Abstract 17417: ABCC6 Deficiency Promotes Atherosclerosis

Introduction: Vascular calcification is associated with aging and common conditions such as hypercholesterolemia and certain genetic disorders. A molecular pathway inhibiting ectopic calcification is initiated by ABCC6, a membrane transporter primarily expressed in liver. ABCC6 facilitates the cellular efflux of ATP from hepatocytes, which is rapidly converted into pyrophosphate (PPi) in the liver vasculature. ABCC6 is responsible for the majority of the PPi release from the liver, and ~60% of plasma PPi in both in humans and mice. As PPi is a major inhibitor of calcification, mutations in ABCC6 underlie the currently incurable calcification disorder pseudoxanthoma elasticum (PXE), some cases of generalized arterial calcification of infancy (GACI). Hypothesis: Multiple lines of evidence have suggested a pathological synergy between ABCC6 and hyperlipidemia. Methods: We examined crosses between Abcc6-/- and Ldlr-/- mice and serum samples from human PXE patients. Three mouse genotypes were generated Ldlr-/-, Ldlr-/-xAbcc6-/- and Ldlr-/- xAbcc6+/-. Results: When subjected to a high fat diet, mice with reduced or no Abcc6 expression displayed a 2-fold increase of atherosclerotic plaque area (p=0.0001). Interestingly, atherosclerotic plaque was also found in Abcc6-deficient mice fed a normal diet but not in control Ldlr-/- animals. Aortic calcification was not significantly affected by Abcc6 expression except in Ldlr-/-xAbcc6-/- mice fed regular chow (p=0.0001). We observed an increased proliferation of smooth muscle cells of but no increase in monocyte-macrophage infiltration in the plaque of Ldlr-/-xAbcc6-/- mice. Importantly, we determined that the cholesterol efflux from isolated macrophages towards HDL (mediated by ABCG1) was significantly decreased (-28%, p=0.006) in Ldlr-/-xAbcc6-/- mice while the efflux towards ApoA1 (mediated by ABCA1) was unchanged. The analysis of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) fractions in these mice showed altered profiles similar to those found with human PXE plasma samples. Conclusions: Our results indicated that, in addition to being an important inhibitor of vascular calcification, ABCC6 inhibits atherogenesis by modulating reverse cholesterol transport.