MicroRNA-122-5p promotes renal fibrosis and injury in spontaneously hypertensive rats by targeting FOXO3.

Hypertensive renal injury is accompanied by tubular interstitial fibrosis leading to increased risk for renal failure. This study aimed to explore the influences of miR-122-5p in hypertension-mediated renal fibrosis and damage. 14-week-old male SHR and WKY rats were randomly assigned to treat with rAAV-miR-122-5p or rAAV-GFP for 8 weeks. There were marked increases in miR-122-5p and Kim-1 levels and decreases in FOXO3 and SIRT6 levels in hypertensive rats. Transfection with rAAV-miR-122-5p triggered exacerbation of renal fibrosis, apoptosis and inflammatory injury in SHR, associated with downregulated levels of FOXO3, SIRT6, ATG5 and BNIP3 as well as upregulated expression of Kim-1, NOX4, CTGF, and TGF-ß1. In cultured primary mouse renal tubular interstitial fibroblasts, exposure to angiotensin II resulted in obvious downregulation of FOXO3, SIRT6, ATG5, BNIP3 and nitric oxide levels as well as augmented cellular migration, oxidative stress, and inflammation, which were exacerbated by miR-122-5p mimic while rescued by miR-122-5p inhibitor and rhFOXO3, respectively. Notably, knockdown of FOXO3 strikingly blunted cellular protective effects of miR-122-5p inhibitor. In summary, miR-122-5p augments renal fibrosis, inflammatory and oxidant injury in hypertensive rats by suppressing the expression of FOXO3. Pharmacological inhibition of miR-122-5p has potential therapeutic significance for hypertensive renal injury and fibrosis-related kidney diseases.

Targeting the forkhead box protein P1 pathway as a novel therapeutic approach for cardiovascular diseases.

Cardiovascular disease (CVD) is the leading cause of death worldwide and encompasses diverse diseases of the vasculature, myocardium, cardiac electrical circuit, and cardiac development. Forkhead box protein P1 (Foxp1) is a large multi-domain transcriptional regulator belonging to the Fox family with winged helix DNA-binding protein, which plays critical roles in cardiovascular homeostasis and disorders. The broad distribution of Foxp1 and alternative splicing isoforms implicate its distinct functions in diverse cardiac and vascular cells and tissue types. Foxp1 is essential for diverse biological processes and has been shown to regulate cellular proliferation, apoptosis, oxidative stress, fibrosis, angiogenesis, cardiovascular remodeling, and dysfunction. Notably, both loss-of-function and gain-of-function approaches have defined critical roles of Foxp1 in CVD. Genetic deletion of Foxp1 results in pathological cardiac remodeling, exacerbation of atherosclerotic lesion formation, prolonged occlusive thrombus formation, severe cardiac defects, and embryo death. In contrast, activation of Foxp1 performs a wide range of physiological effects, including cell growth, hypertrophy, differentiation, angiogenesis, and cardiac development. More importantly, Foxp1 exerts anti-inflammatory and anti-atherosclerotic effects in controlling coronary thrombus formation and myocardial infarction (MI). Thus, targeting for Foxp1 signaling has emerged as a pre-warning biomarker and a novel therapeutic approach against progression of CVD, and an increased understanding of cardiovascular actions of the Foxp1 signaling will help to develop effective interventions. In this review, we focus on the diverse actions and underlying mechanisms of Foxp1 highlighting its roles in CVD, including heart failure, MI, atherosclerosis, congenital heart defects, and atrial fibrillation.

