Abstract Body: Background: Functional HDL exhibiting antioxidant and anti-inflammatory properties and supports cardiovascular health by regulating cellular cholesterol. Oxidative stress impairs HDL function, leading to its dysfunction (dHDL). Here, we tested whether reductive stress (RS), characterized by excess antioxidants, promotes atherosclerosis.
Methods: HDL from CVD patients with RS was tested for cholesterol efflux, Ly6c expression, and MMP9 release in RAW macrophages. Next, we assessed whether RS trigger foam cell formation in the bone marrow derived macrophages (BMDMs) of CAG-caNrf2-TG mice (RS) using oil Red-O staining. 2D-aortic echocardiography was conducted to examine the aortic dimension in CAG-caNrf2-TG (TG) vs WT mice.
Results: We found that RS-CVD subjects had lower total HDL cholesterol, reduced Apo A1 content, and decreased Paraoxonase activity. Sulforaphane treatment (2µM; 24 hr) enhanced foam cell formation in RAW macrophages treated with RS-CVD HDL, suggesting RS worsens atheroma. Elevated MMP9 release and LY6C expression indicate increased matrix remodeling and macrophage susceptibility to foam cell formation under RS. Notably, BMDMs from the TG/RS-mice showed significantly increased foam cell formation and elevated Ly6C expression, a pro-inflammatory marker. In vivo echocardiography demonstrated decreased aortic root diameter (AoR: 1.5 vs 0.94 mm, n=3-5/group)) and increased pulse wave velocity in TG/RS-mice, suggesting vascular remodeling.
Conclusion: This study shows that RS imapirs HDL function and aggravates atherosclerosis progression.