Salt Restriction and Angiotensin-Converting Enzyme Inhibitor Improve the Responsiveness of the Small Artery in Salt-Sensitive Hypertension.

For salt-sensitive hypertension (SSH), salt restriction and angiotensin-converting enzyme (ACE) inhibitors are essential treatments, but their effect on the function of resistance arteries is unclear. Here, we present an intravital study to detect the effect of salt restriction and ACE inhibitors on the function of the mesenteric small artery (MSA) in SSH. Dahl salt-sensitive rats were randomized into the following groups: ACE inhibitor gavage, salt restriction, ACE inhibitor combined with salt restriction, and high-salt diet. After a 12-week intervention, the mesenteric vessels maintained their perfusion in vivo, and the changes in the diameter and blood perfusion of the MSAs to norepinephrine (NE) and acetylcholine (ACh) were detected. Switching from a high-salt diet to a low-salt diet (i.e., salt restriction) attenuated the vasoconstriction of the MSAs to NE and promoted the vasodilatation to ACh, while ACE inhibitor improved the vasodilatation more obviously. Pathologically, changes in local ACE, AT1R, and eNOS expression were involved in these processes induced by a high-salt diet. Our study suggests that salt restriction and ACE inhibitor treatment improve high salt intake-induced MSA dysfunction in SSH, and salt restriction is a feasible and effective treatment. Our findings may provide a scientific basis for the treatment of hypertension.

Risk factors for revascularization and in-stent restenosis in patients with triple-vessel disease after second-generation drug-eluting stent implantation: a retrospective analysis.

OBJECTIVES: Coronary artery disease (CAD) is a common cardiac disease with high morbidity and mortality, and triple-vessel disease (TVD) is a severe type of CAD. This study investigated risk factors for revascularization and in-stent restenosis (ISR) in TVD patients who underwent second-generation drug-eluting stent implantation. METHODS: A retrospective clinical study was conducted, and 246 triple-vessel disease (TVD) patients with 373 vessels after second-generation drug-eluting stent (DES) implantation who received follow-up coronary angiography (CAG) were consequently enrolled. According to the follow-up angiography, patients were categorized into the revascularization group and nonrevascularization group as well as the in-stent restenosis (ISR) group and non-ISR group. Univariate and multivariate logistic regression analyses were used to identify risk factors for revascularization and ISR. Receiver operating characteristic (ROC) curve with area under the curve (AUC) analysis was performed to assess the predictive power of these risk factors. RESULTS: In the median follow-up period of 28.0 (14.0, 56.0) months, 142 TVD patients (57.7%) with 168 vessels underwent revascularization, and ISR occurred in 43 TVD patients (17.5%) with 47 vessels after second-generation DES implantation. Compared to the nonrevascularization group, the revascularization group presented with an increased rate of current smoking and higher levels of TC, LDL-C, HDL-C, non-HDL-c, ApoB, neutrophils, and Hs-CRP as well as a longer follow-up of months but with a lower level of HDL-C. In addition, patients in the ISR group had an older age, longer follow-up (months) and elevated rates of current smoking and stage 4-5 chronic kidney disease (CKD4-5). In multivariate analysis, current smoking and higher non-HDL-c were independent risk factors for revascularization. In addition, older age, current smoking and CKD4-5 were considered independent risk factors for ISR. Importantly, the receiver operating characteristic curve showed that non-HDL-C and age displayed predictive power for revascularization and ISR, respectively. CONCLUSION: Current smoking is an independent risk factor for both revascularization and in-stent restenosis. Higher non-HDL-c is independently related to revascularization; moreover, increased age and CKD4-5 are potential risk factors for ISR in TVD patients after second-generation drug-eluting stent implantation.

Unique mechanistic insights into the beneficial effects of angiotensin-(1-7) on the prevention of cardiac fibrosis: A metabolomic analysis of primary cardiac fibroblasts.

