miR-96-5p Regulates Proliferation, Migration, and Apoptosis of Vascular Smooth Muscle Cell Induced by Angiotensin II via Targeting NFAT5.

BACKGROUND: Aberrant proliferation, migration, and apoptosis of vascular smooth muscle cells (VSMCs) are major pathological phenomenon in hypertension. MicroRNAs (miRNAs/miRs) serve crucial roles in the progression of hypertension. We aimed to determine the role of miR-96-5p in the proliferation, migration, and apoptosis of VSMCs and its underlying mechanisms. METHODS: Angiotensin II (Ang II) was employed to treat VSMCs, and the expression of miR-96-5p was detected by RT-qPCR. Then, miR-96-5p mimic was transfected into VSMCs. Cell Counting Kit-8 assay, flow cytometry, transwell assay, and wound healing assay were applied to measure proliferation, cell cycle, and migration of VSMCs. The expression of proteins associated with proliferation, migration, and apoptosis was assessed. A luciferase reporter assay was applied to confirm the target binding between miR-96-5p and nuclear factors of activated T-cells 5 (NFAT5). Subsequently, siRNA was used to silence NFAT5, and cell proliferation, migration, and apoptosis were assessed. RESULTS: The results revealed that the expression of miR-96-5p was downregulated in Ang II-induced VSMCs. MiR-96-5p overexpression inhibited cell proliferation and migration but promoted cell apoptosis, enhanced the percentages of cells in the G1 and G2 phases, and reduced those in the S phase, accompanied by changes in the expression associated proteins. NFAT5 was confirmed as a direct target of miR-96-5p. NFAT5 silencing had the same results with miR-96-5p overexpression on VSMC proliferation, migration, and apoptosis, whereas miR-96-5p inhibitor reversed these effects. CONCLUSIONS: Our findings concluded that miR-96-5p could regulate proliferation, migration, and apoptosis of VSMCs induced by Ang II via targeting NFAT5.

Jatrorrhizine Hydrochloride alleviates tert-butyl hydroperoxide-induced endothelial cell injury through its anti-inflammatory activity and PPAR-γ activation.

The aim of this study was to investigate whether Jatrorrhizine hydrochloride (JAH) can attenuate oxidative damage of endothelial cells by regulating mitochondrial function and inflammatory response. It was found that JAH inhibited tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in mouse brain endothelial cells (MBECs) by increasing cell viability and inhibiting cell apoptosis. Moreover, JAH significantly inhibited the production of reactive oxygen species (ROS) and lipid peroxidation. It enhanced mitochondrial membrane potential (MMP) and maintained ATP synthesis. In addition, JAH regulated the expressions of inflammatory cytokines and increased the activation of endothelial nitric oxide synthase (eNOS). The protective effect of JAH was related to the protein expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) gene. In conclusion, these results suggest that JAH may have therapeutic potential for ischemic stroke associated with endothelial dysfunction through its antioxidant and anti-inflammatory properties.

MiR-30s Family Inhibit the Proliferation and Apoptosis in Human Coronary Artery Endothelial Cells Through Targeting the 3'UTR Region of ITGA4 and PLCG1.

Atherosclerosis (As) is a common disease, which is serious hazard to human health. As the main pathological basis of ischemic cardiac and cerebral vascular disease, including coronary heart disease, cerebrovascular disease, and thromboembolic disease, it is a chronic inflammatory lesion of the arterial vessel wall. So far the pathogenesis of As has not been fully understood. Therefore, it is still lack of effective clinical prevention and treatment of drugs. More and more evidence indicate that miRNA plays an important role in the pathophysiology of many diseases, especially the occurrence and development of cardiovascular diseases. MiRNAs are widely detected in human coronary artery endothelial cells, which might participate in diverse biological functions through targeting different As associated genes. The aim of this study was to investigate the molecular mechanisms underlying miR-30s roles in As. Our study found the high expression of miR-30b and miR-30e in As clinical samples, identified the regulatory relationship of miR-30b and miR-30e to ITGA4 and PLCG1, respectively, and initially explored the effects of miR-30b and miR-30e on cell cycle and apoptosis through targeting ITGA4 and PLCG1. These data may provide a theoretical basis for clarifying the mechanism of miR-30s in As.

Quercetin Prevents HSpertension in Dahl Salt-sensitive Rats Fed a High-salt Diet Through Balancing Endothelial Nitric Oxide Synthase and Sirtuin 1.

