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

Bibliographic Collection: 
CARTA-Inspired Publication
Publication Type: Journal Article
Authors: Kawanishi, K; Dhar, C; Do, R; Varki, N; Gordts, PLSM; Varki, A
Year of Publication: 2019
Journal: Proc Natl Acad Sci U S A
Volume: 116
Number: 32
Pagination: 16036-16045
Date Published: 08/06/2019
Publication Language: eng
ISBN Number: 0027-8424
Accession Number: 31332008
Abstract:

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.

DOI: https://doi.org/10.1073/pnas.1902902116
Author Address:

Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093. Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA 92093. Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093. Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA 92093. Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093. Department of Pathology, University of California San Diego, La Jolla, CA 92093. Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093. Department of Pathology, University of California San Diego, La Jolla, CA 92093. Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093; pgordts@ucsd.edu a1varki@ucsd.edu. Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093; pgordts@ucsd.edu a1varki@ucsd.edu. Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA 92093. Department of Medicine, University of California San Diego, La Jolla, CA 92093. Center for Academic Research and Training in Anthropogeny, University of California San Diego, La Jolla, CA 92093.

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