Abstract 411: Human Species-specific Loss of the CMP-N-acetylneuraminic Acid Hydroxylase Fuels Atherosclerosis Development via Intrinsic and Extrinsic Mechanisms

Abstract

Cardiovascular disease (CVD) events due to atherosclerosis are very common in humans, but rarely occur spontaneously in other mammals, absent experimental manipulation. All humans exhibit a species-specific deficiency of the common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc), due to pseudogenization of the CMP-N-acetylneuraminic acid (Neu5Ac) hydroxylase (CMAH) gene, which occurred in hominin ancestors about 2-3 million years ago. Human-like Cmah -/- mice that express only the precursor sialic acid Neu5Ac are more prone to insulin resistance and have more reactive macrophages and T cells. Human dietary consumption of Neu5Gc (primarily from red meat), can acts as a foreign “xenoantigen” in humans that gets metabolically incorporated into endogenous glycoproteins. Humans with circulating anti-Neu5Gc “xeno-autoantibodies” can thus potentially develop local chronic inflammation or “xenosialitis” at sites of Neu5Gc accumulation such as endothelial cells and in atherosclerotic plaques. In this study we set out to test if human CMAH deficiency contributes to CVD via multiple intrinsic and extrinsic mechanisms. Cmah -/- Ldlr -/- mice had increased atherogenesis on a Neu5Gc-free high fat diet (HFD), compared to Cmah +/+ Ldlr -/- mice. This was not associated with cytokine levels in plasma, but increased cytokine expression was seen in Cmah -/- Ldlr -/- macrophages in comparison to Cmah +/+ Ldlr -/- . The baseline relative hyperglycemia of the Cmah -/- Ldlr -/- mice was also enhanced on a Neu5Gc-free HFD. When such mice were immunized to develop human-like levels of anti-Neu5Gc antibodies, they had a 2.5-fold increase in atherosclerosis on a Neu5Gc-rich HFD compared to control Neu5Ac-rich or sialic acid-free HFD feeding. Drastically advanced lesions with increased necrotic core areas and infiltration of macrophages and T-cells accompanied increases in atherosclerotic area and lesion volume. None of these differences were explained by changes in lipoprotein profiles or insulin sensing. Human evolutionary loss of CMAH likely contributes to atherosclerosis propensity, via both intrinsic mechanisms such as amplified chronic inflammatory response and hyperglycemia; and extrinsic mechanisms such as red meat-derived Neu5Gc-induced xenosialitis.