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SERCA overexpression reduces hydroxyl radical injury in murine myocardium

Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio

Submitted 14 December 2005 ; accepted in final form 22 June 2006

Hydroxyl radicals (·OH) are involved in the pathogenesis of ischemia-reperfusion injury and are observed in clinical situations, including acute heart failure, stroke, and myocardial infarction. Acute transient exposure to ·OH causes an intracellular Ca²⁺ overload and leads to impaired contractility. We investigated whether upregulation of sarcoplasmic reticulum Ca²⁺-ATPase function (SERCA) can attenuate ·OH-induced dysfunction. Small, contracting right ventricular papillary muscles from wild-type (WT) SERCA1a-overexpressing (transgenic, TG) and SERCA2a heterogeneous knockout (HET) mice were directly exposed to ·OH. This brief 2-min exposure led to a transient elevation of diastolic force (F_dia) and depression of developed force (F_dev). In WT mice, F_dia increased to 485 ± 49% and F_dev decreased to 11 ± 3%. In sharp contrast, in TG mice F_dia increased only to 241 ± 17%, whereas F_dev decreased only to 51 ± 5% (P < 0.05 vs. WT). In HET mice, F_dia rose more than WT (to 597 ± 20%, P < 0.05), whereas F_dev was reduced in a similar amount. After 45 min after ·OH exposure, a new steady state was reached: F_dev returned to 37 ± 6% and 32 ± 6%, whereas F_dia came back to 238 ± 28% and 292 ± 17% in WT and HET mice, respectively. In contrast, the sustained dysfunction was significantly less in TG mice: F_dia and F_dev returned to 144 ± 20% and 67 ± 6%, respectively. Before exposure to ·OH, there is decrease in phospholamban (PLB) phosphorylation at Ser16 (pPLBSer16) and PLB phosphorylation at Thr17 (pPLBThr17) in TG mice and an increase in pPLBSer16 and pPLBThr17 in HET mice versus WT. After exposure to ·OH there is decrease in pPLBSer16 in WT, TG, and HET mice but no significant change in the level of pPLBThr17 in any group. The results indicate that SERCA overexpression can reduce the ·OH-induced contractile dysfunction in murine myocardium, whereas a reduced SR Ca²⁺-ATPase activity aggravates this injury. Loss of pPLB levels at Ser16 likely amplifies the differences observed in injury response.

contractile function; calcium pump; ischemia; oxygen radicals

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