Genetic deletion of CMG2 exacerbates systemic-to-pulmonary shunt-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) secondary to congenital heart disease (CHD-PAH) with systemic-to-pulmonary shunt (SPS) is characterized by proliferative vascular remodeling. Capillary morphogenesis gene-2 (CMG2) plays a key role in cell proliferation and apoptosis. This study aimed to determine the role of CMG2 in the pathogenesis of SPS-induced PAH. CMG2 levels were significantly downregulated in pulmonary arterioles from patients with Eisenmenger syndrome and rats with SPS-induced PAH. CMG2 was highly expressed in several cells including human pulmonary arterial smooth muscle cells (HPASMCs). CMG2-/- rats exhibited more severe PAH and pulmonary vascular remodeling than wild-type rats when exposed to SPS for 8 weeks. Overexpression of CMG2 significantly inhibited proliferation and promoted apoptosis of HPASMCs, while knockdown of CMG2 promoted cell proliferation and inhibited cell apoptosis. Next-generation sequencing and subsequent validation results suggested that PI3K-AKT was the most prominent signaling pathway regulated by differentially expressed genes (DEGs) in CMG2-/- rat lungs. Our work identified a novel role for CMG2 in SPS-induced PAH based on the findings that CMG2 deficiency exacerbates SPS-induced vascular remodeling in the development of PAH, indicating that CMG2 might act as a potential target for the treatment of CHD-PAH.

Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2.

ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1-7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases.

Association between Gut Microbiota Dysbiosis and the CHA2DS2-VASc Score in Atrial Fibrillation Patients.

Background: In our previous studies, we found a disordered taxonomic composition and function of gut microbiota (GM) in atrial fibrillation (AF) patients. However, direct evidence about the association between dysbiotic microbiota and thromboembolic risk in AF is lacking. Aims: In this study, we analyzed the interaction of GM and related functional patterns in AF with different CHA2DS2-VASc scores to assess its potential as a biomarker for predicting stroke risk. Patients and Methods. The CHA2DS2-VASc score was used for thromboembolic risk stratification in AF according to American Heart Association (AHA) guidelines. We investigated the taxonomic and functional annotation of GM based on metagenomic data from 50 AF patients (32 with high thromboembolic risk (CHA2DS2-VASc score ≥2 (males) or CHA2DS2-VASc score ≥3 (females)) and 18 individuals with low thromboembolic risk (CHA2DS2-VASc score <2 (males) or CHA2DS2-VASc score <3 (females))). Results: The gut microbial diversity, composition, and function in AF were different in high and low CHA2DS2-VASc score groups. In high thromboembolic risk group, the abundance of Prevotella, Lachnospiraceae, and Eubacterium rectale, related to the production of short-chain fatty acids and anti-inflammatory were reduced (all P < 0.05). Furthermore, annotated by Kyoto Encyclopedia of Genes and Genomes (KEGG), a database of genes and genomes, the KEGG orthology-based scoring approach exhibited a significant association with thromboembolic risk in AF patients. Conclusions: Imbalance of GM and microbial dysfunction are involved in aggravated thromboembolic risk of AF.

Diagnostic value of miRNA expression and right ventricular echocardiographic functional parameters for chronic thromboembolic pulmonary hypertension with right ventricular dysfunction and injury.

BACKGROUND: We aimed to establish the relationships between the expression of microRNAs (miRNAs) and echocardiographic right ventricular (RV) function parameters, and to explore the effectiveness and clinical value of miRNA expression in predicting RV injury and dysfunction in patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: In this retrospective study, clinical data were collected from eight CTEPH patients and eight healthy individuals. RV parameters on echocardiography were analyzed, and the expression levels of specific miRNAs were measured by quantitative real-time PCR. Correlation analysis was performed on structural and functional RV parameters and five candidate miRNAs (miR-20a-5p, miR-17-5p, miR-93-5p, miR-3202 and miR-665). The diagnostic value of RV functional parameters and miRNAs expression was assessed by receiver operating characteristic (ROC) curve analysis and C statistic. RESULTS: Among the tested miRNAs, miR-20a-5p expression showed the best correlation with echocardiographic RV functional parameters (P < 0.05), although the expression levels of miR-93-5p, miR-17-5p and miR-3202 showed positive associations with some RV parameters. ROC curve analysis demonstrated the ability of miR-20a-5p expression to predict RV dysfunction, with a maximum area under the curve of 0.952 (P = 0.003) when the predicted RV longitudinal strain was less than -20%. The C index for RV dysfunction prediction by the combination of miRNAs (miR-20a-5p, miR-93-5p and miR-17-5p) was 1.0, which was significantly larger than the values for miR-93-5p and miR-17-5p individually (P = 0.0337 and 0.0453, respectively). CONCLUSION: Among the tested miRNAs, miR -20a-5p, miR -93-5p and miR -17-5p have potential value in the diagnosis of CTEPH based on the correlation between the abnormal expression of these miRNAs and echocardiographic parameters in CTEPH patients. miR-20a-5p showed the strongest correlation with echocardiographic RV functional parameters. Moreover, expression of a combination of miRNAs seemed to show excellent predictive power for RV dysfunction.

