Mechanisms of Western-Diet Induced Endothelial Stiffening: Endothelial CD36 and Long-Chain Fatty Acids

Western diet (WD) refers to a diet high in saturated fat and refined carbohydrates. WD is known to be detrimental to cardiovascular health. These studies present novel insights into the mechanism undergirding WD-associated cardiovascular dysfunction: stiffening (an increase in the elastic modulus) of the aortic endothelial layer associates with barrier disruption, and both are mediated by endothelial scavenger lipid receptor CD36. Through the use of an inducible, endothelial-specific CD36 knockdown mouse model, we discovered that loss of endothelial CD36 prevents endothelial stiffening and minimizes barrier leakage. We discovered that WD-induced endothelial stiffening in vivo is mimicked by exposure to saturated LCFA palmitic acid in vitro, a phenomenon that is dependent on CD36. Activation of CD36 by non-lipid ligands, however, does not elicit stiffening. To elucidate how lipids elicit stiffening, we focused on RhoA and its association with RhoGDI1, which maintains RhoA inactive. We show that RhoA and RhoGDI1 are required for palmitic acid-induced stiffening. These findings point to RhoGDI1 as a target for the development of studies into WD-induced cardiovascular dysfunction.