Genetic variants in nitric oxide signalling have been associated with coronary heart disease and myocardial infarction in genome-wide association studies. One such variant is located in the GUCY1A1 gene, which encodes a subunit of soluble guanylate cyclase (sGC), the receptor for nitric oxide. While it was known that the risk variant leads to decreased sGC activity, it remained unclear through which molecular mechanism and cell type the increased atherosclerosis risk is mediated.
In this study, DZHK scientists led by PD Dr. Thorsten Kessler and Prof. Dr. Heribert Schunkert at the German Heart Center Munich investigated the influence of an absence of sGC in platelets on the development of atherosclerosis. Using a transgenic mouse model in which sGC is only switched off in platelets, the scientists showed that the formation of atherosclerotic plaques is increased. As a molecular mechanism, the authors identified decreased secretion of the glycoprotein angiopoietin-1 from sGC-deficient platelets, which resulted in increased adhesion of leukocytes to endothelial cells in vivo and in vitro. These data not only explain the role of sGC in the formation of atherosclerotic plaques but also indicate that platelets play a crucial role in atherothrombosis and atherogenesis.
The sGC is also an attractive therapeutic target, as stimulators are already used in the clinic for pulmonary hypertension and heart failure. In this study, the scientists showed that such a stimulator not only increases angiopoietin-1 release from platelets but also reduces the formation of atherosclerotic plaques and the recruitment of leukocytes to the vessel wall in a mouse model.
The work is an example of a translational research project: After the identification of the genetic variant in the GUCY1A1 gene, the molecular mechanisms for the variant and the mechanistic role of the gene in atherosclerosis were also deciphered. Furthermore, with sGC stimulation, a new therapeutic approach for the prevention of coronary heart disease is available.
January 2023