Association of plasma bone morphogenetic protein-4 levels with arterial stiffness in hypertensive patients.

BACKGROUND: Arterial stiffness interacts with hypertension, becoming an early marker of hypertension-mediated target organ damage. This study aimed to assess the association between plasma concentrations of bone morphogenetic protein-4 (BMP-4) and arterial stiffness during hypertension. METHODS: Using cardio-ankle vascular index (CAVI) to determine arterial stiffness status, 204 individuals with essential hypertension were classified into two groups, high CAVI (abnormal) group (n = 94) and low (normal) CAVI group (n = 110). Data were collected including clinical characteristics and laboratory measurements. Plasma levels of BMP-4 were tested by using ELISA analysis. RESULTS: Plasma levels of BMP-4 were substantially greater in high CAVI group than that in low CAVI group [38.51 (31.79-50.83) pg/mL vs. 31.15 (29.38-32.37) pg/mL; p < 0.001]. As shown by spearman correlation analysis, BMP-4 concentrations were correlated with CAVI values in hypertensive individuals (r = 0.406, p < 0.001). After adjustment for potential confounders, elevated BMP-4 levels were related with high CAVI (OR, 1.070; 95% CI, 1.003-1.108; p < 0.001). The best BMP-4 cutoff value for identifying high CAVI, as determined by ROC curve analysis, was 33.34 pg/mL (AUC, 0.751; 95% CI, 0.683-0.818; p < 0.001). CONCLUSION: Plasma levels of BMP-4 are increased in hypertensive individuals with high CAVI. Elevated BMP-4 levels are strongly correlated with higher CAVI values, implying a predictive value of BMP-4 in arterial stiffness during hypertension.

The association between visceral adiposity index and leukocyte telomere length in adults: results from National Health and Nutrition Examination Survey.

BACKGROUND: Leukocyte telomere length (LTL) is a robust marker of biological aging, which is associated with obesity. Recently, the visceral adiposity index (VAI) has been proposed as an indicator of adipose distribution and function. OBJECTIVE: To evaluated the association between VAI and LTL in adult Americans. METHODS: There were 3193 participants in U.S. National Health and Nutrition Examination Surveys (1999-2002) included in this analysis. LTL was measured using quantitative PCR (qPCR) and expressed as telomere to single-gene copy ratio (T/S ratio). We performed multiple logistic regression models to explore the association between VAI and LTL by adjusting for potential confounders. RESULTS: Among all participants, VAI was associated with the shorter LTL (ß: - 14.81, 95% CI - 22.28 to - 7.34, p < 0.001). There were significant differences of LTL in VAI tertiles (p < 0.001). Participants in the higher VAI tertile had the shorter LTL (1.26 ≤ VAI < 2.46: ß = - 130.16, 95% CI [ - 183.44, - 76.87]; VAI ≥ 2.46: ß = - 216.12, 95% CI [ - 216.12, - 81.42], p for trend: < 0.001) comparing with the lower VAI tertile. We also found a non-linear relationship between VAI and LTL. VAI was negatively correlated with LTL when VAI was less than 2.84. CONCLUSIONS: The present study demonstrates that VAI is independently associated with telomere length. A higher VAI is associated with shorter LTL. The results suggest that VAI may provide prediction for LTL and account for accelerating the biological aging.

Altered synthesis of genes associated with short-chain fatty acids in the gut of patients with atrial fibrillation.

