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Atherosclerosis and platelets

Soluble guanylyl cyclase in platelets keeps atherosclerosis at bay

Nature Cardiovascular Research volume 1, pages 1124–1126 (2022)Cite this article

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The contribution of platelets to atherothrombosis is well established. Accumulating genome-wide association studies have revealed several variants of genes encoding molecules along the nitric oxide (NO)–soluble guanylyl cyclase (sGC)–cyclic guanosine-3′,5′-monophosphate (cGMP) pathway that are associated with increased risk of coronary artery disease; however, the cell types and functional impact of these risk variants remain poorly understood. Mauersberger et al. now demonstrate that platelet-specific knockout of a transcript encoding sGC increased atherosclerosis, whereas pharmacological stimulators of sGC reduced lesions via a paracrine effect of angiopoietin-1 on endothelial cell–leukocyte interactions.

Atherosclerosis, a complex, chronic, lipid-driven arterial disease, contributes substantively to cardiovascular morbidity and mortality despite current medical therapies. Although the roles of macrophages, endothelial cells and smooth muscle cells in atherosclerosis have been explored comprehensively, studies in the past decade have shed light on some of the more under-investigated factors that contribute to this pathology. The role of platelets in atherosclerosis has been studied extensively for decades. However, the scope of these studies has been largely limited due to their well-known primary function in thrombosis. This is partly due to their anucleate structure: they are fragments of their parent cell type, the megakaryocyte. Lacking a nucleus, platelets were thought to be relatively passive entities. Over the years, it has become apparent that platelets are a dynamic cell type capable of immune interactions and cytokine signaling, and that they harbor a diverse pool of soluble factors (for example, α-granules) and release RNA-laden microvesicles to further amplify their inter-cellular crosstalk1. In the context of cardiovascular disease, platelets induce thrombus formation after an atherosclerotic plaque ruptures, a pathology known as ‘atherothrombosis’. The thrombus often occludes a blood vessel such as the coronary artery, causing a myocardial infarction (MI). Therefore, factors that enhance thrombus formation increase the risk of coronary artery disease (CAD) and MI. Classically, pharmacological inhibition of platelet activation limits platelet aggregation and thrombus formation. Drugs such as aspirin, an irreversible inhibitor of cyclooxygenase-1 that prevents thromboxane A2 synthesis and platelet aggregation, and clopidogrel, an inhibitor of the ADP receptor P2Y12 that prevents platelet aggregation, are used in patients with CAD to prevent major adverse cardiovascular events that are driven mainly by thrombotic events such as MI or ischemic stroke. However, accumulating pre-clinical and clinical studies have highlighted the non-thrombotic, anti-inflammatory mechanisms by which these anti-platelet therapies may confer benefit2,3.

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Fig. 1: Atheroprotective effects of the non-risk sGC allele.

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Acknowledgements

Supported by the US National Institutes of Health (HL115141, HL134849, HL148207, HL148355, HL153356 to M.W.F.) and the American Heart Association (18SFRN33900144 and 20SFRN35200163 to M.W.F.).

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  1. Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Anurag Jamaiyar, Jingshu Chen & Mark W. Feinberg

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  1. Anurag Jamaiyar
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Correspondence to Mark W. Feinberg.

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Jamaiyar, A., Chen, J. & Feinberg, M.W. Soluble guanylyl cyclase in platelets keeps atherosclerosis at bay. Nat Cardiovasc Res 1, 1124–1126 (2022). https://doi.org/10.1038/s44161-022-00188-5

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