BACKGROUND: Cell metabolic pathways are highly conserved among species and change rapidly in response to drug stimulation. Therefore, we explore the effects of angiotensin-(1-7) in a primary cell model of cardiac fibrosis established in angiotensin II-stimulated cardiac fibroblasts via metabolomics analysis and further clarify the potential protective mechanism of angiotensin-(1-7). METHODS AND RESULTS: After exposing cardiac fibroblasts to angiotensin II and/or angiotensin-(1-7), 172 metabolites in these cells were quantified and identified by gas chromatography-mass spectrometry. The data were subsequently analyzed by orthogonal partial least squares discriminant analysis to shortlist biochemically significant metabolites associated with the antifibrotic action of angiotensin-(1-7). Seven significant metabolites were identified: 10,13-dimethyltetradecanoic acid, arachidonic acid, aspartic acid, docosahexaenoic acid (DHA), glutathione, palmitelaidic acid, and pyroglutamic acid. By metabolic network analysis, we found that these metabolites were involved in six metabolic pathways, including arachidonic acid metabolism, leukotriene metabolism, and the γ-glutamyl cycle. Since these metabolic pathways are related to calcium balance and oxidative stress, we further verified that angiotensin-(1-7) suppressed the abnormal extracellular calcium influx and excessive accumulation of intracellular reactive oxygen species (ROS) in angiotensin II-stimulated cardiac fibroblasts. Furthermore, we found that angiotensin-(1-7) suppressed the abnormal calcium- and ROS-dependent activation of calcium/calmodulin-dependent protein kinase II delta (CaMKIIδ), the increased expression of CaMKIIδ-related proteins (NADPH oxidase 4 (Nox4), cellular communication network factor 2 (CTGF), and p-ERK1/2), and excessive collagen deposition in vitro and in vivo. CONCLUSIONS: Angiotensin-(1-7) can ameliorate the angiotensin II-stimulated metabolic perturbations associated with cardiac fibroblast activation. These metabolic changes indicate that modulation of calcium- and ROS-dependent activation of CaMKIIδ mediates the activity of angiotensin-(1-7) against cardiac fibrosis. Moreover, pyroglutamic acid and arachidonic acid may be potential biomarkers for monitoring the antifibrotic action of angiotensin-(1-7).

N-Methylquinuclidinium-Based Anion Exchange Membrane with Ultrahigh Alkaline Stability.

Anion-exchange-membrane (AEM) water electrolysis is a promising technology for hydrogen production from renewable energy sources. However, the bottleneck of its development is the poor comprehensive performance of AEM, especially the stability at highly concentrated alkaline condition and temperature. Herein, a new cationic group N-methylquinuclidinium with enhanced alkaline stability is proposed and hereby a full-carbon chain poly(aryl quinuclidinium) AEM is prepared. Compared with reported AEMs, it shows ultrahigh comprehensive alkaline stability (no chemical decomposition, no decay of conductivity) in 10 m NaOH aqueous solution at 80 °C for more than 1800 h, excellent dimensional stability (swelling ratio: <10% in pure water, <2% in 10 m NaOH) in OH- form at 80 °C, high OH- conductivity (≈139.1 mS cm-1 at 80 °C), and high mechanical properties (tensile strength: 41.5 MPa, elongation at break: 50%). The water electrolyzer using the AEM exhibits a high current density (1.94 A cm-2 at 2.0 V) when assembled with nickel-alloy foam electrodes, and high durability when assembled with nickel foam electrodes.

Arctigenin Attenuates Vascular Inflammation Induced by High Salt through TMEM16A/ESM1/VCAM-1 Pathway.

