Deletion of the p66 ^Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet

TLDR

Oxidized low‑density lipoprotein and related oxidative mechanisms are key drivers of vascular dysfunction and atherogenesis, and the p66(Shc-/-) mouse is a unique genetic model of heightened resistance to oxidative stress and extended lifespan. The study aimed to investigate how a high‑fat diet affects systemic and tissue oxidative stress and the development of early vascular lesions in p66(Shc-/-) versus wild‑type mice. The authors compared p66(Shc-/-) and WT mice fed a 21 % high‑fat diet, measuring oxidative stress markers and lesion area to assess the impact of the diet. High‑fat feeding increased aortic early lesion area by ~21 % in WT but only ~3 % in p66(Shc-/-) mice, with the latter showing fewer macrophage foam cells, less apoptotic vascular cells, and reduced systemic and tissue oxidative stress, supporting p66(Shc-/-) as a protective factor and potential therapeutic target for vascular disease.

Abstract

Several experimental and clinical studies have shown that oxidized low-density lipoprotein and oxidation-sensitive mechanisms are central in the pathogenesis of vascular dysfunction and atherogenesis. Here, we have used p66(Shc-/-) and WT mice to investigate the effects of high-fat diet on both systemic and tissue oxidative stress and the development of early vascular lesions. To date, the p66(Shc-/-) mouse is the unique genetic model of increased resistance to oxidative stress and prolonged life span in mammals. Computer-assisted image analysis revealed that chronic 21% high-fat treatment increased the aortic cumulative early lesion area by approximately 21% in WT mice and only by 3% in p66(Shc-/-) mice. Early lesions from p66(Shc-/-) mice had less content of macrophage-derived foam cells and apoptotic vascular cells, in comparison to the WT. Furthermore, in p66(Shc-/-) mice, but not WT mice, we found a significant reduction of systemic and tissue oxidative stress (assessed by isoprostanes, plasma low-density lipoprotein oxidizability, and the formation of arterial oxidation-specific epitopes). These results support the concept that p66(Shc-/-) may play a pivotal role in controlling systemic oxidative stress and vascular diseases. Therefore, p66(Shc) might represent a molecular target for therapies against vascular diseases.