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Cell Stress Chaperones. 2014 Nov;19(6):801-12. doi: 10.1007/s12192-014-0504-9. Epub 2014 Mar 4.

Differential hypoxic tolerance is mediated by activation of heat shock response and nitric oxide pathway.

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  • 1Cellular Biochemistry Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054, India.


The fall in ambient oxygen pressure in high-altitude milieu elicits a wide range of physiological responses in the myocardium, which may differ from individual to individual. This condition, known as hypobaric hypoxia, invokes the cardioprotective heat shock response. The present study focuses on the role played by this ubiquitous response in mediating a differential tolerance to acute hypoxic stress. Sprague Dawley rats were exposed to simulated hypoxia equivalent to 223 mmHg pressure, screened on the basis of time taken for onset of a characteristic hyperventilatory response, and categorized as susceptible (<10 min), normal (10-25 min), or tolerant (>25 min). The tolerant animals displayed a significant upregulation of heat shock protein (Hsp)70/HSPA, evident through immunohistochemical staining of the cardiac tissue. The increased expression of transcription factor heat shock factor-1 led to the downstream activation of other chaperones, including Hsp90/HSPC, Hsp60/HSPD1, and Hsp27/HSPB1. The higher induction of HSPs in tolerant animals contributed to higher nitric oxide synthesis mediated by both endothelial nitric oxide synthase and inducible nitric oxide synthase activation. Conversely, susceptible animals showed significantly higher expression of the proinflammatory markers tumor necrosis factor alpha and nuclear factor kappa-light-chain enhancer of activated B cells in the myocardium. Evaluation of circulatory stress markers identified increased levels of reactive oxygen species, corticosterone and endothelin-1 in the susceptible animals highlighting their vulnerability to hypoxic stress. The heat shock response, through the action of chaperones and enhanced NO generation thus contributes substantially to the ability to sustain survival under acute sub lethal hypoxia.

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