Inhibition of YTHDF1 prevents hypoxia-induced pulmonary artery smooth muscle cell proliferation by regulating Foxm1 translation in an m6A-dependent manner.

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by pulmonary vascular remodeling. It refers to the abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs), and hypoxia is an important risk factor for this progression. The present study aims to investigate the role of YTHDF1 in the regulation of hypoxic PASMC proliferation and the underlying mechanism. Human PASMCs were transfected with si-YTHDF1/2/3 followed by treatment of hypoxia, and the PASMC proliferation and Foxm1 expression were detected. Through RNA pull-down, RNA immunoprecipitation, and protein synthesis assay, the mechanism of YTHDF1 regulating Foxm1 was explored. Next, Foxm1 was inhibited by thiostrepton, and cell proliferation was detected. In vivo, mice received a tail vein injection of adenovirus containing si-YTHDF1 and were exposed to hypoxia treatment. Pulmonary vascular changes, right ventricular systolic pressure (RVSP), and genes involving proliferation were analyzed. YTHDF1 silencing reduced more hypoxic PASMC proliferation and Foxm1 protein level than YTHDF2/3 silencing. Mechanical results showed that YTHDF1 interacted with Foxm1 mRNA and up-regulated Foxm1 protein level by enhancing the translation efficiency in an m6A-dependent manner. Furthermore, YTHDF1 facilitated hypoxic PASMC proliferation and proliferation marker expressions through up-regulation of Foxm1 in an m6A-dependent manner. In vivo, the YTHDF1 silencing alleviated pulmonary vascular changes and fibrosis, reduced RVSP, inhibited the interaction of YTHDF1 and Foxm1, and reduced proliferation marker levels, as compared to the PAH group. In conclusion, YTHDF1 silencing inhibits hypoxic PASMC proliferation by regulating Foxm1 translation in an m6A-dependent manner.

PINK1/Parkin-mediated mitophagy in cardiovascular disease: From pathogenesis to novel therapy.

Cardiovascular disease(CVD)is one of the predominant causes of death and morbidity. Mitochondria play a key role in maintaining cardiac energy metabolism. However, mitochondrial dysfunction leads to excessive production of ROS, resulting in oxidative damage to cardiomyocytes and contributing to a variety of cardiovascular diseases. In such a case, the clearance of impaired mitochondria is necessary. Currently, most studies have indicated an essential role for mitophagy in maintaining cardiac homeostasis and regulating CVD-related metabolic transition. Recent studies have implicated that PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy has been implicated in maintaining cardiomyocyte homeostasis. Here, we discuss the physiological and pathological roles of PINK1/Parkin-mediated mitophagy in the cardiovascular system, as well as potential therapeutic strategies based on PINK1/Parkin-mediated mitophagy modulation, which are of great significance for the prevention and treatment of cardiovascular diseases.

Integrated Bioinformatics-Based Analysis of Hub Genes and the Mechanism of Immune Infiltration Associated With Acute Myocardial Infarction.

Background: Acute myocardial infarction (AMI) is a fatal disease that causes high morbidity and mortality. It has been reported that AMI is associated with immune cell infiltration. Now, we aimed to identify the potential diagnostic biomarkers of AMI and uncover the immune cell infiltration profile of AMI. Methods: From the Gene Expression Omnibus (GEO) data set, three data sets (GSE48060, GSE60993, and GSE66360) were downloaded. Differentially expressed genes (DEGs) from AMI and healthy control samples were screened. Furthermore, DEGs were performed via gene ontology (GO) functional and kyoto encyclopedia of genes and genome (KEGG) pathway analyses. The Gene set enrichment analysis (GSEA) was used to analyze GO terms and KEGG pathways. Utilizing the Search Tool for Retrieval of Interacting Genes/Proteins (STRING) database, a protein-protein interaction (PPI) network was constructed, and the hub genes were identified. Then, the receiver operating characteristic (ROC) curves were constructed to analyze the diagnostic value of hub genes. And, the diagnostic value of hub genes was further validated in an independent data set GSE61144. Finally, CIBERSORT was used to represent the compositional patterns of the 22 types of immune cell fractions in AMI. Results: A total of 71 DEGs were identified. These DEGs were mainly enriched in immune response and immune-related pathways. Toll-like receptor 2 (TLR2), interleukin-1B (IL1B), leukocyte immunoglobulin-like receptor subfamily B2 (LILRB2), Fc fragment of IgE receptor Ig (FCER1G), formyl peptide receptor 1 (FPR1), and matrix metalloproteinase 9 (MMP9) were identified as diagnostic markers with the value of p < 0.05. Also, the immune cell infiltration analysis indicated that TLR2, IL1B, LILRB2, FCER1G, FPR1, and MMP9 were correlated with neutrophils, monocytes, resting natural killer (NK) cells, gamma delta T cells, and CD4 memory resting T cells. The fractions of monocytes and neutrophils were significantly higher in AMI tissues than in control tissues. Conclusion: TLR2, IL1B, LILRB2, FCER1G, FPR1, and MMP9 are involved in the process of AMI, which can be used as molecular biomarkers for the screening and diagnosis of AMI. In addition, the immune system plays a vital role in the occurrence and progression of AMI.

