Penumatsa Krishna C, Sharma Yamini, Warburton Rod R, Singhal Adit, Toksoz Deniz, Bhedi Chinmayee D, Qi Guanming, Preston Ioana R, Anderlind Christina, Hill Nicholas S, Fanburg Barry L
Pulmonary, Critical Care and Sleep Division, Department of Medicine, Tufts Medical Center, Boston, MA, United States.
Front Immunol. 2024 Apr 8;15:1371706. doi: 10.3389/fimmu.2024.1371706. eCollection 2024.
Pulmonary hypertension (PH) pathogenesis is driven by inflammatory and metabolic derangements as well as glycolytic reprogramming. Induction of both interleukin 6 (IL6) and transglutaminase 2 (TG2) expression participates in human and experimental cardiovascular diseases. However, little is known about the role of TG2 in these pathologic processes. The current study aimed to investigate the molecular interactions between TG2 and IL6 in mediation of tissue remodeling in PH. A lung-specific IL6 over-expressing transgenic mouse strain showed elevated right ventricular (RV) systolic pressure as well as increased wet and dry tissue weights and tissue fibrosis in both lungs and RVs compared to age-matched wild-type littermates. In addition, IL6 over-expression induced the glycolytic and fibrogenic markers, hypoxia-inducible factor 1α, pyruvate kinase M2 (PKM2), and TG2. Consistent with these findings, IL6 induced the expression of both glycolytic and pro-fibrogenic markers in cultured lung fibroblasts. IL6 also induced TG2 activation and the accumulation of TG2 in the extracellular matrix. Pharmacologic inhibition of the glycolytic enzyme, PKM2 significantly attenuated IL6-induced TG2 activity and fibrogenesis. Thus, we conclude that IL6-induced TG2 activity and cardiopulmonary remodeling associated with tissue fibrosis are under regulatory control of the glycolytic enzyme, PKM2.
肺动脉高压（PH）的发病机制由炎症和代谢紊乱以及糖酵解重编程驱动。白细胞介素6（IL6）和转谷氨酰胺酶2（TG2）表达的诱导均参与人类和实验性心血管疾病。然而，关于TG2在这些病理过程中的作用知之甚少。本研究旨在探讨TG2与IL6在PH组织重塑介导中的分子相互作用。与年龄匹配的野生型同窝小鼠相比，一种肺特异性IL6过表达转基因小鼠品系显示右心室（RV）收缩压升高，肺和RV的湿重、干重以及组织纤维化增加。此外，IL6过表达诱导了糖酵解和纤维化标志物、缺氧诱导因子1α、丙酮酸激酶M2（PKM2）和TG2。与这些发现一致，IL6在培养的肺成纤维细胞中诱导了糖酵解和促纤维化标志物的表达。IL6还诱导了TG2的激活以及TG2在细胞外基质中的积累。糖酵解酶PKM2的药理学抑制显著减弱了IL6诱导的TG2活性和纤维化。因此，我们得出结论，IL6诱导的TG2活性以及与组织纤维化相关的心肺重塑受糖酵解酶PKM2的调控。
