心肌梗塞(MI)或心脏病发作是由心肌中的急性或慢性长期缺血状况引起的。尽管有几个危险因素与MI病理生理学相关,危险因素之一是氧气供应不平衡。由于MI病理生理学的复杂性,目前可用的MI疗法仍然不足。丙酮酸激酶M2(PKM2)与许多CVD病理有关。然而,针对PKM2的特异性药物干预在MI中的作用尚未研究。因此,在这项研究中,我们探索了化合物3K的效果,PKM2特异性抑制剂,在异丙肾上腺素诱导的急性MI模型中。在这项研究中,为了在大鼠中诱发MI,异丙肾上腺素(ISO)以100mg/kg的剂量在两天内以24小时的间隔给药。化合物3K(2和4mg/kg),在MI大鼠中施用以研究其心脏保护潜力。在最后一次给药化合物3K后,使用PV环系统记录ECG和血液动力学参数。心脏组织学,西方印迹,和血浆心脏损伤标志物进行了评估,以阐明潜在的机制。化合物3K的治疗显著减少ISO诱导的ECG改变,心室功能,心脏损伤,梗死面积,和心脏纤维化。化合物3K处理产生PKM1表达的显著增加和PKM2表达的降低。此外,HIF-1α,caspase-3,c-Myc,和PTBP1表达在化合物3K处理后也降低。这项研究证明了化合物3K在MI中的心脏保护潜力,及其心脏保护作用机制。
Myocardial infarction (MI) or heart attack arises from acute or chronic prolonged ischemic conditions in the myocardium. Although several risk factors are associated with MI pathophysiology, one of the risk factors is an imbalance in the oxygen supply. The current available MI therapies are still inadequate due to the complexity of MI pathophysiology. Pyruvate kinase M2 (PKM2) has been implicated in numerous CVDs pathologies. However, the effect of specific pharmacological intervention targeting PKM2 has not been studied in MI. Therefore, in this
study, we explored the effect of compound 3K, a PKM2-specific inhibitor, in
isoproterenol-induced acute MI model. In this
study, in order to induce MI in rats,
isoproterenol (ISO) was administered at a dose of 100 mg/kg over two days at an interval of 24 h. Specific PKM2 inhibitor, compound 3K (2 and 4 mg/kg), was administered in MI rats to investigate its cardioprotective potential. After the last administration of compound 3K, ECG and hemodynamic parameters were recorded using a PV-loop system. Cardiac histology, western blotting, and plasmatic cardiac damage markers were evaluated to elucidate the underlying mechanisms. Treatment of compound 3K significantly reduced ISO-induced alterations in ECG, ventricular functions, cardiac damage, infarct size, and cardiac fibrosis. Compound 3K treatment produced significant increase in PKM1 expression and decrease in PKM2 expression. In addition, HIF-1α, caspase-3, c-Myc, and PTBP1 expression were also reduced after compound 3K treatment. This
study demonstrates the cardioprotective potential of compound 3K in MI, and its mechanisms of cardioprotective action.