Dapagliflozin improves left ventricular remodeling and aorta sympathetic tone in a pig model of heart failure with preserved ejection fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a difficult disease with high morbidity and mortality rates and lacks an effective treatment. Here, we report the therapeutic effect of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), on hypertension + hyperlipidemia-induced HFpEF in a pig model. METHODS: HFpEF pigs were established by infusing a combination of deoxycorticosterone acetate (DOCA) and angiotensin II (Ang II), and Western diet (WD) feeding for 18 weeks. In the 9th week, half of the HFpEF pigs were randomly assigned to receive additional dapagliflozin treatment (10 mg/day) by oral gavage daily for the next 9 weeks. Blood pressure, lipid levels, echocardiography and cardiac hemodynamics for cardiac structural and functional changes, as well as epinephrine and norepinephrine concentrations in the plasma and tissues were measured. After sacrifice, cardiac fibrosis, the distribution of tyrosine hydroxylase (TH), inflammatory factors (IL-6 and TNF-α) and NO-cGMP-PKG pathway activity in the cardiovascular system were also determined. RESULTS: Blood pressure, total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) were markedly increased in HFpEF pigs, but only blood pressure was significantly decreased after 9 weeks of dapagliflozin treatment. By echocardiographic and hemodynamic assessment, dapagliflozin significantly attenuated heart concentric remodeling in HFpEF pigs, but failed to improve diastolic function and compliance with the left ventricle (LV). In the dapagliflozin treatment group, TH expression and norepinephrine concentration in the aorta were strongly mitigated compared to that in the HFpEF group. Moreover, inflammatory cytokines such as IL-6 and TNF-α in aortic tissue were markedly elevated in HFpEF pigs and inhibited by dapagliflozin. Furthermore, the reduced expression of eNOS and the PKG-1 protein and the cGMP content in the aortas of HFpEF pigs were significantly restored after 9 weeks of dapagliflozin treatment. CONCLUSION: 9 weeks of dapagliflozin treatment decreases hypertension and reverses LV concentric remodeling in HFpEF pigs partly by restraining sympathetic tone in the aorta, leading to inhibition of the inflammatory response and NO-cGMP-PKG pathway activation.

Long noncoding RNA uc003pxg.1 regulates endothelial cell proliferation and migration via miR­25­5p in coronary artery disease.

Long noncoding RNAs (lncRNAs) have been reported to be associated with the progression of coronary artery disease (CAD). In our previous study, the levels of lncRNA uc003pxg.1 were upregulated in patients with CAD compared with those in control subjects. However, the role and underlying mechanism of the effects of uc003pxg.1 in CAD remain unknown. Therefore, the aim of the present study was to investigate the expression pattern and biological function of uc003pxg.1 in CAD. First, uc003pxg.1 expression levels were assessed in peripheral blood mononuclear cells isolated from patients with CAD by reverse transcription­quantitative (RT­q)PCR. The results demonstrated that the levels of uc003pxg.1 were significantly upregulated (~4.6­fold) in samples from 80 patients with CAD compared with those in 80 healthy subjects. Subsequently, the present study demonstrated that small interfering RNA­mediated uc003pxg.1 knockdown inhibited human umbilical vein endothelial cell (HUVEC) proliferation and migration, which was analyzed using the Cell Counting Kit­8, cell cycle, EdU and Transwell assays. Additionally, the results of RT­qPCR and western blot analyses revealed that uc003pxg.1 regulated the mRNA and protein levels of cyclin D1 and cyclin­dependent kinase. Through high­throughput sequencing and dual­luciferase reporter assays, the present study demonstrated that microRNA (miR)­25­5p was a downstream target of uc003pxg.1. Further experiments verified that uc003pxg.1 regulated HUVEC proliferation and migration via miR­25­5p. The results of the present study may enhance the current understanding of the role of lncRNA uc003pxg.1 in CAD.

Rs10757274 gene polymorphisms in coronary artery disease: A systematic review and a meta-analysis.

BACKGROUND: It has been reported the rs10757274 SNP (present on locus 9p21 in the gene for CDKN2BAS1) might be associated with susceptibility to coronary artery disease (CAD). Owing to mixed and inconclusive results, we conducted a meta-analysis to investigate the association between rs10757274 polymorphism and the risk of CAD. OBJECTIVES: The present study aimed to investigate the relationship between rs10757274 polymorphism and the risk of CAD. METHODS: All studies of the rs10757274 SNP with CAD that were published between 2007 and 2018 were retrieved from the PubMed database. Meta-analysis was performed with Stata 14.0 software. The effect size of the rs10757274 SNP with CAD risk was assessed based on the odds ratios (ORs) with calculation of 95% confidence interval (CI). RESULTS: Eleven studies including 52,209 subjects (cases: 7990, controls: 44,219) were included in the final data combination. Pooled overall analyses showed that rs10757274 (allele model: P < .001; dominant model: P < .001; recessive model: P < .001; Heterozygote codominant: P = .002; Homozygote codominant: P < .001) polymorphisms were significantly associated with the likelihood of CAD. Significant heterogeneity between individual studies appears in all 5 models. Further subgroup analyses revealed that rs10757274 polymorphisms were all significantly correlated with the likelihood of CAD and no heterogeneity were observed in West Asians. CONCLUSIONS: Our findings indicated that rs10757274 polymorphisms may serve as genetic biomarkers of CAD, especially in West Asians.