G6PD抑制预防Ang II联合高盐诱导小鼠腹主动脉瘤形成的机制研究

Abstract

Background and aims Aortic aneurysms (AAs) are life-threatening conditions characterized by pathological dilation of the aorta and disruption of vascular structural integrity. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), has been implicated in vascular pathologies, however, its specific role in AA pathogenesis remains unclear. Here, we investigate the contribution of G6PD to AA development and assess its potential as a therapeutic target. Method and results We introduced a robust mouse model of AA induced by Angiotensin II (Ang II, 1000 ng/kg/min) combined with high salt (HS) drinking water (0.9% NaCl and 0.2% KCl) in C57BL/6J mice for 28 days. This method induced AAs in both thoracic aorta (TAA; 33%) and abdominal aorta (AAA; 56%), with pathophysiological features resembling those in humans. The untargeted plasma metabolomics revealed the PPP as the most significantly enriched metabolic module. Concordantly, G6PD was upregulated in aneurysmal tissues from mice and humans, with prominent expression in vascular smooth muscle cells (VSMC). Pharmacological inhibition of G6PD significantly attenuated AAA incidence and aortic dilation. Moreover, G6PD inhibition suppressed VSMC dysfunction, NADPH oxidase (NOX)-mediated oxidative stress and reduced matrix metalloproteinase activity induced by Ang II+HS. In vitro, both NOX inhibitor and fatty acid synthesis inhibitor suppressed G6PD activation-induced VSMC phenotypic switching. Conclusions G6PD promotes VSMC phenotypic switching in an Ang II+HS-induced AAA model by modulating NADPH-dependent oxidative stress and lipogenesis.