BACKGROUND: The gut microbiota provides health benefits in humans by producing short-chain fatty acids (SCFAs), whose deficiency causes multiple disorders and inflammatory diseases. However, gut bacteria producing SCFAs in patients with atrial fibrillation (AF), an arrhythmia with increasing prevalence, have not been reported. To investigate major gut microbial organisms related to SCFA synthesis, SCFAs-associated KEGG orthologues (KOs), enzymatic genes, and potential producers were examined according to metagenomic data-mining in a northern Chinese cohort comprising 50 non-AF control and 50 AF patients. RESULTS: Compared with non-AF controls, individuals with AF had marked differences in microbial genes involved in SCFA-related synthesis, including 125 KOs and 5 SCFAs-related enzymatic genes. Furthermore, there were 10 species that harbored SCFA-synthesis related enzymatic genes, and were markedly decreased in the gut of AF patients. Notably, discriminative features about SCFA-synthesis related function, including 8 KOs (K01752, K01738, K00175, K03737, K01006, K01653, K01647 and K15023), 4 genes (menI, tesB, yciA and CO dehydrogenase acetyl-CoA synthase complex) and 2 species (Coprococcus catus and Firmicutes bacterium CAG:103), were selected as key factors based on LASSO analysis. Furthermore, PLS-SEM analysis showed that 72.8 and 91.14 % of the overall effects on gut microbiota diversity and key species on AF, respectively, were mediated by the key KOs. Meanwhile, 46.31 % of the total effects of SCFA-synthesis related function on left atrial enlargement was mediated by hsCRP. Upon incorporation of clinical properties in AF, the KO score was still significantly associated with AF incidence (OR = 0.004, P = 0.001). CONCLUSIONS: The current study revealed that dysbiotic gut microbiota in AF is coupled with disrupted SCFA-synthesis related genes, characterized by decreased abundances of KEGG orthologues, synthesis enzymatic genes and harboring species.

The Elabela-APJ axis: a promising therapeutic target for heart failure.

Heart failure (HF) is a growing epidemic with high morbidity and mortality at an international scale. The apelin-APJ receptor pathway has been implicated in HF, making it a promising therapeutic target. APJ has been shown to be activated by a novel endogenous peptide ligand known as Elabela (ELA, also called Toddler or Apela), with a critical role in cardiac development and function. Activation of the ELA-APJ receptor axis exerts a wide range of physiological effects, including depressor response, positive inotropic action, diuresis, anti-inflammatory, anti-fibrotic, and anti-remodeling, leading to its cardiovascular protection. The ELA-APJ axis is essential for diverse biological processes and has been shown to regulate fluid homeostasis, myocardial contractility, vasodilation, angiogenesis, cellular differentiation, apoptosis, oxidative stress, cardiorenal fibrosis, and dysfunction. The beneficial effects of the ELA-APJ receptor system are well-established by treating hypertension, myocardial infarction, and HF. Additionally, administration of ELA protects human embryonic stem cells against apoptosis and stress-induced cell death and promotes survival and self-renewal in an APJ-independent manner (X receptor) via the phosphatidylinositol 3-kinase/Akt pathway, which may provide a new therapeutic approach for HF. Thus, targeting the ELA-APJ axis has emerged as a pre-warning biomarker and a novel therapeutic approach against progression of HF. An increased understanding of cardiovascular actions of ELA will help to develop effective interventions. This article gives an overview of the characteristics of the ELA-apelin-APJ axis and summarizes the current knowledge on its cardioprotective roles, potential mechanisms, and prospective application for acute and chronic HF.

TRPC5 in cardiovascular diseases.

Cardiovascular diseases (CVD), especially acute myocardial infarction, are the leading cause of death, morbidity and disability across the world, affecting millions of people each year. Atherosclerosis (AS) is the major cause of CVD, and is a chronic inflammation involving different cell types and various molecular mechanisms. Ca2+ dynamics of endothelial cells (ECs) and smooth muscle cells (SMCs) exert a significant influence on many aspects of CVD. Transient receptor potential channel 5 (TRPC5) is a member of the transient receptor potential (TRP) channels, which consists of a large number of nonselective cation channels with variable degrees of Ca2+-permeability. As a Ca2+-permeable cation channel, Human TRPC5 is expressed in a number of cell types, including ECs and muscle cells, as well as lungs and kidneys. TRPC5 is involved in renal, tumorous, neuronal and vascular diseases. In recent years, the roles of TRPC5 in CVD have been widely implicated in various disorders, such as AS, cardiac hypertrophy and blood pressure regulation. The TRPC5 mechanism of action may be associated with regulation of calcium homeostasis, oxidative stress and apoptosis. In this review, we highlight the significant roles of TRPC5 in the heart, and evaluate the potential of therapeutics targets which block TRPC5 for the treatment of CVD and related diseases.

