ischaemic myocardium through a heat shock response with up‐regulation of haeme oxygenase‐1
Author(s) -
Der Sarkissian S,
Cailhier JF,
Borie M,
Stevens LM,
Gaboury L,
Mansour S,
Hamet P,
Noiseux N
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12838
Subject(s) - celastrol , cytoprotection , heat shock protein , myofibroblast , heat shock , cardiac function curve , pharmacology , reactive oxygen species , nox4 , chemistry , medicine , cardiac fibrosis , oxidative stress , fibrosis , microbiology and biotechnology , biology , nadph oxidase , apoptosis , biochemistry , heart failure , gene
Background and Purpose C elastrol, a triterpene from plants, has been used in traditional oriental medicine to treat various diseases. Here, we investigated the cardioprotective effects of celastrol against ischaemia. Experimental Approach Protective pathways induced by celastrol were investigated in hypoxic cultures of H 9 c 2 rat cardiomyoblasts and in a rat model of myocardial infarction, assessed with echocardiographic and histological analysis. Key Results In H 9 c 2 cells, celastrol triggered reactive oxygen species ( ROS ) formation within minutes, induced nuclear translocation of the transcription factor heat shock factor 1 ( HSF 1) resulting in a heat shock response ( HSR ) leading to increased expression of heat shock proteins ( HSPs ). ROS scavenger N ‐acetylcysteine reduced expression of HSP 70 and HSP 32 (haeme oxygenase‐1, HO ‐1). Celast rol improved H 9 c 2 survival under hypoxic stress, and functional analysis revealed HSF 1 and HO ‐1 as key effectors of the HSR, induced by celastrol, in promoting cytoprotection. In the rat ischaemic myocardium, celastrol treatment improved cardiac function and reduced adverse left ventricular remodelling at 14 days. C elastrol triggered expression of cardioprotective HO ‐1 and inhibited fibrosis and infarct size. In the peri‐infarct area, celastrol reduced myofibroblast and macrophage infiltration, while attenuating up‐regulation of TGF ‐β and collagen genes. Conclusions and Implications C elastrol treatment induced an HSR through activation of HSF 1 with up‐regulation of HO ‐1 as the key effector, promoting cardiomyocyte survival, reduction of injury and adverse remodelling with preservation of cardiac function. C elastrol may represent a novel potent pharmacological cardioprotective agent mimicking ischaemic conditioning that could have a valuable impact in the treatment of myocardial infarction.