Insulin Resistance Triggers Atherosclerosis: Caveolin 1 Cooperates with PKCzeta to Block Insulin Signaling in Vascular Endothelial Cells

Abstract

Objective To date, therapies for endothelial dysfunction have primarily focused on ameliorating identified atherosclerosis (AS) risk factors rather than explicitly addressing endothelium-based mechanism. An in-depth exploration of the pathological mechanisms of endothelial injury was performed herein. Methods Aortic caveolin 1 (Cav1) knockdown was achieved in mice using lentivirus, and AS was induced using a high-fat diet. Mouse body weight, blood glucose, insulin, lipid parameters, aortic plaque, endothelial injury, vascular nitric oxide synthase (eNOS), injury marker, and oxidative stress were examined. The effect of Cav1 knockdown on the content of PKCzeta and PI3K/Akt/eNOS pathway–related protein levels, as well as PKCzeta binding to Akt, was studied. ZIP, a PKCzeta inhibitor, was utilized to treat HUVECs in vitro, and the effect of ZIP on cell viability, inflammatory response, oxidative stress, and Akt activation was evaluated. Results Cav1 knockdown had no significant effect on body weight or blood glucose in mice over an 8-week period, whereas drastically reduced insulin, lipid parameters, endothelial damage, E-selectin, and oxidative stress and elevated eNOS levels. Moreover, Cav1 knockdown triggered decreased PKCzeta enrichment and the activation of the PI3K/Akt/eNOS pathway. PKCzeta has a positive effect on cells without being coupled by Cav1, and ZIP had no marked influence on PKCzeta-Akt binding following Cav1/PKCzeta coupling. Conclusion Cav1/PKCzeta coupling antagonizes the activation of PI3K on Akt, leading to eNOS dysfunction, insulin resistance, and endothelial cell damage.

Associations between estimated glucose disposal rate and arterial stiffness and mortality among US adults with non-alcoholic fatty liver disease

“…Arterial stiffness is considered an independent risk predictor of cardiovascular events ( 38 ). IR can damage the endothelium of blood vessels and lead to inflammatory reactions, which may easily lead to arterial stiffness and arteriosclerosis ( 39 ). A Meta-analysis of 37,780 Individuals showed that IR is closely related to arterial stiffness ( 40 ).…”