Research Highlights

ATHEROSCLEROSIS loss during evolution linked

to predisposition Conway/ Carl Credit: Limited Nature Springer Cardiovascular events associated Nissi Varki, Ajit Varki and colleagues which by interaction with circulating with atherosclerosis, such as now show that the loss of CMAH anti-​Neu5Gc potentiates myocardial infarction and stroke, might also predispose to chronic inflammation (termed are the most common cause of death atherosclerosis. xeno­sialitis). Cmah–/–Ldlr–/– mice worldwide in humans. However, The researchers found that immunized with Neu5Gc antigens (to these events are rare in other animals, Ldlr–/– mice with CMAH deficiency induce the generation of human-like​ even in closely related species, such as that were fed a sialic-acid-free,​ anti-Neu5Gc antibodies) had a ~2.4- chimpanzees, despite having some of high-fat​ diet (HFD) had a ~1.9-fold fold increase in atherosclerosis when the same risk factors. Environmental increase in atherosclerosis compared fed a Neu5Gc-rich​ HFD compared and behavioural factors probably with Ldlr–/– mice with CMAH. The with a Neu5Ac-rich​ diet or a sialic-​ contribute to these differences. A new increased risk seemed to be driven by acid-free HFD. Blood lipoprotein and study shows that the loss of a single higher levels of macrophage-derived​ glucose profiles were unchanged. enzyme in humans during evolution cytokines and hyperglycaemia, given In summary, evolutionary loss of might be another contributing factor. loss of CMAH that triglyceride, cholesterol and CMAH and Neu5Gc in humans might Humans have a species-specific​ also explains lipoprotein levels did not change. be a contributor to atherosclerosis susceptibility via intrinsic and extrinsic deficiency of the the increased Interestingly, loss of CMAH N-glycolylneuraminic​ acid (Neu5Gc) also explains the increased risk of (that is, consumption of Neu5Gc, caused by the loss of a functional risk of cardio­ cardiovascular disease associated with primarily from red meat) mechanisms. form of cytidine monophosphate-​ vascular disease red meat consumption in humans, Irene Fernández-Ruiz​ N-acetylneuraminic acid hydroxylase associated which does not seem to occur in (CMAH). This loss occurred in other carnivorous animals. Neu5Gc Original article Kawanishi, K. et al. Human with red meat species-specific​ loss of CMP-N​ -acetylneuraminic hominin ancestors 2–3 million years is present in red meat and can act acid hydroxylase enhances atherosclerosis via ago, an adaptation possibly linked to a consumption as a ‘xeno-autoantigen’​ in humans intrinsic and extrinsic mechanisms. Proc. Natl parasite that used Neu5Gc to via metabolic incorporation into Acad. Sci. https://doi.org/10.1073/pnas.1902902116 (2019) invade cells. However, Philip Gordts, cellular glycoproteins and glycolipids,

CARDIAC REGENERATION Distinct regulatory pathways are involved in coronary vessel growth Credit: V. Summ ersby /Sp rin Three independent regulatory expression to endothelial cells g e r pathways involved in the development of coronary vessels, Nicola Smart, N a

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of the coronary vasculature are Sarah De Val and colleagues identified r e

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activated in the hearts of embryos three distinct signalling cascades m

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e and neonatal mice after myocardial implicated in coronary vessel growth. Importantly, after MI, all d infarction (MI) but repressed in First, sustained expression of three pathways were activated in adult mice. “[This finding] strongly the homeobox protein HLX3:lacZ neonatal mouse hearts, which have indicates a fundamental divergence transgene, which is activated by regenerative potential, but repressed between the regulatory pathways vascular endothelial growth factor A in the injured hearts of adult mice. intrinsically employed in the healthy (VEGFA)–myocyte-​specific enhancer “These findings were unexpected and and injured adult heart,” summarize factor 2 (MEF2) signalling in endothelial highly relevant given that the VEGFA the researchers. cells, was detected in both neonatal­ pathway has been the main pathway The generation of new coronary and adult endocardial-​derived targeted in preclinical and clinical vessels after MI can attenuate ischaemic ­coronary vessels, confirming the role the mecha­ studies,” comments Smart. injury and cardiac dysfunction, but the of this pathway in coronary vessel nisms under­ To conclude, these results indicate mechanisms underlying vessel growth formation. Development of sinus that distinct pathways are involved in the ischaemic heart are not well venosus (SV)-derived coronary arteries lying vessel in neovascular growth during understood. The cellular processes required activation of the SOXF/RBPJ growth in the developmental coronary vessel involved in coronary vessel formation transcriptional programme. Finally, ischaemic heart formation and ischaemic injury. the bone morphogenetic protein Karina Huynh in the embryonic heart are well are not well characterized, but whether these (BMP)–mothers against decapenta- Original article Payne, S. et al. Regulatory pathways can be reactivated in the plegic homologue (SMAD) pathway understood pathways governing murine coronary vessel adult heart is unclear. By analysing was found to be active in SV-​derived formation are dysregulated in the injured adult heart. Nat. Commun. 10, 3276 (2019) numerous gene enhancers that drive coronary veins.

580 | OCTOBER 2019 | volume 16 www.nature.com/nrcardio