Abstract
Abstract Objectives Patients suffering from myocardial ischemia-reperfusion (IR) injuries usually have varying degrees of negatively-affecting comorbidities like hyperlipidemia. We evaluated the preconditioning effect of ginsenoside-Mc1 on reperfusion injury-induced myocardial arrhythmias, along with cardiac oxidative stress, endoplasmic reticulum stress protein expression, and histological damage in hyperlipidemic rats, and further, explore the role of JAK2/STAT3 activity. Methods Thirty-five Sprague–Dawley rats fed a high-fat diet for eight weeks. Ginsenoside-Mc1 (10 mg/dL, IP) was administered to hyperlipidemic rats daily for one month before IR injury. IR injury was induced by 35 min LAD coronary artery ligation and subsequent 60-min reperfusion. A selective JAK2 inhibitor (AG490) was injected before IR injury. Electrocardiography was recorded and myocardial arrhythmias (ventricular premature complexes, tachycardia, and fibrillation) were evaluated in the reperfusion phase according to Lambeth convention. Hematoxylin-Eosin staining, spectrophotometry, and Western blotting techniques were employed to measure the endpoints. Results IR injury in hyperlipidemic rats significantly increased the reperfusion-induced myocardial arrhythmias counts, timing, incidence, and severity. The expression of proteins of endoplasmic reticulum stress (p-PERK, p-eIF2α, CHOP), and oxidative stress marker malondialdehyde were significantly upregulated following IR induction, whereas antioxidant superoxide-dismutase and JAK2/STAT3 proteins expression significantly reduced, as compared with untreated-hyperlipidemic rats. Administration of ginsenoside-Mc1 to hyperlipidemic rats significantly corrected the arrhythmogenic feature of IR injury, reduced phosphorylation and expression of PERK, eIF2α, CHOP, and improved oxidative stress and histological changes. Interestingly, inhibition of the JAK2/STAT3 pathway via AG490 significantly abolished ginsenoside-Mc1-induced cardioprotection. Conclusions Taken together, ginsenoside-Mc1 exerts substantial anti-arrhythmogenic influences against myocardial IR injury in hyperlipidemic rats through activation of JAK2/STAT3 pathway and subsequent reduction of oxidative/endoplasmic reticulum stress.
Highlights
Despite recent advances in medicine and surgical interventions, ischemic heart disease is still the leading cause of death in the world [1]
Inhibition of JAK2 by AG490, did not have a significant effect on reperfusion-induced myocardial arrhythmias alone, inhibited the protective effect of Ginsenoside-compound Mc1 (GMC) on the number and duration of all three types of arrhythmias compared with the HL + myocardial infarction (MI) + GMC group (Figure 2)
Co-administration of AG490 abolished the effectiveness of GMC in reducing the incidence of these reperfusion-induced myocardial arrhythmias, especially ventricular fibrillation (VF) (p
Summary
Despite recent advances in medicine and surgical interventions, ischemic heart disease is still the leading cause of death in the world [1]. Zhang et al.: Ginsenoside-Mc1 reduces ischemia/reperfusion-induced cardiac arrhythmias myocardial arrhythmias are of determining factors in the survival or death of patients with myocardial infarction (MI) whose severity and incidence increase in the presence of hyperlipidemia [2,3,4]. JAK2/STAT3 has antioxidative features and belongs to the survivor activating factor enhancement (SAFE) signaling pathway that its activity is considerably reduced in the setting of hyperlipidemia [5, 8]. These findings highlight the significance of activation of this pathway in improving the clinical outcomes of MI patients
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