Homeobox A9 is a novel mediator of vascular smooth muscle cell phenotypic switching and proliferation by regulating methyl-CpG binding protein 2.

Aberrant proliferation and phenotypic switching of vascular smooth muscle cells (VSMCs) are considered to be the main pathological processes of atherosclerotic plaque formation. Methyl-CpG binding protein 2 (MECP2) affects cell differentiation via modulating VSMC-specific gene expression and acts as a driver for the development of atherosclerosis (AS). Here, we aimed to elucidate the role of homeobox A9 (HOXA9) on aberrant VSMCs upon injury or AS, and whether HOXA9-mediated VSMC injury was associated with MECP2. Adeno-associated virus serotype 8-mediated knockdown of HOXA9 rescued aortic pathological injury of apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet (HFD), characterized by the reduction of lipid accumulation and foam cell formation. Further in vitro evidence suggested that proliferation and migration of primary mouse VSMCs (mVSMCs) stimulated by oxidized low-density lipoprotein (ox-LDL) were inhibited after HOXA9 silencing. In addition, HOXA9 silencing blocked VSMC phenotypic switching from contractile to a pathological synthetic state. HOXA9 overexpression caused opposite alterations in ox-LDL-stimulated mVSMCs. Mechanistically, MECP2 was transcriptionally activated by HOXA9. Forced expression of MECP2 impaired the anti-proliferation, anti-migration, and phenotypic switching abilities of HOXA9 silencing in VSMCs upon ox-LDL stimulation. Collectively, our findings reveal that the role of HOXA9 in pathological vascular remodeling may attribute to transcriptional regulation of MECP2.

Nonalcoholic Fatty Liver Disease as an Emerging Risk Factor and Potential Intervention Target for Atherosclerotic Cardiovascular Diseases.

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is an underappreciated independent risk factor for atherosclerotic cardiovascular diseases (ASCVDs). In recent years, the risk of ASCVD has increased along with the prevalence of NAFLD. ASCVD events are highly prevalent and are the main contributor to death in patients with NAFLD. The association between NAFLD and ASCVD has been validated in numerous observational, cohort, and genetic studies. Most of these studies agree that NAFLD significantly increases the risk of developing atherosclerosis and ASCVD. In addition, the underlying proatherosclerotic mechanisms of NAFLD have been gradually revealed; both disorders share several common pathophysiologic mechanisms including insulin resistance, whereas systemic inflammation and dyslipidemia driven by NAFLD directly promote atherosclerosis. Recently, NAFLD, as an emerging risk enhancer for ASCVD, has attracted attention as a potential treatment target for ASCVD. This brief review aims to illustrate the potential mechanistic insights, present recent clinically relevant investigations, and further explore the emerging therapies such as novel antidiabetic and lipid-lowering agents that could improve NAFLD and reduce ASCVD risk.

Research progress on the effects of novel hypoglycemic drugs in diabetes combined with myocardial ischemia/reperfusion injury.

Acute myocardial infarction (AMI) reperfusion is associated with ischemia/reperfusion (I/R) injury, which leads to enlarged myocardial infarction size, poor healing of the infarcted myocardium, and poor left ventricular remodeling, thus increasing the risk of major adverse cardiovascular events (MACEs). Diabetes increases myocardial susceptibility to I/R injury, decreases myocardial responsiveness to cardioprotective strategies, exacerbates myocardial I/R injury, and expands the infarct size of AMI, thereby increasing the incidence of malignant arrhythmias and heart failure. Currently, evidence regarding pharmacological interventions for diabetes combined with AMI and I/R injury is lacking. Traditional hypoglycemic drugs have a limited role in the prevention and treatment of diabetes combined with I/R injury. Current evidence suggests that novel hypoglycemic drugs may exert a preventive effect on diabetes combined with myocardial I/R injury, especially glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-dependent glucose transporter protein 2 inhibitors (SGLT2i), which may increase coronary blood flow, reduce acute thrombosis, attenuate I/R injury, decrease myocardial infarction size, inhibit structural and functional remodeling of the ischemic heart, improve cardiac function, and reduce the occurrence of MACEs of diabetes patients combined with AMI via mechanisms such as reduction of inflammatory response, inhibition of oxidative stress, and improvement of vascular endothelial function. This paper will systematically elaborate the protective role and molecular mechanisms of GLP-1 RA and SGLT2i in diabetes combined with myocardial I/R injury, aiming to provide clinical assistance.

