Caveolin-1 alleviates acetaminophen-induced vascular oxidative stress and inflammation in non-alcoholic fatty liver disease

Abstract

Acetaminophen (APAP) is one of the most widely used drugs in the world. The literature shows that excessive or long-term use of APAP can lead to increased cardiovascular dysfunction. An acute increase in angiotensin Ⅱ (Ang Ⅱ) caused by APAP use in fatty liver disease may increase the risk and severity of vascular injury. However, the underlying mechanism remains unclear. Caveolin-1 (CAV1) is a broad-spectrum kinase inhibitor that significantly determines endothelial function. This study aimed to observe the effects of APAP on the vasculature in non-alcoholic fatty liver disease (NAFLD) and to determine whether CAV1 could alleviate vascular oxidative stress and inflammation by targeting Ang Ⅱ or its downstream pathways. In this study, 7-week-old C57BL/6 male mice (18-20 g) were administered APAP by gavage after eight weeks of a high-fat diet. Any resulting vascular oxidative stress and inflammation were assessed. Levels of Ang Ⅱ, CAV1, and other related proteins were measured using ELISA and western blotting. In APAP-treated NAFLD mice, CAV1 expression was downregulated and Ang Ⅱ expression was upregulated compared to normal APAP-treated mice. In vitro, HUVECs were incubated with Ang Ⅱ (300 nM) for 48 h. Overexpression of CAV1 in HUVECs attenuated Ang Ⅱ-induced oxidative stress and inflammation and downregulated the expression of Protein kinase C (PKC) and p-P38/P38. After intervention with CAV1-siRNA, immunofluorescence results showed that the fluorescence intensity of PKC on mitochondria was further increased, and flow cytometry results showed that the mitochondrial membrane potential increased. PKC inhibitors alleviated Ang Ⅱ-induced endothelial injury. In conclusion, our findings confirmed that CAV1 exerts a protective effect against vascular injury by inhibiting oxidative stress and inflammation through the PKC/MAPK pathway. Therefore, restoration of CAV1 may have clinical benefits in reducing APAP-induced vascular damage in NAFLD patients.

Keywords: APAP; Caveolin-1; Non-alcoholic fatty liver disease; Protein kinase C; Vascular injury.