PECAM1, COL4A2, PHACTR1, and LMOD1 Gene Polymorphisms in Patients with Unstable Angina

Coronary artery disease (CAD) is a syndrome resulting from myocardial ischaemia of heterogeneous pathomechanism. Environmental and genetic factors contribute to its development. Atherosclerotic plaques that significantly narrow the lumen of coronary arteries cause symptoms of myocardial ischaemia. Acute coronary incidents are most often associated with plaque rupture or erosion accompanied by local activation of the coagulation system with thrombus formation. Plaque formation and stability are influenced by endothelial function and vascular smooth muscle cell function. In this study, we investigated the association between polymorphisms in genes affecting endothelial and vascular smooth muscle cell (VSMC) function and the occurrence of unstable angina pectoris. The aim of this study was to evaluate the association between the PECAM1 (rs1867624), COL4A2 (rs4773144), PHACTR1 (rs9349379) and LMOD1 (rs2820315) gene polymorphisms and the risk of unstable angina. The study included 232 patients with unstable angina diagnosed on the basis of clinical symptoms and coronary angiography and 144 healthy subjects with no significant coronary lumen stenosis at coronary angiography. There were no statistically significant differences in the distribution of COL4A2 rs4773144 and PECAM1 rs1867624 gene polymorphisms between patients with unstable angina and control subjects. In patients with unstable angina, there was an increased frequency of PHACTR1 rs9349379 G allele carriers (GG and AG genotypes) (GG+AG vs. AA, OR 1.71; 95% CI 1.10–2.66, p = 0.017) and carriers of the LMOD1 rs2820315 T allele (TT and CT genotypes) (TT+CT vs. CC, OR 1.65; 95% CI 1.09–2.51, p = 0.019) compared to the control group. The association between these alleles and unstable angina was confirmed by multivariate logistic regression analysis, in which the number of G (PHACTR1 rs9349379) and T (LMOD1 rs2820315) alleles was an independent risk factor for unstable angina. The results suggest an association between PHACTR1 rs9349379 and LMOD1 rs2820315 polymorphisms and the risk of unstable angina.

High Glucose-Induced Vascular Smooth Muscle Cell Proliferation and Migration are Regulated by the miR-34a-Notch1 Pathway

High glucose(HG)-induced excessive proliferation and migration of the media vascular smooth muscle cell(VSMC) are the main pathological characteristics in diabetes related vascular injuries. Previous studies have shown that microRNA-34a (miR-34a) is involved in cancer metastasis, proliferation and invasion and plays an essential role in cardiovascular disease. However, little is known about the regulating role miR-34a in HG-induced proliferation and migration of VSMC. Here we demonstrated that miR-34a was downregulated at different timepoints under HG stimulation. Then, HG induced proliferation and migration was found to be impaired by miR-34a overexpression using transwell, CCK8 and RT-qPCR assays. Furthermore, the HG-induced depression of “contractile” VSMC-specific markers were reversed by the overexpression of miR-34a. Moreover, we confirmed that miR-34a regulated HG-induced VSMC proliferation and migration through its target gene, Notch1, which has been shown to be associated with cell proliferation and migration in previous studies. Taken together, we propose that the miR34a-Notch1 axis plays an important role in regulating HG-induced VSMC proliferation and migration.

Roles of mTOR in thoracic aortopathy understood by complex intracellular signaling interactions

Thoracic aortopathy–aneurysm, dissection, and rupture–is increasingly responsible for significant morbidity and mortality. Advances in medical genetics and imaging have improved diagnosis and thus enabled earlier prophylactic surgical intervention in many cases. There remains a pressing need, however, to understand better the underlying molecular and cellular mechanisms with the hope of finding robust pharmacotherapies. Diverse studies in patients and mouse models of aortopathy have revealed critical changes in multiple smooth muscle cell signaling pathways that associate with disease, yet integrating information across studies and models has remained challenging. We present a new quantitative network model that includes many of the key smooth muscle cell signaling pathways and validate the model using a detailed data set that focuses on hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and its inhibition using rapamycin. We show that the model can be parameterized to capture the primary experimental findings both qualitatively and quantitatively. We further show that simulating a population of cells by varying receptor reaction weights leads to distinct proteomic clusters within the population, and that these clusters emerge due to a bistable switch driven by positive feedback in the PI3K/AKT/mTOR signaling pathway.