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Arterial stiffness, a consequence of smoking, is an underlying risk factor of cardiovascular diseases. Epoxyeicosatrienoic acids (EETs), hydrolyzed by soluble epoxide hydrolase (sEH), have beneficial effects against vascular dysfunction. However, the role of sEH knockout in nicotine-induced arterial stiffness was not characterized. We hypothesized that sEH knockout could prevent nicotine-induced arterial stiffness. In the present study

Backgroud The association between underlying comorbidities and cardiac injury and the prognosis in coronavirus disease 2019 (COVID‐19) patients was assessed in this study. Hypothesis The underlying comorbidities and cardiac injury may be associated with the prognosis in COVID‐19 patients. Methods A systematic search was conducted in PubMed, EMBASE, Web of science, and The Cochrane library from December 2019 to July 2020. The odds ratio (OR) and 95% confidence intervals (95% CI) were used to estimate the probability of comorbidities and cardiac injury in COVID‐19 patients with or without severe type, or in survivors vs nonsurvivors of COVID‐19 patients. Results A total of 124 studies were included in this analysis. A higher risk for severity was observed in COVID‐19 patients with comorbidities. The pooled result in patients with hypertension (OR 2.57, 95% CI: 2.12‐3.11), diabetes (OR 2.54, 95% CI: 1.89‐3.41), cardiovascular diseases (OR 3.86, 95% CI: 2.70‐5.52), chronic obstractive pulmonary disease (OR 2.71, 95% CI: 1.98‐3.70), chronic kidney disease (OR 2.20, 95% CI: 1.27‐3.80), and cancer (OR 2.42, 95% CI: 1.81‐3.22) respectively. All the comorbidities presented a higher risk of mortality. Moreover, the prevalence of acute cardiac injury is higher in severe group than in nonsevere group, and acute cardiac injury is associated with an increased risk for in‐hospital mortality. Conclusion Comorbidities and acute cardiac injury are closely associated with poor prognosis in COVID‐19 patients. It is necessary to continuously monitor related clinical indicators of organs injury and concern comorbidities in COVID‐19 patients.

The optimal antiplatelet therapy after percutaneous coronary intervention (PCI) remains to be elucidated. Monotherapy with a P2Y12 inhibitor may be inferior to dual antiplatelet therapy in patients after PCI. PubMed, EMBASE (by Ovidsp), Web of Science, and The Cochrane Library were searched from database inception to 2 October 2019. The composite of cardiovascular outcomes, all‐cause mortality, myocardial infarction (MI), stroke, stent thrombosis, and major bleeding were evaluated. Pooled outcomes were presented as relative risk (RR) and 95% confidence intervals (CIs). A total of four trials randomizing 29 089 participants were included. Compared with the dual antiplatelet therapy group (n = 14 559), the P2Y12 inhibitor monotherapy group (n = 14 530) significantly decreased the incidence of bleeding events (2.0% vs 3.1%; RR: 0.60; 95% CI: 0.43‐0.84; P = .005). There were no significant differences in all‐cause mortality (1.3% vs 1.5%; RR: 0.87; 95% CI, 0.71‐1.06; P = .16), myocardial infarction (2.1% vs 1.9%; RR, 1.06; 95% CI, 0.90‐1.25; P = .46), stroke (0.6% vs 0.5%; RR, 1.18; 95% CI, 0.67‐2.07; P = .57), or stent thrombosis (0.5% vs 0.4%; RR, 1.14; 95% CI, 0.81‐1.61; P = .44) between the two groups. P2Y12 inhibitor monotherapy did not show any significant difference in the adverse cardiac and cerebrovascular events, but markedly decreased the risk of bleeding among patients after PCI vs dual antiplatelet therapy. However, it still needs to be further confirmed due to limited data.

