Expression of SERCA isoform with faster Ca²⁺ transport properties improves postischemic cardiac function and Ca²⁺ handling and decreases myocardial infarction

Abstract

Myocardial ischemia-reperfusion (I/R) injury is associated with contractile dysfunction, arrhythmias, and myocyte death. Intracellular Ca(2+) overload with reduced activity of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) is a critical mechanism of this injury. Although upregulation of SERCA function is well documented to improve postischemic cardiac function, there are conflicting reports where pharmacological inhibition of SERCA improved postischemic function. SERCA2a is the primary cardiac isoform regulating intracellular Ca(2+) homeostasis; however, SERCA1a has been shown to substitute SERCA2a with faster Ca(2+) transport kinetics. Therefore, to further address this issue and to evaluate whether SERCA1a expression could improve postischemic cardiac function and myocardial salvage, in vitro and in vivo myocardial I/R studies were performed on SERCA1a transgenic (SERCA1a(+/+)) and nontransgenic (NTG) mice. Langendorff-perfused hearts were subjected to 30 min of global ischemia followed by reperfusion. Baseline preischemic coronary flow and left ventricular developed pressure were significantly greater in SERCA1a(+/+) mice compared with NTG mice. Independent of reperfusion-induced oxidative stress, SERCA1a(+/+) hearts demonstrated greatly improved postischemic (45 min) contractile recovery with less persistent arrhythmias compared with NTG hearts. Morphometry showed better-preserved myocardial structure with less infarction, and electron microscopy demonstrated better-preserved myofibrillar and mitochondrial ultrastructure in SERCA1a(+/+) hearts. Importantly, intraischemic Ca(2+) levels were significantly lower in SERCA1a(+/+) hearts. The cardioprotective effect of SERCA1a was also observed during in vivo regional I/R with reduced myocardial infarct size after 24 h of reperfusion. Thus SERCA1a(+/+) hearts were markedly protected against I/R injury, suggesting that expression of SERCA 1a isoform reduces postischemic Ca(2+) overload and thus provides potent myocardial protection.

Mitigation of muscular dystrophy in mice by SERCA overexpression in skeletal muscle

“…Interestingly, cardiac overexpression of SERCA1 also resulted in similar enhancement in cardiac function at baseline (37). In dystrophic muscle, the kinetics of SR Ca 2+ handling are likely depressed, potentially due to reduced SERCA activity (16)(17)(18)38).…”

eNOS is required for acute in vivo ischemic preconditioning of the heart: effects of ischemic duration and sex

“…In vivo myocardial I/R protocol was performed as previously described with slight modifications (48). Briefly, mice were anesthetized with a mixture of intraperitoneal ketamine (55 mg/kg) and xylazine (15 mg/kg).…”

Impact of citrate pretreatment on ventricular arrhythmia and myocardial capase-3 expression in ischemia/reperfusion injury

“…Triggers of apoptosis induce a caspase cascade, with caspase-3 performing a key function. Apoptosis and caspase-3 overexpression appear in the same region of the ischemic myocardial area (Talukder et al, 2007;Dow et al, 2009). Our results showed that myocardial cell apoptosis increased during the I/R process, but caspase-3 protein expression decreased in the citrate-treated groups.…”