Declined ELABELA plasma levels in hypertension patients with atrial fibrillation: a case control study.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia in patients with hypertension. ELABELA, which has cardioprotective effects, is decreased in the plasma of patients with hypertension and might be associated with AF in the hypertensive population. This study aims to measure the ELABELA plasma levels in hypertension patients with and without AF and to analyse the related factors. METHODS: A total of 162 hypertension patients with or without AF were recruited for our monocentric observational study. Subjects were excluded if they had a history of valvular heart disease, rheumatic heart disease, cardiomyopathy, thyroid diseases, or heart failure. The patients' histories were recorded, and laboratory examinations were conducted. Plasma ELABELA was detected by immunoassay. Echocardiographs were performed, and parameters were collected by two experienced doctors. Binary logistic regression analysis was used to identify the association between ELABELA plasma level and AF in patients with hypertension. RESULTS: Plasma ELABELA levels were lower in hypertension patients with AF than in those without AF (2.0 [1.5, 2.8] vs. 4.0 [3.4, 5.0] ng/ml, P < 0.001). ELABELA levels were correlated with age, heart rate, BNP levels and left atrial dimension. In addition to the left atrial dimension, ELABELA plasma levels were associated with AF in patients with hypertension (OR 0.081, 95% CI 0.029-0.224, P < 0.001). ELABELA levels were further decreased in the persistent AF subgroup compared with the paroxysmal AF subgroup (1.8 [1.4, 2.5] vs. 2.2 [1.8, 3.0] ng/ml, P = 0.012) and correlated with HR, BNP and ESR levels. CONCLUSIONS: ELALABELA levels were decreased in hypertension patients with AF and further lowered in the persistent AF subgroup. Decreased ELABELA plasma levels were associated with AF in hypertension patients and may be an underlying risk factor.

The long-term impact of a chronic total occlusion in a non-infarct-related artery on acute ST-segment elevation myocardial infarction after primary coronary intervention.

OBJECTIVES: To investigate the long-term outcome of patients with acute ST-segment elevation myocardial infarction (STEMI) and a chronic total occlusion (CTO) in a non-infarct-related artery (IRA) and the risk factors for mortality. METHODS: The enrolled cohort comprised 323 patients with STEMI and multivessel diseases (MVD) that received a primary percutaneous coronary intervention between January 2008 and November 2013. The patients were divided into two groups: the CTO group (n = 97) and the non-CTO group (n = 236). The long-term major adverse cardiovascular and cerebrovascular events (MACCE) experienced by each group were compared. RESULTS: The rates of all-cause mortality and MACCE were significantly higher in the CTO group than they were in the non-CTO group. Cox regression analysis showed that an age ≥ 65 years (OR = 3.94, 95% CI: 1.47-10.56, P = 0.01), a CTO in a non-IRA(OR = 5.09, 95% CI: 1.79 ~ 14.54, P < 0.01), an in-hospital Killip class ≥ 3 (OR = 4.32, 95% CI: 1.71 ~ 10.95, P < 0.01), and the presence of renal insufficiency (OR = 5.32, 95% CI: 1.49 ~ 19.01, P = 0.01), stress ulcer with gastraintestinal bleeding (SUB) (OR = 6.36, 95% CI: (1.45 ~ 28.01, P = 0.01) were significantly related the 10-year mortality of patients with STEMI and MVD; an in-hospital Killip class ≥ 3 (OR = 2.97,95% CI:1.46 ~ 6.03, P < 0.01) and the presence of renal insufficiency (OR = 5.61, 95% CI: 1.19 ~ 26.39, P = 0.03) were significantly related to the 10-year mortality of patients with STEMI and a CTO. CONCLUSIONS: The presence of a CTO in a non-IRA, an age ≥ 65 years, an in-hospital Killip class ≥ 3, and the presence of renal insufficiency, and SUB were independent risk predictors for the long-term mortality of patients with STEMI and MVD; an in-hospital Killip class ≥ 3 and renal insufficiency were independent risk predictors for the long-term mortality of patients with STEMI and a CTO.

