Abstract：
Pulmonary hypertension (PH) is a severe cardiovascular disease characterised by pulmonary vascular remodelling. The pivotal role of cellular senescence in vascular remodelling has been acknowledged. Transglutaminase type 2 (TG2), a calcium-dependent enzyme, is intricately linked to both cellular senescence and PH. However, the precise mechanisms underlying the involvement of TG2 in PH remain unclear. In this study, we explored the expression of TG2 and the cellular senescence marker p16INK4a in the pulmonary vasculature of mice with PH induced by hypoxia combined with SU5416. Our findings revealed upregulation of both TG2 and p16INK4a expression in the pulmonary vasculature of PH mice. Additionally, a notable increase in TG2 expression was observed in senescent pulmonary artery smooth muscle cells (PASMC). To delve deeper, we employed proteomic sequencing to reveal seven genes associated with cellular senescence, with a subsequent focus on MAPK14. Our investigation revealed that TG2 regulates senescence in PASMC by modulating the phosphorylation levels of MAPK14. Additionally, in the context of hypoxia combined with SU5416, our observations revealed a noteworthy reduction in both pulmonary vascular remodelling and senescent manifestations in smooth muscle-specific TG2 knockout mice compared with their wild-type counterparts. In summary, our findings indicate that TG2 deficiency lowers the senescence levels of PASMC by inhibiting the activity of MAPK14. This inhibition of senescence in the pulmonary vasculature of PH mice helps to decelerate the progression of pulmonary vascular remodelling and consequently hinders the onset and development of PH.
摘要：
肺动脉高压(PH)是以肺血管重塑为特征的严重心血管疾病。细胞衰老在血管重塑中的关键作用已得到认可。转谷氨酰胺酶2型(TG2),一种钙依赖性酶，与细胞衰老和PH密切相关。然而,TG2参与PH的确切机制尚不清楚.在这项研究中,我们探讨了TG2和细胞衰老标志物p16INK4a在低氧联合SU5416诱导的PH小鼠肺血管中的表达。我们的发现揭示了PH小鼠肺血管中TG2和p16INK4a表达的上调。此外,在衰老的肺动脉平滑肌细胞(PASMC)中观察到TG2表达显著增加.为了更深入地研究，我们使用蛋白质组测序来揭示与细胞衰老相关的七个基因，随后重点关注MAPK14。我们的研究表明，TG2通过调节MAPK14的磷酸化水平来调节PASMC的衰老。此外,在低氧合并SU5416的情况下,我们的观察显示,与野生型小鼠相比,平滑肌特异性TG2基因敲除小鼠的肺血管重塑和衰老表现均显著减少.总之,我们的发现表明，TG2缺乏通过抑制MAPK14的活性来降低PASMC的衰老水平。PH小鼠的肺脉管系统中衰老的这种抑制有助于减缓肺血管重塑的进展,并因此阻碍PH的发生和发展。
