Role of Golgi stress-induced ferroptosis on vascular dysfunction after traumatic hemorrhagic shock through connexin43-SLC7A11 pathway.

Abstract

Vascular dysfunction, particularly vascular hyporeactivity, has been identified as a critical factor for limiting the treatment of patients with traumatic hemorrhagic shock (THS). Nevertheless, the precise mechanisms underlying THS-induced vascular dysfunction remain inadequately understood. Increasing attention has been directed toward the role of Golgi apparatus stress (GAS)-induced cell death in cardiovascular disease, closely linked to redox imbalance. Recent studies indicate that inhibition of connexin43 (Cx43, a key regulator of vascular dysfunction) induces ferroptosis. However, it remains unclear whether THS-induced vascular dysfunction is regulated by GAS through Cx43 and ferroptosis. In this study, we showed that GAS was responsible for inducing vascular hyporeactivity following THS. Using a Cx43-knockout mice model, we subsequently found that GAS reduced the reactivity of superior mesenteric arteries after THS based on the inhibition of Cx43. Furthermore, cell experiments showed that hypocontraction of vascular smooth muscle cells (VSMCs) was induced by GAS; meanwhile, gap junctional intercellular communication (GJIC) disruption and ferroptosis were also triggered. We generated Cx43-knockdown or overexpressed VSMCs and verified that GAS induced hypocontraction of VSMCs through inhibition of Cx43 and SLC7A11. Moreover, increasing the level of SLC7A11 could attenuate GAS-induced ferroptosis and hypocontraction of VSMCs. These results suggest that GAS-induced ferroptosis can cause vascular dysfunction, which is mediated by the inhibition of the Cx43-SLC7A11 pathway in THS.The results highlight the important role of Golgi stress and ferroptosis in traumatic hemorrhagic shock-induced vascular dysfunction and inhibition of Golgi stress and its target pathway (connexin43-SLC7A11 pathway) may be the potential therapeutic target.