Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, 510080, China.
Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, 510080, China.
Biochem Biophys Res Commun. 2021 Jan 1;534:933-940. doi: 10.1016/j.bbrc.2020.10.070. Epub 2020 Nov 6.
Myocardial ischemia-reperfusion (MIR) represents critical challenge for the treatment of acute myocardial infarction diseases. Presently, identifying the molecular basis revealing MIR progression is scientifically essential and may provide effective therapeutic strategies. Phosphoglycerate mutase 1 (PGAM1) is a key aerobic glycolysis enzyme, and exhibits critical role in mediating several biological events, such as energy production and inflammation. However, whether PGAM1 can affect MIR is unknown. Here we showed that PGAM1 levels were increased in murine ischemic hearts. Mice with cardiac knockout of PGAM1 were resistant to MIR-induced heart injury, evidenced by the markedly reduced infarct volume, improved cardiac function and histological alterations in cardiac sections. In addition, inflammatory response, apoptosis and fibrosis in hearts of mice with MIR operation were significantly alleviated by the cardiac deletion of PGAM1. Mechanistically, the activation of nuclear transcription factor κB (NF-κB), p38, c-Jun NH2-terminal kinase (JNK) and transforming growth factor β (TGF-β) signaling pathways were effectively abrogated in MI-operated mice with specific knockout of PGAM1 in hearts. The potential of PGAM1 suppression to inhibit inflammatory response, apoptosis and fibrosis were verified in the isolated cardiomyocytes and fibroblasts treated with oxygen-glucose deprivation reperfusion (OGDR) and TGF-β, respectively. Importantly, PGAM1 directly interacted with TGF-β to subsequently mediate inflammation, apoptosis and collagen accumulation, thereby achieving its anti-MIR action. Collectively, these findings demonstrated that PGAM1 was a positive regulator of myocardial infarction remodeling due to its promotional modulation of TGF-β signaling, indicating that PGAM1 may be a promising therapeutic target for MIR treatment.
心肌缺血再灌注（MIR）是急性心肌梗死疾病治疗的重大挑战。目前，确定揭示 MIR 进展的分子基础在科学上至关重要，并且可能提供有效的治疗策略。磷酸甘油酸变位酶 1（PGAM1）是一种关键的有氧糖酵解酶，在介导多种生物学事件中发挥着重要作用，如能量产生和炎症。然而，PGAM1 是否会影响 MIR 尚不清楚。在这里，我们发现 PGAM1 水平在鼠缺血心脏中增加。PGAM1 心脏敲除的小鼠对 MIR 诱导的心脏损伤具有抗性，这表现在梗死面积明显减小、心脏功能改善和心脏切片的组织学改变。此外，PGAM1 心脏敲除显著减轻了 MIR 操作小鼠心脏中的炎症反应、细胞凋亡和纤维化。从机制上讲，NF-κB、p38、c-Jun NH2-末端激酶（JNK）和转化生长因子-β（TGF-β）信号通路的核转录因子κB（NF-κB）的激活在心脏特异性敲除 PGAM1 的 MIR 操作小鼠中被有效阻断。在经氧葡萄糖剥夺再灌注（OGDR）和 TGF-β处理的分离心肌细胞和成纤维细胞中，验证了 PGAM1 抑制的抑制炎症反应、细胞凋亡和纤维化的潜力。重要的是，PGAM1 直接与 TGF-β相互作用，随后介导炎症、细胞凋亡和胶原蛋白积累，从而发挥其抗 MIR 作用。总之，这些发现表明 PGAM1 是心肌梗死重构的正调节剂，因为它促进了 TGF-β信号的调节，表明 PGAM1 可能是 MIR 治疗的有前途的治疗靶点。