CISD1 protects against atherosclerosis by suppressing lipid accumulation and inflammation via mediating Drp1.

Atherosclerosis still remains the leading cause of morbidity and mortality worldwide, and deeper understanding of target signaling that protect from the atherosclerosis progression may provide novel therapeutic strategies. CDGSH iron-sulfur domain-containing protein 1 (CISD1) is a protein localized on the outer membrane of mitochondria, and plays key roles in regulating cell death and oxidative stress. However, its potential on atherosclerosis development and the underlying mechanisms are largely unknown. Here, in our study, we found markedly decreased CISD1 expression in lipid-laden THP1 macrophages. Notably, lentivirus (LV)-mediated CISD1 over-expression remarkably ameliorated lipid deposition in macrophages stimulated by ox-LDL. Furthermore, cellular total ROS and mitochondrial ROS generation, and impairment of mitochondrial membrane potential (MMP) were highly induced by ox-LDL in THP1 cells, while being considerably reversed upon CISD1 over-expression. Inflammatory response caused by ox-LDL was also significantly restrained in macrophages with CISD1 over-expression. Mechanistically, we found that CISD1 could interact with dynamin-related protein 1 (Drp1). Intriguingly, CISD1-improved mitochondrial dysfunction and inflammation in ox-LDL-treated macrophages were strongly abolished by Drp1 over-expression, indicating that Drp1 suppression might be necessary for CISD1 to perform its protective effects in vitro. In high fat diet (HFD)-fed apolipoprotein E-deficient (ApoE-/-) mice, tail vein injection of lentiviral vector expressing CISD1 remarkably decreased atherosclerotic lesion area, serum LDL cholesterol levels and triglyceride contents. Inflammatory response, cellular total and mitochondrial ROS production, and Drp1 expression levels in aorta tissues were also dramatically ameliorated in HFD-fed ApoE-/- mice, contributing to the inhibition of atherosclerosis in vivo. Therefore, improving CISD1 expression may be a novel therapeutic strategy for atherosclerosis treatment.

De Winter syndrome as an emergency electrocardiogram sign of ST-elevation myocardial infarction: a case report.

The case report aims to reveal de Winter's electrocardiogram (ECG) pattern as an equivalent to anterior ST-segment elevation myocardial infarction (STEMI). We report a case of a 49-year-old man with a history of smoking who presented to the emergency department with a 1 day history of chest pain that was exacerbated 5 h prior to presentation. Detailed clinical investigations and coronary angiographic characteristics were recorded. The first ECG of the patient was consistent with de Winter syndrome. Acute coronary artery angiography showed that the proximal left anterior descending coronary artery was completely occluded after the first diagonal branch artery was given off. A percutaneous coronary intervention was immediately performed. Our case indicates that early identification and diagnosis of such ECGs and timely reperfusion therapy of de Winter syndrome as a STEMI equivalent are required to improve the prognosis of such patients.

A CRM1 Inhibitor Alleviates Cardiac Hypertrophy and Increases the Nuclear Distribution of NT-PGC-1α in NRVMs.