Genetic screening for monogenic hypertension in hypertensive individuals in a clinical setting.

BACKGROUND: Monogenic hypertension describe a series of hypertensive syndromes that are inherited by Mendelian laws. Sometimes genetic testing is required to provide evidence for their diagnoses, precise classification and targeted treatment. This study is the first to investigate the clinical utility of a causative gene screening and the combined yield of gene product expression analyses in cases with suspected monogenic hypertension. METHODS: We performed a large-scale multi-centre clinical genetic research of 1179 expertly selected hypertensive individuals from the Chinese Han population. Targeted sequencing were performed to evaluate 37 causative genes of potential cases of monogenic hypertension. Pathogenic and likely pathogenic variants were classified using the American College of Medical Genetics guidelines. Additionally, 49 variants of unknown significance (VUS) that had relatively high pathogenicity were selected and analysed using immunoblot protein expression assays. RESULTS: 21 pathogenic or likely pathogenic variants were identified in 33 of 1179 cases (2.80%). Gene product expression analyses showed 27 VUSs harboured by 49 individuals (4.16%) could lead to abnormally expressed protein levels. Consequently, combining genetic screening with gene product expression analyses increased the diagnostic yield from 2.80% to 6.79%. The main aetiologies established were primary aldosteronism (PA; 27, 2.29%) and pheochromocytoma and paraganglioma (PPGL; 10, 0.85%). CONCLUSION: Molecular diagnoses obtained using causative gene screening combined with gene product expression analyses initially achieved a modest diagnostic yield. Our data highlight the predominant roles of PA and PPGL. Furthermore, we provide evidence indicating the enhanced diagnostic ability of combined genetic and functional evaluation.

Circulating exosomal long non-coding RNAs in patients with acute myocardial infarction.

Exosomes are attracting considerable interest in the cardiovascular field as the wide range of their functions is recognized in acute myocardial infarction (AMI). However, the regulatory role of exosomal long non-coding RNAs (lncRNAs) in AMI remains largely unclear. Exosomes were isolated from the plasma of AMI patients and controls, and the sequencing profiles and twice qRT-PCR validations of exosomal lncRNAs were performed. A total of 518 differentially expressed lncRNAs were detected over two-fold change, and 6 kinds of lncRNAs were strikingly elevated in AMI patients with top fold change and were selected to perform subsequent validation. In the two validations, lncRNAs ENST00000556899.1 and ENST00000575985.1 were significantly up-regulated in AMI patients compared with controls. ROC curve analysis revealed that circulating exosomal lncRNAs ENST00000556899.1 and ENST00000575985.1 yielded the area under the curve values of 0.661 and 0.751 for AMI, respectively. Moreover, ENST00000575985.1 showed more significant relationship with clinical parameters, including inflammatory biomarkers, prognostic indicators and myocardial damage markers. Multivariate logistic model exhibited positive association of ENST00000575985.1 with the risk of heart failure in AMI patients. In summary, our data demonstrated that circulating exosomal lncRNAs ENST00000556899.1 and ENST00000575985.1 are elevated in patients with AMI, functioning as potential biomarkers for predicting the prognosis of pateints with AMI.

Myofibroblast-Derived Exosomes Contribute to Development of a Susceptible Substrate for Atrial Fibrillation.