Increased risk of adverse cardiovascular events by strict glycemic control after percutaneous coronary intervention (HbA1c < 6.5% at 2 years) in type 2 diabetes mellitus combined with acute coronary syndrome: a 5-years follow-up study.

OBJECTIVE: This study assessed the association between HbA1c level measured 2 years after percutaneous coronary intervention (PCI) and long-term clinical outcomes in type 2 diabetes mellitus combined with acute coronary syndrome (ACS) who underwent PCI. METHODS: This prospective observational study analyzed 2877 ACS patients with type 2 diabetes mellitus whose baseline HbA1c ≥ 7.0% and underwent PCI. All patients were divided into 6 groups according to the HbA1c level at 2 years after PCI. The clinical outcome was major adverse cardiovascular events (MACEs), defined as all-cause death, all myocardial infarction, any revascularization, congestive heart failure, ischemic stroke. The median follow-up duration was 4.1 years. RESULTS: All 2877 patients were divided into 6 groups: 2-year after PCI HbA1c < 6.0% (n = 219), 6.0-6.5% (n = 348), 6.5-7.0% (n = 882), 7.0-7.5% (n = 567), 7.5-8.0% (n = 441), ≥8.0% (n = 420). The 5-year incidence rate of MACEs in HbA1c <6.0% and 6.0-6.5% groups were similar to 7.5-8.0% and ≥8.0% groups, which were significantly higher than in 6.5-7.0% and 7.0-7.5% groups (p = .044). The cumulative incidence rate of MACEs significantly differed among the groups (p = .046). Multivariate Cox regression analysis revealed a U-shaped relationship between 2-year HbA1c level after PCI and risk of MACEs. 2-year HbA1c <6.5% after PCI was an independent risk factor for MACEs in type 2 diabetes mellitus combined with ACS who underwent PCI (p < .001). CONCLUSIONS: The findings indicated an increased risk of MACEs by strict glycemic control after PCI (2-year HbA1c < 6.5% after PCI) in type 2 diabetes mellitus combined with ACS who underwent PCI.

CircMAPK1 promotes the proliferation and migration of vascular smooth muscle cells through miR-22-3p/ methyl-CpG binding protein 2 axis.

BACKGROUND AND AIMS: Atherosclerosis is a chronic inflammatory disease. The proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to intimal hyperplasia. CircRNAs are class of endogenous RNA and implicated in the various biological processes. However, the role of circRNAs in atherosclerosis remains largely unknown. METHODS AND RESULTS: Mice models of atherosclerosis were established using APOE-/- mice fed with high-fat diet. High-throughput sequencing was performed to profile the expression of circRNAs in atherosclerosis. A total of 1289 circRNAs were identified. Six circRNAs were up-regulated and 12 circRNAs were down-regulated in the atherosclerotic plaque tissues. Then we focused on circMAPK1, which showed a high level in atherosclerosis. Silencing circMAPK1 suppressed the proliferation and migration of VSMCs. Further study showed that circMAPK1 bound with miR-22-3p. CircMAPK1 silencing increased the level of miR-22-3p and suppressed the level of MECP2, a known target of miR-22-3p. Interestingly, suppression of miR-22-3p rescued the effect of circMAPK1 silencing on the proliferation and migration of VSMCs. CONCLUSION: CircMPAK1 promoted the proliferation and migration of VSMCs through miR-22-3p/MECP2 axis. Our study revealed the role of circMAPK1 in atherosclerosis and shed lights on the treatment of atherosclerosis.

