Human species-specific loss of CMP-N-acetylneuraminic acid hydroxylase enhances atherosclerosis via intrinsic and extrinsic mechanisms

Cardiovascular disease (CVD) events due to atherosclerosis cause one-third of worldwide deaths and risk factors include physical inactivity, age, dyslipidemia, hypertension, diabetes, obesity, smoking, and red meat consumption. However, similar to 15% of first-time events occur without such factors. In contrast, coronary events are extremely rare even in closely related chimpanzees in captivity, despite human-like CVD-risk-prone blood lipid profiles, hypertension, and mild atherosclerosis. Similarly, red meat-associated enhancement of CVD event risk does not seem to occur in other carnivorous mammals. Thus, heightened CVD risk may be intrinsic to humans, and genetic changes during our evolution need consideration. Humans exhibit a species-specific deficiency of the sialic acid N-glycolylneuraminic acid (Neu5Gc), due to pseudogenization of cytidine monophosphate-Nacetylneuraminic acid (Neu5Ac) hydroxylase (CMAH), which occurred in hominin ancestors similar to 2 to 3 Mya. Ldlr(-/-) mice with human-like Cmah deficiency fed a sialic acids (Sias)-free high-fat diet (HFD) showed similar to 1.9-fold increased atherogenesis over Cmah wild-type Ldlr(-/-) mice, associated with elevated macrophage cytokine expression and enhanced hyperglycemia. Human consumption of Neu5Gc (from red meat) acts as a xeno-autoantigen via metabolic incorporation into endogenous glycoconjugates, as interactions with circulating anti-Neu5Gc xeno-autoantibodies potentiate chronic inflammation (xenosialitis). Cmah(-/-)Ldlr(-/-) mice immunized with NeuSGc-bearing antigens to generate human-like anti-NeuSGc antibodies suffered a similar to 2.4-fold increased atherosclerosis on a NeuSGc-rich HFD, compared with Neu5Ac-rich or Sias-free HFD. Lesions in Neu5Gc-immunized and NeuSGc-rich HFD-fed Cmah(-/-)Ldlr(-/-) mice were more advanced but unexplained by lipoprotein or glucose changes. Human evolutionary loss of CMAH likely contributes to atherosclerosis predisposition via multiple intrinsic and extrinsic mechanisms, and future studies could consider this more human-like model.