title: Metallothionein prevents intermittent hypoxia-induced cardiac endoplasmic reticulum stress and cell death likely via activation of Akt signaling pathway in mice.
abstract: Endoplasmic reticulum (ER) stress, an adaptive response normally, causes apoptotic cell death under pathological conditions. Cardiac ER stress and associated cell death involve in the inflammatory responses that often cause cardiac remodeling and dysfunction. Here we examined whether chronic intermittent hypoxia (IH) induces cardiac ER stress and associated cell death along with inflammatory response and if so, whether these effects can be affected by transgenic overexpression or deletion of metallothionein gene (MT-TG or MT-KO). IH exposures for 3 days to 4 weeks significantly increased cardiac ER stress and apoptosis, shown by the increased expression of GRP78, ATF6 and CHOP, the activation of caspase-12 and capase-3, and the decreased Bcl2/Bax expression ratio, predominantly in the 3rd week of IH exposures. These effects were significantly exacerbated in MT-KO mice, but completely prevented in MT-TG mice. In vitro mechanistic study with H9c2 cardiac and primary neonatal cardiomyocytes showed that MT protection from ER stress-induced apoptosis was mediated by up-regulating Akt phosphorylation since inhibition of Akt phosphorylation abolished MT's protection MT from ER stress and apoptosis. These findings suggest that chronic IH is able to induce cardiac ER stress, cell death and inflammation can be prevented by MT, probably via up-regulation of Akt function.
authors.affiliation: The Center of Cardiovascular Diseases at the First Hospital of Jilin University, Changchun 130021, China; KCHRI at the Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhou
authors.affiliation: The Center of Cardiovascular Diseases at the First Hospital of Jilin University, Changchun 130021, China; KCHRI at the Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Yin
authors.affiliation: The Center of Cardiovascular Diseases at the First Hospital of Jilin University, Changchun 130021, China. Electronic address: zhengyang@jlu.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: KCHRI at the Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA; Department of Ophthalmology, the Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Miao
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY, USA.
authors.forename: Wenke
authors.initials: W
authors.lastname: Feng
authors.affiliation: KCHRI at the Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Cai
authors.affiliation: KCHRI at the Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA; Department of Medicine, University of Louisville, Louisville, KY, USA. Electronic address: l0cai001@louisville.edu.
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death; D002460:Cell Line; D004334:Drug Administration Schedule; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D017353:Gene Deletion; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000473:pathology*; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000166:cytology*; D010100:Oxygen / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D008668:Metallothionein; D051057:Proto-Oncogene Proteins c-akt; D010100:Oxygen
keywords: Cardiomyopathy; ER stress; Intermittent hypoxia; Metallothionein; Obstructive sleep apnea