The value of fragmented QRS in predicting the prognosis of chronic total occlusion patients with myocardial infarction history undergoing percutaneous coronary intervention: A 24-months follow-up study.

BACKGROUND: Fragmented QRS (fQRS) is a marker of local myocardial scar. This study aimed to analyze the relationship between fQRS and coronary collateral circulation (CCC) and evaluate the predictive value of fQRS for long-term clinical outcomes among patients with chronic total occlusion (CTO) and prior myocardial infarction (MI) who underwent percutaneous coronary intervention (PCI). METHODS: A total of 862 patients with a definite history of MI who had one CTO coronary artery and underwent PCI between 2013 and 2018 were continuously analyzed. Patients were divided into group A (no Q wave and fQRS, n = 206), group B (fQRS, n = 265), group C (Q wave, n = 391). All patients were followed up for 2 years. RESULTS: The incidence rate of major adverse cardiovascular events (MACE) in group B was significantly lower than in group C (group B vs. C: 7.2% vs. 11.3%, P = 0.043). The percentage of good CCC was 94.2%, 88.3%, and 82.9% in group A, B, and C (p < .001), respectively. The improvement of cardiac function in group B and A were more significant than in group C. Multivariate Cox regression analysis showed fQRS was an independent protective factor of MACE after PCI within 2 years in CTO patients with prior MI (RR = 0.668, 95% CI [0.422-0.917], p = .001). CONCLUSION: fQRS is an independent protective factor of prognosis in patients with prior MI and one CTO vessel who underwent PCI, presenting with a higher rate of good CCC, less occurrence of MACE, and better heart function than in Q wave patients.

Secular trends of hypertension prevalence based on 2017 ACC/AHA and 2018 Chinese hypertension guidelines: Results from CHNS data (1991-2015).

This study aimed to assess the impact of the 2017 American College of Cardiology and American Heart Association (ACC/AHA) guideline and the 2018 Chinese hypertension guidelines on the different secular trends for hypertension prevalence. A total of 82 665 eligible individuals aged ≥20 years were selected from nine cross-sectional study periods (1991-2015) from the China Health and Nutrition Survey (CHNS). Over the 24-year period, the long-term trend for the prevalence of the 2017 ACC/AHA-defined age-adjusted hypertension showed an increase from 32.2% (95% confidence interval (CI): 31.0%-33.3%) in 1991 to 60.0% (95% CI: 58.6%-61.3%) in 2015 (Ptrend  < 0.001). According to the 2018 Chinese guideline for hypertension, the weighted hypertension prevalence increased from 10.0% (95% CI: 9.4%-10.5%) in 1991 to 28.7% (95% CI: 27.9%-29.6%) in 2015 (Ptrend  < 0.001). However, slopes of increasing prevalence of hypertension were significantly greater according to the 2017 ACC/AHA guideline than that based on Joint National Committee (JNC 7) report (ß = 1.00% vs ß = 0.67% per year, respectively, P = 0.041). Based on the 2017 ACC/AHA definition, the prevalence of stage 1 hypertension and elevated blood pressure significantly increase from 22.3% and 6.9% in 1991 to 31.2% and 10.1% in 2015 (all P < 0.05), respectively. The secular trend for the prevalence of hypertension according to the 2017 ACC/AHA guideline showed a greater rate of increase compared with the prevalence based on the 2018 Chinese hypertension guidelines. Public health initiatives should focus on the current status of hypertension in China because of the possible high prevalence of hypertension and concomitant vascular risks.

Non-ST-elevated myocardial infarction with "N" wave on electrocardiogram and culprit vessel in left circumflex has a risk equivalent to ST-elevated myocardial infarction.

