Lee Katie C Y, Williams Allison L, Hara Akitoshi, Khadka Vedbar S, Hayashi Jeffrey, Shohet Ralph V
Department of Medicine, John A. Burns School of Medicine, University of Hawaii Mānoa, Honolulu, Hawaii, USA.
Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii Mānoa, Honolulu, Hawaii, USA.
Physiol Rep. 2025 Jan;13(1):e70193. doi: 10.14814/phy2.70193.
Inflammation and a metabolic shift from oxidative metabolism to glycolysis are common in the ischemic heart, the latter partly controlled by pyruvate kinase (muscle, PKM). We previously identified alternative splicing promoting the PKM2 isoform after myocardial infarction (MI). We examined the role of PKM2 physiological upregulation after MI, modeled by ligation of the left anterior descending coronary artery, using global PKM2 knockout (PKM2) mice. Echocardiography showed similar cardiac function between PKM2 and control mice after MI. However, PKM2 infarcted hearts had increased abundances of transcripts associated with oxidative stress and immune responses. Immunohistochemistry revealed greater abundance of macrophages in PKM2 hearts prior to MI, with a small increase in CD86 macrophages in PKM2 infarcted hearts. Elevated baseline plasma IL-6, IL-1β, and C-reactive protein, and cardiac IL-6, 3 days post-MI, were observed in PKM2 mice. Oxidative lipid products were also elevated in baseline PKM2 hearts, while antioxidant glutathione peroxidase 4 was reduced. Greater fibrosis was seen in PKM2 hearts 28 days after MI. These findings suggest Pkm2 ablation primes the heart for increased oxidative stress, inflammation, and fibrosis post-MI. The natural upregulation of PKM2 may mitigate fibrosis by reducing oxidative stress and inflammation, highlighting its protective role in the infarcted heart.
炎症以及从氧化代谢向糖酵解的代谢转变在缺血性心脏中很常见，后者部分受丙酮酸激酶（肌肉型，PKM）控制。我们之前发现心肌梗死后会发生促进PKM2亚型的可变剪接。我们使用全身性PKM2基因敲除（PKM2）小鼠，通过结扎左冠状动脉前降支建立心肌梗死模型，研究了心肌梗死后PKM2生理性上调的作用。超声心动图显示心肌梗死后PKM2小鼠和对照小鼠的心脏功能相似。然而，PKM2基因敲除的梗死心脏中与氧化应激和免疫反应相关的转录本丰度增加。免疫组织化学显示，在心肌梗死之前，PKM2基因敲除的心脏中巨噬细胞丰度更高，在PKM2基因敲除的梗死心脏中CD86阳性巨噬细胞略有增加。在PKM2小鼠中，观察到心肌梗死后3天血浆白细胞介素-6、白细胞介素-1β和C反应蛋白以及心脏白细胞介素-6水平升高。PKM2基因敲除的心脏基线氧化脂质产物也升高，而抗氧化剂谷胱甘肽过氧化物酶4减少。心肌梗死后28天，PKM2基因敲除的心脏中纤维化更严重。这些发现表明，敲除Pkm2会使心脏在心肌梗死后更易发生氧化应激、炎症和纤维化。PKM2的自然上调可能通过减少氧化应激和炎症来减轻纤维化，突出了其在梗死心脏中的保护作用。