OBJECTIVE: Atrial fibrosis plays a critical role in atrial fibrillation (AF). A key event in the pathogenesis of fibrosis is the activation of fibroblasts (FBs) into myofibroblasts (MFBs). Paracrine factors released from MFBs lead to ion channel expression changes in cardiomyocytes (CMs). Downregulation of L-type calcium channel Cav1.2 expression is a hallmark of AF-associated ionic remodeling. However, whether exosome (Exo)-mediated crosstalk between MFBs and CMs regulates Cav1.2 expression remains unknown. METHODS: Atrial FBs and CMs were isolated and cultured from neonatal rats by enzymatic digestion. The activation of FBs into MFBs was induced by angiotensin II. Co-culture assay and in vitro Exo treatment were used to determine the effect of MFB-derived Exos on Cav1.2 expression. Confocal Ca2+ imaging was performed to examine the adrenergic stimulation-elicited Ca2+ influx signals. The levels of potential Cav1.2-inhibitory microRNAs (miRNAs) were measured by qRT-PCR. RESULTS: Untreated FBs expressed limited amounts of alpha smooth muscle actin (α-SMA), while angiotensin II induced a significant upregulation of α-SMA-expressing MFBs. Co-cultures of MFBs and CMs resulted in downregulation of Cav1.2 expression in CMs, which was largely abolished by pretreatment of MFBs with exosomal inhibitor GW4869. More importantly, treatment with MFB-derived Exos caused repression of Cav1.2 expression in CMs. Additionally, the adrenergic receptor agonist-elicited Ca2+ influx signals in CMs were remarkably attenuated by pretreatment with MFB-derived Exos, corresponding to the paralleled change in Cav1.2 expression. Finally, miR-21-3p, a potential Cav1.2-inhibitory miRNA, was enriched in MFB-derived Exos and upregulated in CMs in response to MFB-derived Exos. CONCLUSION: We uncover an Exo-mediated crosstalk between MFBs and CMs, contributing to increased vulnerability to AF by reducing the expression of Cav1.2 in CMs.

Prognostic values of the SYNTAX score II and the erythrocyte sedimentation rate on long-term clinical outcomes in STEMI patients with multivessel disease: a retrospective cohort study.

BACKGROUND: There is a paucity of evidence on the combination of the SYNTAX score II (SSII) and erythrocyte sedimentation rate (ESR) in assessing the long-term prognosis of patients with ST-elevated myocardial infarction (STEMI) and multivessel disease. The objective of this study was to investigate whether the ESR could enhance the predictive value of SSII on the long-term prognosis of STEMI patients. METHODS: A retrospective cohort study involving 483 STEMI and multivessel disease subjects receiving primary percutaneous coronary intervention was conducted. Major adverse cardiovascular events (MACE) included cardiovascular death, acute heart failure, recurrent myocardial infarction, revascularization, and nonfatal stroke. The predicted values of different models were estimated by a likelihood ratio test, Akaike's information criteria (AIC), receiver operating characteristic (ROC) curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: During the follow-up period of up to 52 months, both the SSII and ESR were independently associated with MACE (hazard ratio [HR] = 1.032, p < 0.001; and HR = 1.021, p < 0.001, respectively). The likelihood test indicated that ESR could improve the prognostic model containing SSII (p < 0.001), while the combined model of SSII and ESR attained a lower AIC (p < 0.001). The area under the ROC curve of the combined model containing SSII and ESR increased by 0.05 (p = 0.04) compared to that of the model with SSII alone. The net reclassification and integrated discrimination of the SSII alone model improved significantly with ESR (NRI = 0.0319, p < 0.001; IDI = 0.0334, p < 0.001). CONCLUSIONS: The prognostic model containing SSII, which is an independent risk factor of MACE, had a significantly enhanced predictive probability with the addition of ESR.

Hsa_circ_0046159 is involved in the development of chronic thromboembolic pulmonary hypertension.

The present study was performed to screen for potential molecular biomarkers and to assess the underlying mechanisms of chronic thromboembolic pulmonary hypertension (CTEPH) by using sequencing data analysis of microRNAs (miRNAs) and circular RNAs (circRNAs). Total RNA was isolated from peripheral-blood samples from five CTEPH patients and from five normal individuals. Based upon the identification of differentially expressed miRNAs (Affymetrix miRNA chip) and circRNAs (Agilent circRNA chip), target predictions for these differentially expressed miRNAs and functional enrichment analyses of the miRNAs and circRNAs were performed. Subsequently, the miRNA partner predictions of these differentially expressed circRNAs and co-expression analyses of differentially expressed circRNAs and miRNAs were conducted. Based on the results of these analyses, a competing endogenous RNA (ceRNA) network was constructed. Finally, the expression of circRNAs was detected by quantitative real-time PCR (qRT-PCR). Within the miRNA-circRNA regulatory network, hsa_circ_0026480 and hsa_circ_0046159 were predicted to interact with miR-27a-3p and miR-1226-3p, respectively with greater degree. Specially, ATP2A2-that had a ceRNA relationship with hsa_circ_0046159-was predicted as a target of miR-1226-3p. The results of RT-PCR also revealed a significantly increased expression of hsa_circ_0046159 in CTEPH samples than that in normal samples.

