title: The sarcoplasmic reticulum luminal thiol oxidase ERO1 regulates cardiomyocyte excitation-coupled calcium release and response to hemodynamic load.
abstract: Two related ER oxidation 1 (ERO1) proteins, ERO1α and ERO1β, dynamically regulate the redox environment in the mammalian endoplasmic reticulum (ER). Redox changes in cysteine residues on intralumenal loops of calcium release and reuptake channels have been implicated in altered calcium release and reuptake. These findings led us to hypothesize that altered ERO1 activity may affect cardiac functions that are dependent on intracellular calcium flux. We established mouse lines with loss of function insertion mutations in Ero1l and Ero1lb encoding ERO1α and ERO1β. The peak amplitude of calcium transients in homozygous Ero1α mutant adult cardiomyocytes was reduced to 42.0 ± 2.2% (n=10, P ≤ 0.01) of values recorded in wild-type cardiomyocytes. Decreased ERO1 activity blunted cardiomyocyte inotropic response to adrenergic stimulation and sensitized mice to adrenergic blockade. Whereas all 12 wild-type mice survived challenge with 4 mg/kg esmolol, 6 of 8 compound Ero1l and Ero1lb mutant mice succumbed to this level of β adrenergic blockade (P ≤ 0.01). In addition, mice lacking ERO1α were partially protected against progressive heart failure in a transaortic constriction model [at 10 wk postprocedure, fractional shortening was 0.31 ± 0.02 in the mutant (n=20) vs. 0.23 ± 0.03 in the wild type (n=18); P ≤ 0.01]. These findings establish a role for ERO1 in calcium homeostasis and suggest that modifying the lumenal redox environment may affect the progression of heart failure.
authors.affiliation: Kimmel Center for Biology and Medicine, Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: King-Tung
authors.initials: KT
authors.lastname: Chin
authors.forename: Guoxin
authors.initials: G
authors.lastname: Kang
authors.forename: Jiaxiang
authors.initials: J
authors.lastname: Qu
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Gardner
authors.forename: William A
authors.initials: WA
authors.lastname: Coetzee
authors.forename: Ester
authors.initials: E
authors.lastname: Zito
authors.forename: Glenn I
authors.initials: GI
authors.lastname: Fishman
authors.forename: David
authors.initials: D
authors.lastname: Ron
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling; D015687:Cell Hypoxia; D004721:Endoplasmic Reticulum / Q000378:metabolism; D056966:Excitation Contraction Coupling / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism*; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D006439:Hemodynamics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D016254:Mutagenesis, Insertional; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D010084:Oxidation-Reduction; D010088:Oxidoreductases; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D006023:Glycoproteins; D011412:Propanolamines; C491864:Ero1l protein, mouse; D010088:Oxidoreductases; D050862:Oxidoreductases Acting on Sulfur Group Donors; C036604:esmolol