Abstract 14092: Reduction of Atherosclerosis in Gucy1a3 Deficient Mice

Abstract

Introduction: GUCY1A3 encodes the α1 subunit of the soluble guanylate cyclase (sGC) and has been associated with CAD/MI by genome-wide association studies (GWAS) and in a rare extended family with MI. The α1 and the β1 subunit form the heterodimeric sGC, the nitric oxide (NO) receptor. NO plays an important role in the human cardiovascular system. The aim of our study is to define the role of GUCY1A3 in atherosclerosis using a mouse atherogenic model. Methods: Gucy1a3 KO mice were backcrossed on an Ldlr KO atherogenic background. Four groups were used, i.e. C57BL/6 (WT), Gucy1a3 KO, Ldlr KO and Gucy1a3-Ldlr double KO. All groups were fed high fat diet (HFD) or standard diet (SD) starting at the age of 12-14w and for 20 weeks. Blood pressure was studied at the end of the experiment in the HFD. At the start and end of the diet, lipid metabolism parameters (TC, HDLC, LDLC and TG) were analyzed. Plaque lesion size and collagen and macrophages content were studied. As smooth muscle cells play a key role in atherosclerosis, primary mouse aortic smooth muscle cells (maSMC) were isolated from WT and Gucy1a3 KO animals and subjected to proliferation and migration assays. Results: Blood pressure was studied in HFD animals, showing, as expected, an increase of systolic and diastolic blood pressure in double KO animals when compared to Ldlr KO animals. Regarding lipid levels, no differences were found in the double KO to Ldlr KO comparison under HFD, but a reduction in total cholesterol was found in double KO under SD. For atherosclerosis, a significant reduction in plaque area at the aortic root of double KO when compared to the Ldlr KO animals was demonstrated in both SD and HFD. The reduction was further confirmed in an additional independent experiment under SD. Similarly, a significant reduction of plaque lesion was found in the whole aorta of double KO when compared to the Ldlr KO under HFD. Moreover, a reduction in collagen content was found in double KO mice under HFD when compared to Ldlr KO animals. The migration and proliferation assays show a significant reduction in both migration and proliferation of the Gucy1a3 KO maSMC compared to WT. Conclusions: Our results point to an atherogenic role of Gucy1a3 in mice probably induced via smooth muscle migration and proliferation defects.