Ablation of SGK1 Impairs Endothelial Cell Migration and Tube Formation Leading to Decreased Neo-Angiogenesis Following Myocardial Infarction

Serum and glucocorticoid inducible kinase 1 (SGK1) plays a pivotal role in early angiogenesis during embryonic development. In this study, we sought to define the SGK1 downstream signalling pathways in the adult heart and to elucidate their role in cardiac neo-angiogenesis and wound healing after myocardial ischemia. To this end, we employed a viable SGK1 knockout mouse model generated in a 129/SvJ background. Ablation of SGK1 in these mice caused a significant decrease in phosphorylation of SGK1 target protein NDRG1, which correlated with alterations in NF-κB signalling and expression of its downstream target protein, VEGF-A. Disruption of these signalling pathways was accompanied by smaller heart and body size. Moreover, the lack of SGK1 led to defective endothelial cell (ECs) migration and tube formation in vitro, and increased scarring with decreased angiogenesis in vivo after myocardial infarct. This study underscores the importance of SGK1 signalling in cardiac neo-angiogenesis and wound healing after an ischemic insult in vivo.

血清和糖皮质激素诱导激酶1（Serum and glucocorticoid inducible kinase 1, SGK1）在胚胎发育早期的血管生成过程中发挥关键作用。本研究旨在明确成年心脏中SGK1的下游信号通路，并阐明其在心肌缺血后心脏新生血管生成与伤口愈合中的作用。为此，我们采用了在129/SvJ遗传背景下构建的可存活SGK1基因敲除小鼠模型。在该模型小鼠中敲除SGK1可导致其靶蛋白NDRG1的磷酸化水平显著降低，这一变化与核因子κB（NF-κB）信号通路的改变及其下游靶蛋白血管内皮生长因子A（VEGF-A）的表达变化密切相关。上述信号通路的紊乱同时伴随心脏与体型的缩小。此外，SGK1缺失会导致内皮细胞（ECs）的体外迁移与管腔形成能力受损，并在体内心肌梗死模型中加重瘢痕形成，同时降低血管生成水平。本研究凸显了SGK1信号通路在体内缺血损伤后心脏新生血管生成与伤口愈合中的重要性。