<br>化合物 3K 通过抑制丙酮酸激酶 M2 (PKM2) 途径减轻异丙肾上腺素诱导的心脏肥大,Life Sciences

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化合物 3K 通过抑制丙酮酸激酶 M2 (PKM2) 途径减轻异丙肾上腺素诱导的心脏肥大
Life Sciences ( IF 5.2 ) Pub Date : 2024-06-13 , DOI: 10.1016/j.lfs.2024.122837
Mohd Rihan ₁ , Shyam Sunder Sharma ₁

Affiliation

慢性交感神经刺激已被确定为心脏肥大（CH）发病机制的主要因素。然而，尚无适当的治疗方法可用于治疗 CH。最近，研究发现丙酮酸激酶 M2 (PKM2) 在心脏重塑、纤维化和肥大中发挥重要作用。然而，选择性 PKM2 抑制剂在心脏肥大中的治疗潜力尚未得到探索。因此，在本研究中，我们研究了化合物 3K（一种选择性 PKM2 抑制剂）在异丙肾上腺素诱导的 CH 模型中的心脏保护潜力。为了诱导心脏肥大，雄性 Wistar 大鼠皮下注射异丙肾上腺素（ISO，5 mg/kg/天）14 天。将2和4 mg/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心电图、心室功能、肥大标志物、组织学、炎症和蛋白质表达的影响。 ISO 给药 14 天导致 CH 的诱导，心电图改变、心室功能障碍、肥大标志物增加和纤维化证明了这一点。肥大心脏的免疫印迹显示 PKM2 蛋白表达显着升高，而 PKM1 蛋白表达显着降低。用化合物3K治疗导致PKM2蛋白表达下调和PKM1蛋白表达上调。化合物 3K 通过改善心电图、心脏功能、肥大标志物、炎症和纤维化显示出心脏保护作用。此外，它还降低了 PKM2 相关剪接蛋白、HIF-1α 和 caspase-3 的心脏表达。我们的研究结果表明，Compound 3K 在异丙肾上腺素诱导的 CH 中具有潜在的心脏保护作用 PKM2 抑制作用。

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Compound 3K attenuates isoproterenol-induced cardiac hypertrophy by inhibiting pyruvate kinase M2 (PKM2) pathway

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. 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. 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. Our findings suggest that Compound 3K has a potential cardioprotective effect PKM2 inhibition in isoproterenol-induced CH.

更新日期：2024-06-13

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