Salt-sensitive hypertension is closely related to inflammation, but the mechanism is barely known. Transmembrane member 16A (TMEM16A) is the Ca2+-activated chloride channel in epithelial cells, smooth muscle cells, and sensory neurons. It can promote inflammatory responses by increasing proinflammatory cytokine release. Here, we identified a positive role of TMEM16A in vascular inflammation. The expression of TMEM16A was increased in high-salt-stimulated vascular smooth muscle cells (VSMCs), whereas inhibiting TMEM16A or silencing TMEM16A with small interfering RNA (siRNA) can abolish this effect in vitro or in vivo. Transcriptome analysis of VSMCs revealed some differential downstream genes of TMEM16A related to inflammation, such as endothelial cell-specific molecule 1 (ESM1) and CXC chemokine ligand 16 (CXCL16). Overexpression of TMEM16A in VSMCs was accompanied by high levels of ESM1, CXCL16, intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1). We treated VSMCs cultured with high salt and arctigenin (ARC), T16Ainh-A01 (T16), and TMEM16A siRNA (siTMEM16A), leading to greatly decreased ESM1, CXCL16, VCAM-1, and ICAM-1. Beyond that, silencing ESM1, the expression of VCAM-1 and ICAM-1, and CXCL16 was attenuated. In conclusion, our results outlined a signaling scheme that increased TMEM16 protein upregulated ESM1, which possibly activated the CXCL16 pathway and increased VCAM-1 and ICAM-1 expression, which drives VSMC inflammation. Beyond that, arctigenin, as a natural inhibitor of TMEM16A, can reduce the systolic blood pressure (SBP) of salt-sensitive hypertension mice and alleviate vascular inflammation.

Appropriate Exogenous Expression Stoichiometry of GATA4 as an Important Factor for Cardiac Reprogramming of Human Dermal Fibroblasts.

Reprogramming of human dermal fibroblasts (HDFs) into induced cardiomyocyte-like cells (iCMs) represents a promising strategy for human cardiac regeneration. Different cocktails of cardiac transcription factors can convert HDFs into iCMs, although with low efficiency and immature phenotype. Here, GATA4, MEF2C, TBX5, MESP1, and MYOCD (GMTMeMy for short) were used to reprogram HDFs by retrovirus infection. We found that the exogenous expression stoichiometry of GATA4 (GATA4 stoichiometry) significantly affected reprogramming efficiency. When 1/8 dosage of GATA4 virus (GATA4 dosage) plus MTMeMy was used, the reprogramming efficiency was obviously improved compared with average pooled virus encoding each factor, which measured, by the expression level of cardiac genes, the percentage of cardiac troponin T and alpha-cardiac myosin heavy-chain immunopositive cells and the numbers of iCMs showing calcium oscillation or beating synchronously in co-culture with mouse CMs. In addition, we prepared conditioned maintenance medium (CMM) by CM differentiation of H9 human embryonic stem cell line. We found that compared with traditional maintenance medium (TMM), CMM made iCMs show well-organized sarcomere formation and characteristic calcium oscillation wave earlier. These findings demonstrated that appropriate GATA4 stoichiometry was essential for cardiac reprogramming and some components in CMM were important for maturation of iCMs.

MYOCD is Required for Cardiomyocyte-like Cells Induction from Human Urine Cells and Fibroblasts Through Remodeling Chromatin.

Despite direct reprogramming of human cardiac fibroblasts into induced cardiomyocytes (iCM) holds great potential for heart regeneration, the mechanisms are poorly understood. Whether other human somatic cells could be reprogrammed into cardiomyocytes is also unknown. Here, we report human urine cells (hUCs) could be converted into CM-like cells from different donors and the related chromatin accessibility dynamics (CAD) by assay for transposase accessible chromatin(ATAC)-seq. hUCs transduced by MEF2C, TBX5, MESP1 and MYOCD but without GATA4 expressed multiple cardiac specific genes, exhibited Ca2+ oscillation potential and sarcomeric structures, and contracted synchronously in coculture with mouse CM. Additionally, we found that MYOCD is required for both closing and opening critical loci, mainly by hindering the opening of loci enriched with motifs for the TEAD and AP1 family and promoting the closing of loci enriched with ETS motifs. These changes differ partially from CAD observed during iCM induction from human fibroblasts. Collectively, our study offers one practical platform for iCM generation and insights into mechanisms for iCM fate determination.

