Abstract：
OBJECTIVE: Chronic sympathetic stimulation has been identified as a primary factor in the pathogenesis of cardiac hypertrophy (CH). However, there is no appropriate treatment available for the management of CH. Recently, it has been revealed that pyruvate kinase M2 (PKM2) plays a significant role in cardiac remodeling, fibrosis, and hypertrophy. However, the therapeutic potential of selective PKM2 inhibitor has not yet been explored in cardiac hypertrophy. Thus, in the current study, we have studied the cardioprotective potential of Compound 3K, a selective PKM2 inhibitor in isoproterenol-induced CH model.
METHODS: To induce cardiac hypertrophy, male Wistar rats were subcutaneously administered isoproterenol (ISO, 5 mg/kg/day) for 14 days. Compound 3K at dosages of 2 and 4 mg/kg orally was administered to ISO-treated rats for 14 days to explore its effects on various parameters like ECG, ventricular functions, hypertrophic markers, histology, inflammation, and protein expression were performed.
RESULTS: Fourteen days administration of ISO resulted in the induction of CH, which was evidenced by alterations in ECG, ventricular dysfunctions, increase in hypertrophy markers, and fibrosis. The immunoblotting of hypertrophy heart revealed the significant rise in PKM2 and reduction in PKM1 protein expression. Treatment with Compound 3K led to downregulation of PKM2 and upregulation of PKM1 protein expression. Compound 3K showed cardioprotective effects by improving ECG, cardiac functions, hypertrophy markers, inflammation, and fibrosis. Further, it also reduced cardiac expression of PKM2-associated splicing protein, HIF-1α, and caspase-3.
CONCLUSIONS: Our findings suggest that Compound 3K has a potential cardioprotective effect via PKM2 inhibition in isoproterenol-induced CH.
METHODS: To induce cardiac hypertrophy, male Wistar rats were subcutaneously administered isoproterenol (ISO, 5 mg/kg/day) for 14 days. Compound 3K at dosages of 2 and 4 mg/kg orally was administered to ISO-treated rats for 14 days to explore its effects on various parameters like ECG, ventricular functions, hypertrophic markers, histology, inflammation, and protein expression were performed.
RESULTS: Fourteen days administration of ISO resulted in the induction of CH, which was evidenced by alterations in ECG, ventricular dysfunctions, increase in hypertrophy markers, and fibrosis. The immunoblotting of hypertrophy heart revealed the significant rise in PKM2 and reduction in PKM1 protein expression. Treatment with Compound 3K led to downregulation of PKM2 and upregulation of PKM1 protein expression. Compound 3K showed cardioprotective effects by improving ECG, cardiac functions, hypertrophy markers, inflammation, and fibrosis. Further, it also reduced cardiac expression of PKM2-associated splicing protein, HIF-1α, and caspase-3.
CONCLUSIONS: Our findings suggest that Compound 3K has a potential cardioprotective effect via PKM2 inhibition in isoproterenol-induced CH.
摘要：
目的：慢性交感神经刺激已被确定为心脏肥大（CH）发病的主要因素。然而,没有适当的治疗方法可用于CH的管理。最近,丙酮酸激酶M2(PKM2)在心脏重构中起重要作用,纤维化，和肥大。然而,选择性PKM2抑制剂在心脏肥大中的治疗潜力尚未被研究.因此，在目前的研究中，我们已经研究了化合物3K的心脏保护潜力，异丙肾上腺素诱导的CH模型中的选择性PKM2抑制剂。
方法：为了诱导心肌肥厚，雄性Wistar大鼠皮下给予异丙肾上腺素(ISO，5mg/kg/天)持续14天。将2和4mg/kg剂量的化合物3K口服给予ISO处理的大鼠14天，以探索其对各种参数如ECG的影响。心室功能,肥大标记,组织学,炎症,并进行蛋白质表达。
结果：14天给予ISO导致CH的诱导，心电图的改变证明了这一点，心室功能障碍,肥大标记的增加，和纤维化。肥大心脏的免疫印迹显示PKM2的显着升高和PKM1蛋白表达的降低。用化合物3K处理导致PKM2的下调和PKM1蛋白表达的上调。化合物3K通过改善心电图表现出心脏保护作用，心功能,肥大标记,炎症,和纤维化。Further,它还减少了PKM2相关剪接蛋白的心脏表达，HIF-1α,和caspase-3。
结论:我们的发现表明化合物3K在异丙肾上腺素诱导的CH中通过PKM2抑制具有潜在的心脏保护作用。
方法：为了诱导心肌肥厚，雄性Wistar大鼠皮下给予异丙肾上腺素(ISO，5mg/kg/天)持续14天。将2和4mg/kg剂量的化合物3K口服给予ISO处理的大鼠14天，以探索其对各种参数如ECG的影响。心室功能,肥大标记,组织学,炎症,并进行蛋白质表达。
结果：14天给予ISO导致CH的诱导，心电图的改变证明了这一点，心室功能障碍,肥大标记的增加，和纤维化。肥大心脏的免疫印迹显示PKM2的显着升高和PKM1蛋白表达的降低。用化合物3K处理导致PKM2的下调和PKM1蛋白表达的上调。化合物3K通过改善心电图表现出心脏保护作用，心功能,肥大标记,炎症,和纤维化。Further,它还减少了PKM2相关剪接蛋白的心脏表达，HIF-1α,和caspase-3。
结论:我们的发现表明化合物3K在异丙肾上腺素诱导的CH中通过PKM2抑制具有潜在的心脏保护作用。
