Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Beijing Lab for Cardiovascular Precision Medicine, Department of Pathology, Capital Medical University, Beijing, China.
Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
J Cell Mol Med. 2021 Nov;25(22):10711-10723. doi: 10.1111/jcmm.17007. Epub 2021 Oct 23.
Hypertensive cardiac remodelling is a common cause of heart failure. However, the molecular mechanisms regulating cardiac remodelling remain unclear. Pyruvate kinase isozyme type M2 (PKM2) is a key regulator of the processes of glycolysis and oxidative phosphorylation, but the roles in cardiac remodelling remain unknown. In the present study, we found that PKM2 was enhanced in angiotensin II (Ang II)-treated cardiac fibroblasts and hypertensive mouse hearts. Suppression of PKM2 by shikonin alleviated cardiomyocyte hypertrophy and fibrosis in Ang-II-induced cardiac remodelling in vivo. Furthermore, inhibition of PKM2 markedly attenuated the function of cardiac fibroblasts including proliferation, migration and collagen synthesis in vitro. Mechanistically, suppression of PKM2 inhibited cardiac remodelling by suppressing TGF-β/Smad2/3, Jak2/Stat3 signalling pathways and oxidative stress. Together, this study suggests that PKM2 is an aggravator in Ang-II-mediated cardiac remodelling. The negative modulation of PKM2 may provide a promising therapeutic approach for hypertensive cardiac remodelling.
高血压性心脏重构是心力衰竭的常见原因。然而，调节心脏重构的分子机制仍不清楚。丙酮酸激酶同工酶 M2（PKM2）是糖酵解和氧化磷酸化过程的关键调节因子，但在心脏重构中的作用尚不清楚。在本研究中，我们发现 PKM2 在血管紧张素 II（Ang II）处理的心肌成纤维细胞和高血压小鼠心脏中增强。通过紫草素抑制 PKM2 可减轻 Ang II 诱导的体内心脏重构中的心肌细胞肥大和纤维化。此外，抑制 PKM2 可显著减弱心肌成纤维细胞的功能，包括增殖、迁移和胶原合成。在机制上，抑制 PKM2 通过抑制 TGF-β/Smad2/3、Jak2/Stat3 信号通路和氧化应激来抑制心脏重构。总之，这项研究表明 PKM2 是 Ang II 介导的心脏重构的加重因素。PKM2 的负调控可能为高血压性心脏重构提供一种有前途的治疗方法。