BACKGROUND: A high-salt diet is a leading dietary risk factor for elevated blood pressure and cardiovascular disease. Quercetin reportedly exhibits cardioprotective and antihypertensive therapeutic effects. OBJECTIVES: The objective of this study is to examine the effect of quercetin on high-salt dietinduced elevated blood pressure in Dahl salt-sensitive (SS) rats and determine the underlying molecular mechanism. MATERIALS AND METHODS: Rats of the Dahl SS and control SS-13 BN strains were separated into five groups, SS-13 BN rats fed a low-salt diet (BL group), SS-13 BN rats fed a high-salt diet (BH group), Dahl SS rats fed a low-salt diet (SL group), Dahl SS rats fed a high-salt diet (SH group), and SH rats treated with quercetin (SHQ group). Blood pressure was checked three weeks into the course of treatment, and biochemical markers in the urine and serum were examined. Additionally, western blot was done to evaluate the sirtuin 1 (SIRT1) and endothelial nitric oxide synthase (eNOS) expression levels. Immunohistochemical analysis was performed to verify SIRT1 levels. RESULTS: We demonstrated that a high-salt diet elevated blood pressure in both SS-13 BN and Dahl SS rats, and quercetin supplementation alleviated the altered blood pressure. Compared with the SH group, quercetin significantly elevated the protein expression of SIRT1 and eNOS. Immunohistochemistry results further confirmed that quercetin could improve the protein expression of SIRT1. CONCLUSION: Quercetin reduced blood pressure by enhancing the expression of SIRT1 and eNOS in Dahl SS rats fed a high-salt diet.

Genome-Wide Association Analysis of Yield-Related Traits and Candidate Genes in Vegetable Soybean.

Owing to the rising demand for vegetable soybean products, there is an increasing need for high-yield soybean varieties. However, the complex correlation patterns among quantitative traits with genetic architecture pose a challenge for improving vegetable soybean through breeding. Herein, a genome-wide association study (GWAS) was applied to 6 yield-related traits in 188 vegetable soybean accessions. Using a BLINK model, a total of 116 single nucleotide polymorphisms (SNPs) were identified for plant height, pod length, pod number, pod thickness, pod width, and fresh pod weight. Furthermore, a total of 220 genes were found in the 200 kb upstream and downstream regions of significant SNPs, including 11 genes encoding functional proteins. Among them, four candidate genes, Glyma.13G109100, Glyma.03G183200, Glyma.09G102200, and Glyma.09G102300 were analyzed for significant haplotype variations and to be in LD block, which encode MYB-related transcription factor, auxin-responsive protein, F-box protein, and CYP450, respectively. The relative expression of candidate genes in V030 and V071 vegetable soybean (for the plant height, pod number, and fresh pod weight of V030 were lower than those of the V071 strains) was significantly different, and these genes could be involved in plant growth and development via various pathways. Altogether, we identified four candidate genes for pod yield and plant height from vegetable soybean germplasm. This study provides insights into the genomic basis for improving soybean and crucial genomic resources that can facilitate genome-assisted high-yielding vegetable soybean breeding.

Associations of E-proteinoid 3 receptor genetic polymorphisms with salt sensitivity, longitudinal blood pressure changes, and hypertension incidence in Chinese adults.

The E-proteinoid 3 receptor (PTGER3), a member of the prostaglandin E2 (PGE2) subtype receptor, belongs to the G-protein-coupled superfamily of receptors. Animal studies have demonstrated its involvement in salt sensitivity by regulating sodium reabsorption. This study aimed to investigate the association between genetic variants of PTGER3 and salt sensitivity, longitudinal blood pressure (BP) changes, and the incidence of hypertension in Chinese adults. A chronic salt intake intervention was conducted involving 514 adults from 124 families in the 2004 Baoji Salt-Sensitivity Study Cohort in northern China. These participants followed a 3-day regular baseline diet, followed by a 7-day low-salt diet (3.0 g/d) and a 7-day high-salt diet (18 g/d), and were subsequently followed for 14 years. The findings revealed a significant relationship between the single nucleotide polymorphism (SNP) rs17482751 of PTGER3 and diastolic blood pressure (DBP) response to high salt intervention. Additionally, SNPs rs11209733, rs3765894, and rs2268062 were significantly associated with longitudinal changes in systolic blood pressure (SBP), DBP, and mean arterial pressure (MAP) during the 14-year follow-up period. SNP rs6424414 was significantly associated with longitudinal changes in DBP over 14 years. Finally, SNP rs17482751 showed a significant correlation with the incidence of hypertension over 14 years. These results emphasize the significant role of PTGER3 gene polymorphism in salt sensitivity, longitudinal BP changes, and the development of hypertension in the Chinese population.

Associations of SGLT2 genetic polymorphisms with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors lowers blood pressure (BP) and exert a salutary effect on the salt sensitivity of BP. This study aimed to examine the associations of SGLT2 genetic variants with salt sensitivity, longitudinal BP changes and the risk of incident hypertension in Baoji Salt-Sensitive Study. A total of 514 participants were recruited when the cohort was established in 2004, and 333 participants received a dietary intervention that consisted of a 3-day usual diet followed sequentially by a 7-day low-salt diet and a 7-day high-salt diet. The cohort was then followed up for 14 years to evaluate the longitudinal BP changes and development of hypertension. We found that SGLT2 SNP rs3813007 was significantly associated with the systolic BP (SBP) responses to the low-salt diet. Over the 14 years of follow-up, SNPs rs3116149 and rs3813008 were significantly associated with the longitudinal SBP changes, and SNPs rs3116149, rs3813008, rs3813007 in SGLT2 were significantly associated with incidence of hypertension. Furthermore, gene-based analyses revealed that SGLT2 was significantly associated with hypertension incidence. Our study suggests that SGLT2 genetic polymorphisms may be involved in salt sensitivity and development of hypertension.