BACKGROUND: It was found that delayed activation wave often appeared in terminal QRS wave in non-ST-elevated myocardial infarction (NSTEMI) with culprit vessel in left circumflex artery (LCX), yet little is known about the similarities among non-"N"-wave non-ST-elevated myocardial infarction (N-NSTEMI) and ST-elevated myocardial infarction (STEMI). HYPOTHESIS: In AMI patients with the culprit vessel in LCX, "N" wave NSTEMI has a risk equivalent to STEMI. METHODS: All 874 patients admitted to Shenjing Hospital of China Medical University between January 1, 2013 and December 30, 2017 were included and whose coronary angiography (CAG) indicated the culprit vessel in LCX. Patients were divided into three groups: ST-elevated myocardial infarction group (STEMI group, n = 322), "N" wave non-ST-elevated myocardial infarction group (N-NSTEMI group, n = 232) and non-"N"-wave NSTEMI group (non N-NSTEMI group, n = 320). The basic data and the incidence of MACE during hospitalization and 12 months were analyzed. RESULTS: In STEMI and N-NSTEMI groups, AST, CK, CK-MB, TnI, and stenosis severity were significantly higher than non N-NSTEMI (P < .05). The lesions in the N-NSTEMI and STEMI groups were more often located proximal LCX before giving rise to OM1 of LCX (P < .05), however, the non N-NSTEMI group was often located distal LCX after giving rise to OM1 and the OM1 (P < .05). The incidence rates of all MACEs, all-cause death, ST, TVR, and rUAP were similar in N-NSTEMI and STEMI groups, which were greater than non N-NSTEMI (P < .05). Both N-NSTEMI and STEMI are independent risk factors for MACE (P < .05). CONCLUSION: The basic data and the incidence of major adverse cardiac event were similar in N-NSTEMI and STEMI patients, N-NSTEMI has a risk equivalent to acute STEMI.

Artemisinin inhibits the proliferation, migration, and inflammatory reaction induced by tumor necrosis factor-α in vascular smooth muscle cells through nuclear factor kappa B pathway.

BACKGROUND: Atherosclerosis is an inflammatory disease with the most common pathologic process leading to cardiovascular diseases. The aim of this study was to evaluate the effect of artemisinin (ART) on the proliferation, migration, and inflammation induced by tumor necrosis factor-α (TNF-α) of rat vascular smooth muscle cells (VSMCs). MATERIALS AND METHODS: Primary rat VSMCs were pretreated with ART and then co-incubated with TNF-α. Cell proliferation was evaluated by MTT assay. Cell migration was assessed by transwell assay. Reactive oxygen species (ROS) production was measured by flow cytometry after staining with dichloro-dihydro-fluorescein diacetate. Inflammation factors of nitric oxide and prostaglandin E2 (PGE2) were measured by responding assay kits. Expression levels of nuclear factor kappa B (NF-κB) subunit NF-κB p65 and the regulator inhibitor of nuclear factor kappa-B kinase-alpha (IκBα) were tested by Western blot, meanwhile, the activation of NF-κB was observed by immunofluorescence assay. RESULTS: The proliferation, migration, and inflammation of VSMCs induced by TNF-α were significantly inhibited by ART treatment in a dose-dependent manner. Treatment with 100 µM ART for 2 h significantly reduced the expression of proliferating cell nuclear antigen and migration-related proteins matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). On the other hand, the same treatment decreased the inflammation factors production of nitric oxide and PGE2. Fluorescence-activated cell sorting analysis revealed that ART suppressed the ROS production induced by TNF-α. Western blot analysis showed that both inflammation mediators inducible nitric oxide synthase and cyclooxygenase and the NF-κB pathway subunit NF-κB p65 were downregulated by ART. CONCLUSIONS: The results suggest that ART can effectively inhibit the proliferation, migration, and inflammation of VSMCs induced by TNF-α through ROS-mediated NF-κB signal pathway.