Cardiovascular events associated with atherosclerosis, such as myocardial infarction and stroke, are the most common cause of death worldwide in humans. However, these events are rare in other animals, even in closely related species, such as chimpanzees, despite having some of the same risk factors. Environmental and behavioural factors probably contribute to these differences. A new study shows that the loss of a single enzyme in humans during evolution might be another contributing factor.

Credit: Carl Conway/Springer Nature Limited

Humans have a species-specific deficiency of the sialic acid N-glycolylneuraminic acid (Neu5Gc) caused by the loss of a functional form of cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH). This loss occurred in hominin ancestors 2–3 million years ago, an adaptation possibly linked to a malaria parasite that used Neu5Gc to invade cells. However, Philip Gordts, Nissi Varki, Ajit Varki and colleagues now show that the loss of CMAH might also predispose to atherosclerosis.

The researchers found that Ldlr–/– mice with CMAH deficiency that were fed a sialic-acid-free, high-fat diet (HFD) had a ~1.9-fold increase in atherosclerosis compared with Ldlr–/– mice with CMAH. The increased risk seemed to be driven by higher levels of macrophage-derived cytokines and hyperglycaemia, given that triglyceride, cholesterol and lipoprotein levels did not change.

Interestingly, loss of CMAH also explains the increased risk of cardiovascular disease associated with red meat consumption in humans, which does not seem to occur in other carnivorous animals. Neu5Gc is present in red meat and can act as a ‘xeno-autoantigen’ in humans via metabolic incorporation into cellular glycoproteins and glycolipids, which by interaction with circulating anti-Neu5Gc antibodies potentiates chronic inflammation (termed xenosialitis). Cmah–/–Ldlr–/– mice immunized with Neu5Gc antigens (to induce the generation of human-like anti-Neu5Gc antibodies) had a ~2.4-fold increase in atherosclerosis when fed a Neu5Gc-rich HFD compared with a Neu5Ac-rich diet or a sialic-acid-free HFD. Blood lipoprotein and glucose profiles were unchanged.

loss of CMAH also explains the increased risk of cardiovascular disease associated with red meat consumption

In summary, evolutionary loss of CMAH and Neu5Gc in humans might be a contributor to atherosclerosis susceptibility via intrinsic and extrinsic (that is, consumption of Neu5Gc, primarily from red meat) mechanisms.