BACKGROUND: Although studies have identified hundreds of genetic variants associated with asthma risk, a large fraction of heritability remains unexplained, especially in Chinese individuals. METHODS: To identify genetic risk factors for asthma in a Han Chinese population, 211 asthma‐related genes were first selected based on database searches. The genes were then sequenced for subjects in a Discovery Cohort (284 asthma patients and 205 older healthy controls) using targeted next‐generation sequencing. Bioinformatics analysis and statistical association analyses were performed to reveal the associations between rare/common variants and asthma, respectively. The identified common risk variants underwent a validation analysis using a Replication Cohort (664 patients and 650 controls). RESULTS: First, we identified 18 potentially functional rare loss‐of‐function (LOF) variants in 21/284 (7.4%) of the asthma cases. Second, using burden tests, we found that the asthma group had nominally significant (p

The epoxyeicosatrienoic acid (EET) exerts beneficial effects on insulin resistance and/or hypertension. EETs could be readily converted to less biological active diols by soluble epoxide hydrolase (sEH). However, whether sEH inhibition can ameliorate the comorbidities of insulin resistance and hypertension and the underlying mechanisms of this relationship are unclear. In this study, C57BL/6 mice were rendered hypertensive and insulin resistant through a high-fat and high-salt (HF–HS) diet. The sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), was used to treat mice (1 mg/kg/day) for 8 weeks, followed by analysis of metabolic parameters. The expression of sEH and the sodium–glucose cotransporter 2 (SGLT2) was markedly upregulated in the kidneys of mice fed an HF–HS diet. We found that TPPU administration increased kidney EET levels, improved insulin resistance, and reduced hypertension. Furthermore, TPPU treatment prevented upregulation of SGLT2 and the associated increased urine volume and the excretion of urine glucose and urine sodium. Importantly, TPPU alleviated renal inflammation. In vitro, human renal proximal tubule epithelial cells (HK-2 cells) were used to further investigate the underlying mechanism. We observed that 14,15-EET or sEH knockdown or inhibition prevented the upregulation of SGLT2 upon treatment with palmitic acid or NaCl by inhibiting the inhibitory kappa B kinase α/β/NF-κB signaling pathway. In conclusion, sEH inhibition by TPPU alleviated insulin resistance and hypertension induced by an HF–HS diet in mice. The increased urine excretion of glucose and sodium was mediated by decreased renal SGLT2 expression because of inactivation of the inhibitory kappa B kinase α/β/NF-κB–induced inflammatory response.

Objective This study investigated the impact of SO2 on rats with hypoxic pulmonary vascular structural remodeling and its possible mechanisms. Materials and methods Pulmonary vascular morphological change was examined by HE staining. RNA-based high-throughput sequencing (RNA-seq) was performed to detect differential expression of mRNAs in Normal and Hypoxia–induced Pulmonary hypertension (HPH) rats. The Real-time quantitative RT-PCR (q RT-PCR) was used for validation of wnt7b, sfrp2, cacna1f, DKK1, CaSR and vimentin mRNA expression levels. Protein levels of CaSR, Vimentin, Caspase3, E-cadherin and P-Akt1/2/3 were detected by Western blot and immunohistochemistry. Results This study showed that SO2 significantly attenuated the interstitial thickening and prominent media hypertrophy of pulmonary arteries. SO2 downregulated p-Akt1/2/3 protein level and upregulated E-cadherin protein level in lung tissues, which inhibited the proliferation and epithelial-to-mesenchymal transition (EMT) in HPH rats. RNA-seq and PCR validation results showed that levels of Wnt7b, Sfrp2 and Cacna1f mRNAs decreased and Dkk1 mRNA level increased obviously in HPH rats. Moreover, SO2 attenuated the mRNA and protein level of CaSR, which was activated in HPH rats and resulted in the proliferation of PASMCs. Besides, the mRNA and protein expression of vimentin in PASMCs significantly reduced after SO2 treatment. Conclusion Together, these findings indicate that SO2 could attenuate hypoxia-induced pulmonary arteriolar remodeling and may suppress the proliferation and migration of PASMCs at least in part through the Dkk1/Wnt signaling pathway.