Forkhead box family transcription factors as versatile regulators for cellular reprogramming to pluripotency.

Forkhead box (Fox) transcription factors play important roles in mammalian development and disease. However, their function in mouse somatic cell reprogramming remains unclear. Here, we report that FoxD subfamily and FoxG1 accelerate induced pluripotent stem cells (iPSCs) generation from mouse fibroblasts as early as day4 while FoxA and FoxO subfamily impede this process obviously. More importantly, FoxD3, FoxD4 and FoxG1 can replace Oct4 respectively and generate iPSCs with germline transmission together with Sox2 and Klf4. On the contrary, FoxO6 almost totally blocks reprogramming through inhibiting cell proliferation, suppressing the expression of pluripotent genes and hindering the process of mesenchymal to epithelial transition (MET). Thus, our study uncovers unexpected roles of Fox transcription factors in reprogramming and offers new insights into cell fate transition.

CHA2DS2-VASc Score for Identifying Patients at High Risk of Postoperative Atrial Fibrillation After Cardiac Surgery: A Meta-analysis.

BACKGROUND: Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery, resulting in an increased risk of morbidity and longer hospital stay. Pharmacologic prophylaxis has been recommended to improve the outcome in patients at high risk of developing POAF after cardiac surgery. Several studies have applied the CHA2DS2-VASc (Congestive heart failure, Hypertension Age [≥65 = 1 point, ≥75 = 2 points], Diabetes, and Stroke/transient ischemic attack (2 points)-vascular disease [peripheral arterial disease, previous myocardial infarction, aortic atheroma]) score in the risk stratification of POAF but yielded contradicting results. This study aims to determine the association between CHA2DS2-VASc score and POAF and further to explore its discriminative ability for the prediction of POAF. METHODS: We systematically searched the Medline, Embase, Cochrane library, and other data sources with key terms "CHA2DS2-VASc," "atrial fibrillation," and "cardiac surgery." Studies designed for CHA2DS2-VASc score in stratifying the risks of POAF in patients undergoing cardiac surgery were included. Statistical analyses were performed with R 3.5.1 and STATA 13.0. RESULTS: Seven hundred twenty-one studies were identified, of which 12 studies with 18,086 patients were finally included in our analysis. The CHA2DS2-VASc score was found to be an independent predictor of POAF after cardiac surgery (odds ratio, 1.46; 95% confidence interval [CI], 1.25-1.72) and exhibited a relatively strong specificity (0.70; 95% CI, 0.61-0.78) and sensitivity (0.72; 95% CI, 0.54-0.85) for predicting POAF. The bivariate model-based pooled area under the receiver operating curve was estimated to be 0.76 (95% CI, 0.72-0.79). CONCLUSIONS: The CHA2DS2-VASc score has relatively good performance in predicting POAF after cardiac surgery and may help identify the patients at high risk of POAF.

BMP4 resets mouse epiblast stem cells to naive pluripotency through ZBTB7A/B-mediated chromatin remodelling.

BMP4 regulates a plethora of developmental processes, including the dorsal-ventral axis and neural patterning. Here, we report that BMP4 reconfigures the nuclear architecture during the primed-to-naive transition (PNT). We first established a BMP4-driven PNT and show that BMP4 orchestrates the chromatin accessibility dynamics during PNT. Among the loci opened early by BMP4, we identified Zbtb7a and Zbtb7b (Zbtb7a/b) as targets that drive PNT. ZBTB7A/B in turn facilitate the opening of naive pluripotent chromatin loci and the activation of nearby genes. Mechanistically, ZBTB7A not only binds to chromatin loci near to the genes that are activated, but also strategically occupies those that are silenced, consistent with a role of BMP4 in both activating and suppressing gene expression during PNT at the chromatin level. Our results reveal a previously unknown function of BMP4 in regulating nuclear architecture and link its targets ZBTB7A/B to chromatin remodelling and pluripotent fate control.