Chromosomal maintenance 1 (CRM1) inhibitors display antihypertrophic effects and control protein trafficking between the nucleus and the cytoplasm. PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1alpha) is a type of transcriptional coactivator that predominantly resides in the nucleus and is downregulated during heart failure. NT-PGC-1α is an alternative splicing variant of PGC-1α that is primarily distributed in the cytoplasm. We hypothesized that the use of a CRM1 inhibitor could shuttle NT-PGC-1α into the nucleus and activate PGC-1α target genes to potentially improve cardiac function in a mouse model of myocardial infarction (MI). We showed that PGC-1α and NT-PGC-1α were decreased in MI-induced heart failure mice. Phenylephrine and angiotensin II were applied to induce hypertrophy in neonatal rat ventricular myocytes (NRVMs). The antihypertrophic effects of the CRM1-inhibitor Selinexor was verified through profiling the expression of ß-MHC and through visualizing the cell cross-sectional area. NRVMs were transfected with adenovirus-NT-PGC-1α or adenovirus-NLS (nucleus localization sequence)-NT-PGC-1α and then exposed to Selinexor. Confocal microscopy was then used to observe the shuttling of NT-PGC-1α. After NT-PGC-1α was shuttled into the nucleus, there was increased expression of its related genes, including PPAR-α, Tfam, ERR-γ, CPT1b, PDK4, and Nrf2. The effects of Selinexor on post-MI C57BL/6j mice were determined by echocardiography and qPCR. We found that Selinexor showed antihypertrophic effects but did not influence the ejection fraction of MI-mice. Interestingly, the antihypertrophic effects of Selinexor might be independent of NT-PGC-1α transportation.

Metformin Increases Cardiac Rupture After Myocardial Infarction via the AMPK-MTOR/PGC-1α Signaling Pathway in Rats with Acute Myocardial Infarction.

BACKGROUND Cardiac rupture often occurs after acute myocardial infarction due to complex and unclear pathogenesis. This study investigated whether metformin increases the incidence of cardiac rupture after myocardial infarction through the AMPK-MTOR/PGC-1α signaling pathway. MATERIAL AND METHODS An acute myocardial infarction (MI) mouse model was established. A series of experiments involving RT-qPCR, Western blot, TUNEL staining, and Masson staining were performed in this study. RESULTS Myocardial infarction occurred, resulting in the cardiac rupture, and the expression level of PGC-1α increased in the cardiac myocardium. Meanwhile, the proportion of myocardial NT-PGC-1α/PGC-1α decreased. The expression level of myocardial PGC-1α in MI mice with cardiac rupture after MI was significantly higher than that in the mice without cardiac rupture, and the ratio of myocardial NT-PGC-1α/PGC-1α was low. In addition, increasing the dose of metformin significantly increased the incidence of cardiac rupture after myocardial infarction in MI mice. High-dose metformin caused cardiac rupture in MI mice. Moreover, high-dose metformin (Met 2.0 nM) reduces the proportion of NT-PGC-1α/PGC-1α in primary cardiomyocytes of SD mice (SD-NRVCs [Neonatal rat ventricular cardiomyocytes]), and its effect was inhibited by Compound C (AMPK inhibitor). Further, after 3 days of treatment with high-dose metformin in MI mice, myocardial fibrin synthesis decreased and fibrosis was significantly inhibited. Meanwhile, cardiomyocyte apoptosis increased significantly. With the increase in metformin concentration, the expression level of myocardial LC3b gradually increased in MI mice, suggesting that metformin enhances the autophagy of cardiomyocytes. CONCLUSIONS These results suggest that metformin increases cardiac rupture after myocardial infarction through the AMPK-MTOR/PGC-1α signaling pathway.

N­terminal truncated peroxisome proliferator­activated receptor­Î³ coactivator­1α alleviates phenylephrine­induced mitochondrial dysfunction and decreases lipid droplet accumulation in neonatal rat cardiomyocytes.