Idiopathic pulmonary fibrosis (IPF) is a genetic heterogeneous disease with high mortality and poor prognosis. However, a large fraction of genetic cause remains unexplained, especially in sporadic IPF (∼80% IPF). By systemically reviewing related literature and potential pathogenic pathways, 92 potentially IPF-related genes were selected and sequenced in genomic DNAs from 253 sporadic IPF patients and 125 matched health controls using targeted massively parallel next-generation sequencing. The identified risk variants were confirmed by Sanger sequencing. We identified two pathogenic and 10 loss-of-function (LOF) candidate variants, accounting for 4.74% (12 out of 253) of all the IPF cases. In burden tests, rare missense variants in three genes (CSF3R, DSP, and LAMA3) were identified that have a statistically significant relationship with IPF. Four common SNPs (rs3737002, rs2296160, rs1800470, and rs35705950) were observed to be statistically associated with increased risk of IPF. In the cumulative risk model, high risk subjects had 3.47-fold (95%CI: 2.07-5.81, P = 2.34 × 10-6 ) risk of developing IPF compared with low risk subjects. We drafted a comprehensive map of genetic risks (including both rare and common candidate variants) in patients with IPF, which could provide insights to help in understanding mechanisms, providing genetic diagnosis, and predicting risk for IPF.

While sulfur dioxide (SO(2)) has been previously known for its toxicological effects, it is now known to be produced endogenously in mammals from sulfur-containing amino acid L-cysteine. L-cysteine is catalyzed by cysteine dioxygenase (CDO) to L-cysteinesulfinate, which converts to β-sulfinylpyruvate through transamination by aspartate aminotransferase (AAT), and finally spontaneously decomposes to pyruvate and SO(2). The present study explored endogenous SO(2) production, and AAT and CDO distribution in different rat tissue. SO(2) content was highest in stomach, followed by tissues in the right ventricle, left ventricle, cerebral gray matter, pancreas, lung, cerebral white matter, renal medulla, spleen, renal cortex and liver. AAT activity and AAT1 mRNA expression were highest in the left ventricle, while AAT1 protein expression was highest in the right ventricle. AAT2 and CDO mRNA expressions were both highest in liver tissue. AAT2 protein expression was highest in the renal medulla, but CDO protein expression was highest in liver tissue. In all tissues, AAT1 and AAT2 were mainly distributed in the cytoplasm rather than the nucleus. These observed differences among tissues endogenously generating SO(2) and associated enzymes are important in implicating the discovery of SO(2) as a novel endogenous signaling molecule.

Pulmonary hypertension (PH) is an important pathophysiological process in the development of many diseases. However, the mechanism responsible for the development of PH remains unknown. The objective of the study was to explore the possible impact of sulfur dioxide (SO2) on the endogenous hydrogen sulfide (H2S) pathway in rats with PH induced by high pulmonary blood flow. Compared with sham group, the systolic pulmonary artery pressure (SPAP) in the shunt group was significantly increased, along with the increased percentage of muscularized arteries and partially muscularized arteries of small pulmonary arteries. Compared with the shunt group, SPAP in the shunt+SO2 group was significantly decreased, and the percentage of muscularized pulmonary arteries was also decreased. Additionally, rats that developed PH had significantly lower levels of SO2 concentration, aspartate aminotransferase (AAT) activity, protein and mRNA expressions of AAT2 in pulmonary tissues. Administration of an SO2 donor could alleviate the elevated pulmonary arterial pressure and decrease the muscularization of pulmonary arteries. At the same time, it increased the H2S production, protein expression of cystathionine-γ-lyase (CSE), mRNA expression of CSE, mercaptopyruvate transsulphurase (MPST) and cystathionine-β-synthase (CBS) in the pulmonary tissue of the rats. The results suggested that endogenous SO2/AAT2 pathway and the endogenous H2S production were downregulated in rats with PH induced by high pulmonary blood flow. However, SO2 could reduce pulmonary arterial pressure and improve the pulmonary vascular pathological changes in association with upregulating endogenous H2S pathway.