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

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Publication Type: Journal Article
Authors: Kawanishi, Kunio; Dhar, Chirag; Do, Raymond; Nissi M Varki; Gordts, Philip L. S. M.; Ajit Varki
Year of Publication: 2019
Journal: Proceedings of the National Academy of Sciences
Pagination: 201902902
Date Published: 2019/07/19
Publication Language: eng

Cardiovascular disease (CVD) events like heart attacks and strokes due to atherosclerotic narrowing of arteries are the commonest cause of worldwide deaths, but many first-time events occur in individuals without known risk factors. In contrast, such events are extremely rare in other animals despite some of the same risk factors. While environmental and behavioral factors likely contribute to the difference, we show here that a human-specific genetic mutation affecting cell-surface molecules called sialic acids may be one other factor. We also show that the same mutation can help explain the apparently human-specific increased risk of CVD events associated with red meat consumption. The humanized mouse systems we present could be explored as models for future studies of atherosclerosis.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, ∼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-N-acetylneuraminic acid (Neu5Ac) hydroxylase (CMAH), which occurred in hominin ancestors ∼2 to 3 Mya. Ldlr−/− mice with human-like Cmah deficiency fed a sialic acids (Sias)-free high-fat diet (HFD) showed ∼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 Neu5Gc-bearing antigens to generate human-like anti-Neu5Gc antibodies suffered a ∼2.4-fold increased atherosclerosis on a Neu5Gc-rich HFD, compared with Neu5Ac-rich or Sias-free HFD. Lesions in Neu5Gc-immunized and Neu5Gc-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.

Short Title: Proc Natl Acad Sci USA
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