N­terminal truncated peroxisome proliferator­activated receptor­Î³ coactivator­1α (NT­PGC­1α) is an alternative splice variant of PGC­1α. NT­PGC­1α exhibits stronger anti­obesity effects in adipose tissue than PGC­1α; however, NT­PGC­1α has not yet been investigated in neonatal rat cardiomyocytes (NRCMs). The present study aimed to investigate the role of NT­PGC­1α in mitochondrial fatty acid metabolism and its possible regulatory mechanism in NRCMs. NRCMs were exposed to phenylephrine (PE) or angiotensin II (Ang II) to induce cardiac hypertrophy. Following this, NRCMs were infected with adenovirus expressing NT­PGC­1α, and adenosine 5'­triphsophate (ATP) levels, reactive oxygen species (ROS) generation and mitochondrial membrane potential were subsequently detected. In addition, western blotting, lipid droplet staining and oxygen consumption assays were performed to examine the function of NT­PGC­1α in fatty acid metabolism. NT­PGC­1α was demonstrated to be primarily expressed in the cytoplasm, which differed from full­length PGC­1α, which was predominantly expressed in the nucleus. NT­PGC­1α overexpression alleviated mitochondrial function impairment, including ATP generation, ROS production and mitochondrial membrane potential integrity. Furthermore, NT­PGC­1α overexpression alleviated the PE­induced suppression of fatty acid metabolism­associated protein expression, increased extracellular oxygen consumption and decreased lipid droplet accumulation in NRCMs. Taken together, the present study demonstrated that NT­PGC­1α alleviated PE­induced mitochondrial impairment and decreased lipid droplet accumulation in NRCMs, indicating that NT­PGC­1α may have ameliorated mitochondrial energy defects in NRCMs, and may be considered as a potential target for the treatment of heart failure.

PTEN induced putative kinase 1 (PINK1) alleviates angiotensin II-induced cardiac injury by ameliorating mitochondrial dysfunction.

BACKGROUND: Mitochondrial quality control is crucial to the development of angiotensin II (AngII)-induced cardiac hypertrophy. PTEN induced putative kinase 1 (PINK1) is rapidly degraded in normal mitochondria but accumulates in damaged mitochondria, triggering autophagy to protect cells. PINK1 mediates mitophagy in general, but whether PINK1 mediates AngII-induced mitophagy and the effects of PINK1 on AngII-induced injury are unknown. This study was designed to investigate the function of PINK1 in an AngII stimulation model and its regulation of AngII-induced mitophagy. METHODS: We studied the function of PINK1 in mitochondrial homeostasis in AngII-stimulated cardiomyocytes via RNA interference-mediated knockdown and adenovirus-mediated overexpression of the PINK1 protein. Mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, adenosine triphosphate (ATP) content, cell apoptosis rates and cardiomyocyte hypertrophy were measured. The expression of LC3B, Beclin1 and p62 was measured. Mitochondrial morphology was examined via electron microscopy. Mitophagy was detected by confocal microscopy based on the co-localization of lysosomes and mitochondria. Additionally, endogenous PINK1, phosphorylated PINK1, mito-PINK1, total Parkin, cyto-Parkin, mito-Parkin and phosphorylated Parkin protein levels were measured. RESULTS: Cardiomyocytes untreated by AngII had very low levels of total and phosphorylated PINK1. However, in the AngII stimulation model, the MMP was decreased, and the levels of total and phosphorylated PINK1 were increased. After PINK1 was knocked down, Parkin translocation to the mitochondria was inhibited. Moreover, levels of phosphorylated Parkin were reduced, and autophagy markers were downregulated. MMP and ATP contents were further reduced, ROS production and the apoptotic rate were further increased, and myocardial hypertrophy was further aggravated compared with those in the AngII group. However, PINK1 overexpression promoted Parkin translocation and phosphorylation, autophagy markers were upregulated, and myocardial injury was reduced. In addition, the effects of PINK1 overexpression were reversed by autophagy inhibitors. CONCLUSION: Decreased MMP induced by AngII maintains the stability of PINK1, causing PINK1 autophosphorylation. PINK1 activation promotes Parkin translocation and phosphorylation and increases autophagy to clear damaged mitochondria. Thus, PINK1/Parkin-mediated mitophagy has a compensatory, protective role in AngII-induced cytotoxicity.

Characterization of the Myocarditis during the worst outbreak of dengue infection in China.

