title: Is reduced SERCA2a expression detrimental or beneficial to postischemic cardiac function and injury? Evidence from heterozygous SERCA2a knockout mice.
abstract: Recent studies have demonstrated that increased expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) 2a improves myocardial contractility and Ca2+ handling at baseline and in disease conditions, including myocardial ischemia-reperfusion (I/R). Conversely, it has also been reported that pharmacological inhibition of SERCA might improve postischemic function in stunned hearts or in isolated myocardium following I/R. The goal of this study was to test how decreases in SERCA pump level/activity affect cardiac function following I/R. To address this question, we used a heterozygous SERCA2a knockout (SERCA2a+/-) mouse model with decreased SERCA pump levels and studied the effect of myocardial stunning (20-min ischemia followed by reperfusion) and infarction (30-min ischemia followed by reperfusion) following 60-min reperfusion. Our results demonstrate that postischemic myocardial relaxation was significantly impaired in SERCA2a+/- hearts with both stunning and infarction protocols. Interestingly, postischemic recovery of contractile function was comparable in SERCA2a+/- and wild-type hearts subjected to stunning. In contrast, following 30-min ischemia, postischemic contractile function was reduced in SERCA2a+/- hearts with significantly larger infarction. Rhod-2 spectrofluorometry revealed significantly higher diastolic intracellular Ca2+ in SERCA2a+/- hearts compared with wild-type hearts. Both at 30-min ischemia and 2-min reperfusion, intracellular Ca2+ levels were significantly higher in SERCA2a+/- hearts. Electron paramagnetic resonance spin trapping showed a similar extent of postischemic free-radical generation in both strains. These data provide direct evidence that functional SERCA2a level, independent of oxidative stress, is crucial for postischemic myocardial function and salvage during I/R.
authors.affiliation: Davis Heart and Lung Research Institute, and The Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: M A Hassan
authors.initials: MA
authors.lastname: Talukder
authors.forename: Anuradha
authors.initials: A
authors.lastname: Kalyanasundaram
authors.forename: Li
authors.initials: L
authors.lastname: Zuo
authors.forename: Murugesan
authors.initials: M
authors.lastname: Velayutham
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nishijima
authors.forename: Muthu
authors.initials: M
authors.lastname: Periasamy
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004452:Echocardiography; D004578:Electron Spin Resonance Spectroscopy; D005456:Fluorescent Dyes; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D017682:Myocardial Stunning / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000096:biosynthesis* / Q000235:genetics; D016277:Ventricular Function, Left / Q000502:physiology
chemical_list: D005456:Fluorescent Dyes; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium