Calcitonin Inhibits Phenotypic Switching of Aortic Smooth Muscle Cells and Neointimal Hyperplasia through the AMP-Activated Protein Kinase/Mechanistic Target of Rapamycin Pathway.

Calcitonin (CT) is a peptide hormone secreted by the parafollicular C cells of the thyroid gland, salmon calcitonin was originally extracted from the hind cheek of salmon. Neointimal hyperplasia refers to the excessive proliferation and migration of vascular smooth muscle cells (VSMCs). In this study, a rat model of restenosis was employed to explore the impact of calcitonin on neointima proliferation. Calcitonin was administered via continuous injections for a duration of 14 days postsurgery, and the expression of proteins associated with proliferation, migration, and phenotypic switching was assessed using the vascular smooth muscle cells. Additionally, metabolomic analyses were conducted to shed light on the mechanisms that underlie the role of calcitonin in the development of cardiovascular disease. In our study, we found that calcitonin possesses the capability to dispute the proliferation, migration, and phenotypic transformation of VSMCs induced by platelet-derived growth factor-BB (PDGF-BB) and 15% fetal bovine serum in vitro. Calcitonin has demonstrated a favorable impact on smooth muscle cells, both in vitro and in vivo. More specifically, it has been observed to mitigate phenotypic switching, proliferation, and migration of these cells. Moreover, calcitonin has been identified as a protective factor against phenotypic switching and the formation of neointima, operating through the AMP-activated protein kinase/mechanistic target of rapamycin (mTOR) pathway.

Identification of predictors for the comprehensive clinical risk and severity of coronary lesions of acute coronary syndrome.

Background: Acute coronary syndrome (ACS) is the most common cause of death in patients with coronary artery disease. The aim of the study was to identify the predictors of both comprehensive clinical risk and severity of coronary lesions by comprehensive use of GRACE and SYNTAX scores in patients with ACS. Methods: Clinical data of 225 ACS patients who underwent coronary angiography between 2015 and 2016 were collected. Multiple logistic regression analysis (stepwise) was used to identify the predictors. The predictive ability of predictors and the model were determined using receiver operating characteristics analyses. Results: Multivariable logistic regression analyses showed that high aspartate aminotransferase (AST) predicted the comprehensive clinical risk with odds ratios (ORs) and 95% confidence intervals (CIs) of 1.011 (1.002-1.021). High total cholesterol (TC) and red blood cell distribution width (RDW) predicted the severity of coronary lesions with ORs and 95% CIs of 1.517 (1.148-2.004) and 1.556 (1.195-2.028), respectively. Low prealbumin predicted both severity of coronary lesions and comprehensive clinical risk of ACS patients with ORs and 95% CIs of 0.743 (0.672-0.821) and 0.836 (0.769-0.909), respectively. The model with a combination of prealbumin and AST had the highest predictive efficacy for comprehensive clinical risk, and the combination of prealbumin, TC, and RDW had the highest predictive efficacy for the severity of coronary lesions. The sensitivity and specificity, and the optimal cut-off values of these four indexes were determined. Conclusions: Four predictors for the comprehensive clinical risk and severity of coronary lesions of ACS were identified, which provided important information for the early diagnosis and appropriate treatment of ACS.

N6-Methyladenosine Methyltransferase METTL3 Promotes Angiogenesis and Atherosclerosis by Upregulating the JAK2/STAT3 Pathway via m6A Reader IGF2BP1.

Atherosclerosis (AS) is a life-threatening vascular disease. RNA N6-methyladenosine (m6A) modification level is dysregulated in multiple pathophysiologic processes including AS. In this text, the roles and molecular mechanisms of m6A writer METTL3 in AS progression were explored in vitro and in vivo. In the present study, cell proliferative, migratory, and tube formation capacities were assessed through CCK-8, Transwell migration, and tube formation assays, respectively. RNA m6A level was examined through a commercial kit. RNA and protein levels of genes were measured through RT-qPCR and western blot assays, respectively. VEGF secretion level was tested through ELISA assay. JAK2 mRNA stability was detected through actinomycin D assay. The relationship of METTL3, IGF2BP1, and JAK2 was investigated through bioinformatics analysis, MeRIP, RIP, RNA pull-down, and luciferase reporter assays. An AS mouse model was established to examine the effect of METTL3 knockdown on AS development in vivo. The angiogenetic activity was examined through chick chorioallantoic membrane assay in vivo. The results showed that METTL3 was highly expressed in ox-LDL-induced dysregulated HUVECs. METTL3 knockdown inhibited cell proliferation, migration, tube formation, and VEGF expression/secretion in ox-LDL-treated HUVECs, hampered AS process in vivo, and prevented in vivo angiogenesis of developing embryos. METTL3 positively regulated JAK2 expression and JAK2/STAT3 pathway in an m6A dependent manner in HUVECs. IGF2BP1 positively regulated JAK2 expression through directly binding to an m6A site within JAK2 mRNA in HUVECs. METTL3 knockdown weakened the interaction of JAK2 and IGF2BP1. METTL3 exerted its functions through JAK2/STAT3 pathway. In conclusion, METTL3 knockdown prevented AS progression by inhibiting JAK2/STAT3 pathway via IGF2BP1.