title: Enhanced gene expression of Na(+)/Ca(2+) exchanger attenuates ischemic and hypoxic contractile dysfunction.
abstract: Enhanced gene expression of the Na(+)/Ca(2+) exchanger in failing hearts may be a compensatory mechanism to promote influx and efflux of Ca(2+), despite impairment of the sarcoplasmic reticulum (SR). To explore this, we monitored intracellular calcium (Ca(i)(2+)) and cardiac function in mouse hearts engineered to overexpress the Na(+)/Ca(2+) exchanger and subjected to ischemia and hypoxia, conditions known to impair SR Ca(i)(2+) transport and contractility. Although baseline Ca(i)(2+) and function were similar between transgenic and wild-type hearts, significant differences were observed during ischemia and hypoxia. During early ischemia, Ca(i)(2+) was preserved in transgenic hearts but significantly altered in wild-type hearts. Transgenic hearts maintained 40% of pressure-generating capacity during early ischemia, whereas wild-type hearts maintained only 25% (P < 0.01). During hypoxia, neither peak nor diastolic Ca(i)(2+) decreased in transgenic hearts. In contrast, both peak and diastolic Ca(i)(2+) decreased significantly in wild-type hearts. The decline of Ca(i)(2+) was abbreviated in hypoxic transgenic hearts but prolonged in wild-type hearts. Peak systolic pressure decreased by nearly 10% in hypoxic transgenic hearts and >25% in wild-type hearts (P < 0.001). These data demonstrate that enhanced gene expression of the Na(+)/Ca(2+) exchanger preserves Ca(i)(2+) homeostasis during ischemia and hypoxia, thereby preserving cardiac function in the acutely failing heart.
authors.affiliation: Charles A. Dana Research Institute and Harvard-Thorndike Laboratories, Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: T G
authors.initials: TG
authors.lastname: Hampton
authors.forename: J F
authors.initials: JF
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: DeAngelis
authors.forename: I
authors.initials: I
authors.lastname: Amende
authors.forename: K D
authors.initials: KD
authors.lastname: Philipson
authors.forename: J P
authors.initials: JP
authors.lastname: Morgan
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003326:Coronary Circulation / Q000502:physiology; D003486:Cyanides / Q000494:pharmacology; D005260:Female; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010477:Perfusion; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics* / Q000378:metabolism
chemical_list: D003486:Cyanides; D019831:Sodium-Calcium Exchanger; D002118:Calcium