Myocarditis is a common complication of severe dengue infection. However, data about prevalence and characterization of myocarditis in dengue are still lacking. In 2014, the worst outbreak of dengue in the last two decades in China occurred. In this study, we described the clinical and laboratory diagnostic features of dengue with myocarditis. Totally, 1782 diagnosed dengue patients were admitted from August to October, 2014, all of whom were subjected to electrocardiogram, ultrasound cardiogram, and cardiac enzyme test. About 201 cases of dengue patients were diagnosed with myocarditis and the prevalence of myocarditis in hospitalized dengue was 11.28%. The prevalence of myocarditis in nonsevere dengue with warning signs and severe dengue [NSD(WS+)/SD] and nonsevere dengue without warning signs [NSD(WS-)] was 46.66% and 9.72%, respectively. The NSD(WS+)/SD patients with myocarditis presented with higher incidence of cardiac symptoms, supraventricular tachycardia (14.29% vs. 0%, P < 0.001), atrial fibrillation (25.71% vs. 10.24%, P = 0.019) and heart failure compared with NSD (WS-) patients with myocarditis. About 150 cases of dengue patients without myocarditis in the same period of time in department of Cardiology were recruited as control group. The proportion of NSD(WS+)/SD in dengue patients with and without myocarditis was 17.41% and 2.53%, respectively. Dengue patients with myocarditis experienced longer hospital stay than those without myocarditis (7.17 ±â€Š4.64 vs. 5.98 ±â€Š2.69, P = 0.008). There was no difference between patients with and without myocarditis in the proportion of symptoms, auxiliary methods abnormality, arrhythmia, and heart failure on the discharge day. Our study demonstrates the prevalence of myocarditis in worst outbreak of dengue in China was 11.28% and the incidence of myocarditis increased with the severity of dengue. The NSD(WS+)/SD patients with myocarditis presented with higher incidence of cardiac complication compared with NSD (WS-) patients with myocarditis. The prognosis of dengue patients with and without myocarditis had no significant difference even if myocarditis patients experienced longer hospital stay.

Association between job strain and risk of incident stroke: A meta-analysis.

OBJECTIVE: Prospective cohort studies regarding job strain and the risk of stroke are controversial. This meta-analysis aimed to evaluate the association between job strain and the risk of stroke. METHODS: The PubMed, Embase, and PsycINFO databases were searched for prospective cohort studies with data on job strain and the risk of stroke. Studies were included if they reported adjusted relative risks (RRs) with 95% confidence intervals (CIs) of stroke from job strain. Subgroup analyses were conducted according to sex and stroke type. RESULTS: Six prospective cohort studies comprising 138,782 participants were included. High strain jobs were associated with increased risk of stroke (RR 1.22, 95% CI 1.01-1.47) compared with low strain jobs. The result was more pronounced for ischemic stroke (RR 1.58, 95% CI 1.12-2.23). The risk of stroke was significant in women (RR 1.33, 95% CI 1.04-1.69) and nonsignificant in men (RR 1.26, 95% CI 0.69-2.27), but the difference in RRs in sex subgroups was not significant. Neither active (RR 1.07, 95% CI 0.90-1.28) nor passive (RR 1.01, 95% CI 0.86-1.18) job characteristics were associated with an increased risk of stroke compared with low strain jobs. CONCLUSIONS: Exposure to high strain jobs was associated with an increased risk of stroke, especially in women. Further studies are needed to confirm whether interventions to reduce work stress decrease the risk of stroke.

Prehypertension and the risk of coronary heart disease in Asian and Western populations: a meta-analysis.

BACKGROUND: The results of studies on the association between prehypertension (blood pressure 120 to 139/80 to 89 mm Hg) and coronary heart disease (CHD) remain controversial. Furthermore, it is unclear whether prehypertension affects the risk of CHD in Asian and Western populations differently. This meta-analysis evaluated the risk of CHD associated with prehypertension and its different subgroups. METHODS AND RESULTS: The PubMed and Embase databases were searched for prospective cohort studies with data on prehypertension and the risk of CHD. Studies were included if they reported multivariate-adjusted relative risks (RRs) with 95% CIs of CHD from prehypertension. A total of 591 664 participants from 17 prospective cohort studies were included. Prehypertension increased the risk of CHD (RR 1.43, 95% CI 1.26 to 1.63, P<0.001) compared with optimal blood pressure (<120/80 mm Hg). The risk of CHD was higher in Western than in Asian participants (Western: RR 1.70, 95% CI 1.49 to 1.94; Asian: RR 1.25, 95% CI 1.12 to 1.38; ratio of RRs 1.36, 95% CI 1.15 to 1.61). The population-attributable risk indicated that 8.4% of CHD in Asian participants was attributed to prehypertension, whereas this proportion was 24.1% in Western participants. CONCLUSIONS: Prehypertension, even at the low range, is associated with an increased risk of CHD. This risk is more pronounced in Western than in Asian populations. These results supported the heterogeneity of target-organ damage caused by prehypertension and hypertension among different ethnicities and underscore the importance of prevention of CHD in Western patients with prehypertension.