Speckle tracking for predicting outcomes of balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension.

BACKGROUND: Right ventricular (RV) function is a prognostic marker of chronic thromboembolic pulmonary hypertension (CTEPH). We used two-dimensional (2D) speckle-tracking echocardiography (STE) to evaluate the therapeutic effects of balloon pulmonary angioplasty (BPA) in CTEPH patients. METHODS: A total of 46 CTEPH patients who underwent 2D STE before and after BPA were enrolled in this retrospective study. The following RV functional parameters were measured: tricuspid annular plane systolic excursion (TAPSE), right ventricular fractional area change (RVFAC), RV index of myocardial performance (RIMP), and free wall longitudinal strain (RVFWLS). Satisfactory BPA was defined as mean pulmonary arterial pressure (mPAP) <25 mm Hg or improvement in mPAP > 10 mm Hg after BPA. Patients were divided into two groups according to mPAP values: group I had satisfactory BPA outcomes; group Ⅱ had unsatisfactory BPA outcomes. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was used to determine the optimal cutoff values and the ability of RVFWLS to predict successful BPA outcomes. RESULTS: After BPA, SPAP measured by echocardiography (SPAPecho ) and RIMP decreased, but TAPSE, RVFAC, and RVFWLS increased. Before BPA, group Ⅰ had significantly better RV function than group Ⅱ. Multifactor logistic regression analysis identified RVFWLS as an independent factor associated with satisfactory BPA outcomes. The optimal cutoff value for RVFWLS in predicting satisfactory BPA outcomes was -12.2%. CONCLUSIONS: Balloon pulmonary angioplasty improves RV function in CTEPH patients. RVFWLS is a valuable noninvasive tool with which to assess the treatment effects of BPA. CTEPH patients with lower RVFWLS may have limited benefit from BPA.

PINK1/Parkin-mediated mitophagy promotes apelin-13-induced vascular smooth muscle cell proliferation by AMPKα and exacerbates atherosclerotic lesions.

Aberrant proliferation of vascular smooth muscle cells (VSMC) is a critical contributor to the pathogenesis of atherosclerosis (AS). Our previous studies have demonstrated that apelin-13/APJ confers a proliferative response in VSMC, however, its underlying mechanism remains elusive. In this study, we aimed to investigate the role of mitophagy in apelin-13-induced VSMC proliferation and atherosclerotic lesions in apolipoprotein E knockout (ApoE-/-) mice. Apelin-13 enhances human aortic VSMC proliferation and proliferative regulator proliferating cell nuclear antigen expression in dose and time-dependent manner, while is abolished by APJ antagonist F13A. We observe the engulfment of damage mitochondria by autophagosomes (mitophagy) of human aortic VSMC in apelin-13 stimulation. Mechanistically, apelin-13 increases p-AMPKα and promotes mitophagic activity such as the LC3I to LC3II ratio, the increase of Beclin-1 level and the decrease of p62 level. Importantly, the expressions of PINK1, Parkin, VDAC1, and Tom20 are induced by apelin-13. Conversely, blockade of APJ by F13A abolishes these stimulatory effects. Human aortic VSMC transfected with AMPKα, PINK1, or Parkin and subjected to apelin-13 impairs mitophagy and prevents proliferation. Additional, apelin-13 not only increases the expression of Drp1 but also reduces the expressions of Mfn1, Mfn2, and OPA1. Remarkably, the mitochondrial division inhibitor-1(Mdivi-1), the pharmacological inhibition of Drp1, attenuates human aortic VSMC proliferation. Treatment of ApoE-/- mice with apelin-13 accelerates atherosclerotic lesions, increases p-AMPKα and mitophagy in aortic wall in vivo. Finally, PINK1-/- mutant mice with apelin-13 attenuates atherosclerotic lesions along with defective in mitophagy. PINK1/Parkin-mediated mitophagy promotes apelin-13-evoked human aortic VSMC proliferation by activating p-AMPKα and exacerbates the progression of atherosclerotic lesions.