AIMTo investigate the effects of U50,488H, a selective kappa-opioid receptor agonist, on mitochondrial fission induced by myocardial ischemia/reperfusion (MI/R) and its underlying mechanisms.
METHODSSprague Dawley rats were randomly assigned into six groups: Sham group; MI/R group; MI/R + U50,488H (MI/R + U) group; MI/R + nor-BNI (a selective kappa-opioid receptor antagonist) + U50,488H (MI/R + N + U) group; MI/R + Wortmannin (a PI3K inhibitor) + U50,488H (MI/R + W + U) group; and MI/R + MK2206 (an Akt inhibitor) + U50,488H (MI/R + M + U) group. Serum creatine kinase (CK) levels were determined by CK kit and myocardial infarct size was analyzed by TTC/Evens blue double staining. Western blotting was used to examine the expressions of phosphorylated PI3K, phosphorylated Akt (Ser 473) and phosphorylated Drp1 (Ser 637) and transmission electron microscope was used to evaluate mitochondrial morphology.
RESULTSCompared with the sham group, MI/R group exhibited increased serum CK (P<0.01), obvious infarct area and enhanced mitochondrial fission (P<0.01), which were accompanied by increased expressions of phosphorylated PI3K and phosphorylated Akt (P<0.05)and decreased expressions of phosphorylated Drp1 (P<0.01). Compared with MI/R group, MI/R + U group showed decreased serum CK (P<0.01), reduced myocardial infarct size (P<0.01), inhibited mitochondrial fission and increased expressions of phosphorylated PI3K, phosphorylated Akt and phosphorylated Drp1 (P<0.01). The above effects of U50,488H were blunted by nor-BNI, wortmannin or MK2206.
CONCLUSIONMI/R causes myocardial injury and mitochondrial fission. Activation of κ-opioid receptor reduces MI/R injury and inhibits mitochondrial fission by increasing the phosphorylation of Drp1 at Ser 637 via PI3K/Akt signaling.
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