title: Amelioration of ER stress by 4-phenylbutyric acid reduces chronic hypoxia induced cardiac damage and improves hypoxic tolerance through upregulation of HIF-1α.
abstract: While endoplasmic reticulum (ER) stress has been observed in several human diseases, few studies have reported the involvement of ER stress in chronic hypoxia (CH) induced cardiac damage. Hypoxia, such as that prevalent at high altitude (HA), forms the underlying cause of several maladies including cardiovascular diseases. While the role of hypoxia inducible factor-1 (HIF-1α) in the adaptive responses to hypoxia is known, the role of the unfolded protein response (UPR) is only recently being explored in the HA pathophysiologies. The present study investigates the effect of ER stress modulation on CH mediated injury and the cardioprotective action of 4-phenylbutyric acid (PBA) in enhancing survival response under hypoxia. Here, we observed that exposure of rats, for 1, 7 and 14days CH to a simulated altitude of 7620m, led to cardiac hypertrophy and significant protein oxidation. This induced the activation of UPR signaling mechanisms, mediated by PERK, IRE1α and ATF6. By 14days, there was a marked upregulation of apoptosis, evident in increased CHOP and caspase-3/9 activity. PBA reduced CH induced right ventricular enlargement and apoptosis. Further, in contrast to tunicamycin, PBA considerably enhanced hypoxic tolerance. An elevation in the level of antioxidant enzymes, HIF-1α and its regulated proteins (HO-1, GLUT-1) was observed in the PBA administered animals, along with a concomitant suppression of UPR markers. Our study thus emphasizes upon the attenuation of ER stress by PBA as a mechanism to diminish CH induced cardiac injury and boost hypoxic survival, providing an insight into the novel relationship between the HIF-1α and UPR under hypoxia.
authors.affiliation: Cellular Biochemistry Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi 110 054, India.
authors.forename: Kanika
authors.initials: K
authors.lastname: Jain
authors.affiliation: Cellular Biochemistry Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi 110 054, India. Electronic address: geethasuryakumar@yahoo.com.
authors.forename: Geetha
authors.initials: G
authors.lastname: Suryakumar
authors.affiliation: Cellular Biochemistry Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi 110 054, India.
authors.forename: Lilly
authors.initials: L
authors.lastname: Ganju
authors.affiliation: Cellular Biochemistry Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi 110 054, India.
authors.forename: Shashi Bala
authors.initials: SB
authors.lastname: Singh
mesh_terms: D000531:Altitude; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002908:Chronic Disease; D019610:Cytoprotection; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D018832:Molecular Chaperones / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010654:Phenylbutyrates / Q000494:pharmacology*; D050050:Protein Carbonylation / Q000187:drug effects; D059748:Proteolysis; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018832:Molecular Chaperones; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid
keywords: Apoptosis; ER stress; HIF-1α; Hypoxia; PBA