Prevalence and risk factors associated with prehypertension in Shunde District, southern China.

OBJECTIVE: To explore the prevalence and combined cardiovascular risk factors of prehypertension in southern China. DESIGN: A retrospective study; the logistic regression model was used to find the risk factors of prehypertension. SETTING: The study was conducted in Shunde District, southern China, using the community-based health check-up information. PARTICIPANTS: Participants aged ≥35 years with complete health check-up information data between January 2011 and December 2013 were enrolled and divided into hypertension, prehypertension and optimal blood pressure (BP) groups. Prehypertension was further divided into low-range (BP 120-129/80-84 mm Hg) and high-range (BP 130-139/85-89 mm Hg) subgroups. OUTCOME MEASURES: The prevalence of prehypertension and the combined cardiovascular risk factors within the prehypertensive subgroups. RESULTS: Of the 5362 initially reviewed cases (aged ≥35 years), 651 were excluded because of missing data. The proportions of optimal BP, prehypertension and hypertension were 39.1%, 38.6% and 22.3%, respectively. The average age, proportion of male sex, overweight, impaired fasting glucose (IFG), dyslipidaemia and hyperuricaemia were significantly higher in the prehypertension group than in the optimal BP group (all p <0.05). Compared with low-range prehypertension, the proportions of overweight, dyslipidaemia and IFG were higher in the high-range prehypertension group (all p<0.05). Multivariate logistic regression analysis showed that overweight (OR=2.84, 95% CI 1.55 to 5.20), male sex (OR=2.19, 95% CI 1.39 to 3.45), age (per 10 years, OR=1.21, 95% CI 1.02 to 1.44, p=0.03) and hyperuricaemia (OR=1.70, 95% CI 1.14 to 2.54) were independent risk factors of prehypertension. CONCLUSIONS: Prehypertension is highly prevalent in southern China. Prehypertensive individuals presented with many other cardiovascular risk factors. There was heterogeneity of combined risk factors within the prehypertensive subgroups.

[Value of biochemical marker detection in risk stratification in patients with acute coronary syndrome].

OBJECTIVE: To assess the value of biochemical marker detection in risk stratification in hospitalized patients with acute coronary syndrome (ACS). METHODS: A total of 264 consecutive patients (180 male and 84 female patients) admitted for complaint of chest tightness or/and pain were evaluated for a decision of coronary angiography (CAG) within 24 h after admission. The patients were divided into two groups to receive emergency or elective CAG. The venous blood samples were taken from the patient immediately after admission for detection of amino-terminal pro-brain natriuretic peptide (NT-pro-BNP), high-sensitivity C-reactive protein (hs-CRP), myeloperoxidase (MPO), monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule (sICAM-1), soluble CD40 ligand (sCD40L), matrix metalloproteinase 9 (MMP-9), interleukin-6 (IL-6), interleukin 27 (IL-27) and creatine kinase isoenzyme (CK-MB) were detected. RESULTS: No significant differences in NT-proBNP, hs-CRP, MPO, sCD40L, and MMP-9 were found between emergency CAG group and elective CAG group (P<0.05). Logistic regression identified significant differences in NT-proBNP, hs-CRP, MPO, IL-27 and CK-MB between the two groups, and a predictive model for risk stratification of ACS was established using these biomarkers. The ROC curves of this predictive model showed an area under the curve of 98.1, suggesting a high predictive value of this model in assessment of the changes or progression of ACS. CONCLUSION: Combined detection of the biochemical markers can be helpful for risk stratification of the hospitalized patients with ACS early after admission.