Editors' ChoiceCardiology

Nitric Oxide Signaling at the Heart of the Matter

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Science Translational Medicine  20 Nov 2013:
Vol. 5, Issue 212, pp. 212ec194
DOI: 10.1126/scitranslmed.3007985

A family history of myocardial infarction (MI) or death from coronary heart disease at a young age is a well-known independent risk factor for cardiovascular disease, but the mechanisms by which the genetic background increases one's risk of suffering a myocardial infarction remain unclear. Recent exponential advances in genomics may facilitate the discovery of novel cardiovascular risk factors and therapeutic targets.

In particular, next-generation sequencing technologies can identify gene mutations linked to a particular disease. Erdmann et al. applied these methodologies to a family in which a large number of members developed coronary heart disease at young ages. The authors used exome sequencing to find heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu). All individuals who carried both mutations were affected, and these mutations were absent in almost 7000 healthy subjects and unrelated MI cases. In human embryonic kidney (HEK) 293 cells, both mutations were associated with a marked reduction in the activity of soluble guanylyl cyclase (sGC), an intracellular enzyme that binds to nitric oxide and catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). Interestingly, platelets from digenic mutation carriers, compared with single mutation carriers or noncarriers, contained fewer α1 and β1 subunits of sGC and produced lower amounts of cGMP when stimulated with nitric oxide. Further experiments showed that mice deficient in the α1 subunit of sGC had enhanced thrombotic activity in the microcirculation, a finding that provides a mechanistic link between the identified mutations and the development of MI.

The results of this research are captivating and constitute a step forward in understanding the familial predisposition to develop an MI; however, there is still a need to further validate the mechanisms by which these two mutations lead to an increase in the risk of coronary heart disease. More importantly, the study raises the question of whether treatment with sGC stimulators such as riociguat may be of benefit for primary or secondary prevention of MI in patients with certain dysfunctions of the nitric oxide pathway.

J. Erdmann et al., Dysfunctional nitric oxide signalling increases risk of myocardial infarction. Nature, published online 10 November 2013 (10.1038/nature12722). [PubMed]

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