Early-Life Cardiovascular Risk Factor Trajectories and Vascular Aging in Midlife: A 30-Year Prospective Cohort Study.

BACKGROUND: Vascular aging, as assessed by structural and functional arterial properties, is an independent predictor of cardiovascular outcomes. We aimed to explore the associations of individual cardiovascular risk factors from childhood to midlife and their accumulation over a 30-year span with vascular aging in midlife. METHODS: Using data from the ongoing cohort of Hanzhong Adolescent Hypertension study, 2180 participants aged 6 to 18 years at baseline were followed for over 30 years. Distinct trajectories of systolic blood pressure (SBP), body mass index (BMI), and heart rate from childhood to midlife were identified by group-based trajectory modeling. Vascular aging was assessed by carotid intima media thickness or brachial-ankle pulse wave velocity. RESULTS: We identified 4 distinct SBP trajectories, 3 distinct BMI trajectories, and 2 distinct heart rate trajectories from childhood to midlife. Persistently increasing SBP, high-increasing BMI, and high-stable heart rate were all shown to have a positive association with brachial-ankle pulse wave velocity in midlife. For carotid intima-media thickness, similar associations were observed for persistently increasing SBP and high-increasing body mass index. After further adjustment for SBP, body mass index and heart rate at the time of vascular assessment in 2017, associations were also observed for cardiovascular risk factor trajectories accumulation with brachial-ankle pulse wave velocity (ß, 0.656 [95% CI, 0.265-1.047]) and with carotid intima media thickness (ß, 0.045 [95% CI, 0.011-0.079]) in adulthood. CONCLUSIONS: Longitudinal exposure to individual cardiovascular risk factors from childhood to midlife and cardiovascular risk factor accumulation were associated with an increased risk of vascular aging in midlife. Our study lends support for early targeting of risk factors in order to prevent cardiovascular disease later in life.

Associations of lipid accumulation product, visceral adiposity index, and triglyceride-glucose index with subclinical organ damage in healthy Chinese adults.

Background and aims: Obesity is an independent risk factor for cardiovascular disease development. Here, we aimed to examine and compare the predictive values of three novel obesity indices, lipid accumulation product (LAP), visceral adiposity index (VAI), and triglyceride-glucose (TyG) index, for cardiovascular subclinical organ damage. Methods: A total of 1,773 healthy individuals from the Hanzhong Adolescent Hypertension Study cohort were enrolled. Anthropometric, biochemical, urinary albumin-to-creatinine ratio (uACR), brachial-ankle pulse wave velocity (baPWV), and Cornell voltage-duration product data were collected. Furthermore, the potential risk factors for subclinical organ damage were investigated, with particular emphasis on examining the predictive value of the LAP, VAI, and TyG index for detecting subclinical organ damage. Results: LAP, VAI, and TyG index exhibited a significant positive association with baPWV and uACR. However, only LAP and VAI were found to have a positive correlation with Cornell product. While the three indices did not show an association with electrocardiographic left ventricular hypertrophy, higher values of LAP and TyG index were significantly associated with an increased risk of arterial stiffness and albuminuria. Furthermore, after dividing the population into quartiles, the fourth quartiles of LAP and TyG index showed a significant association with arterial stiffness and albuminuria when compared with the first quartiles, in both unadjusted and fully adjusted models. Additionally, the concordance index (C-index) values for LAP, VAI, and TyG index were reasonably high for arterial stiffness (0.856, 0.856, and 0.857, respectively) and albuminuria (0.739, 0.737, and 0.746, respectively). Lastly, the analyses of continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI) demonstrated that the TyG index exhibited significantly higher predictive values for arterial stiffness and albuminuria compared with LAP and VAI. Conclusion: LAP, VAI, and, especially, TyG index demonstrated utility in screening cardiovascular subclinical organ damage among Chinese adults in this community-based sample. These indices have the potential to function as markers for early detection of cardiovascular disease in otherwise healthy individuals.

Involvement of the lymphatic system in salt-sensitive hypertension in humans.

BACKGROUND: The mechanisms of salt sensitivity as an important intermediate phenotype of essential hypertension remain elusive. A novel theory proposes that lymphatic vessels regulate sodium and fluid homeostasis. Since vascular endothelial growth factor C (VEGF-C) plays a vital role in lymphatic capillary hyperplasia, we hypothesized that VEGF-C was involved in salt-sensitive hypertension. We therefore investigated its plasma concentration in salt-sensitive subjects. MATERIAL/METHODS: Twenty-seven subjects (BP ≤ 160/100 mmHg; age range 25-50 years) from a rural community of northern China were enrolled in this study. The baseline BP of volunteers was monitored for 3 days, followed by a low-salt diet for 7 days (3 g/day, NaCl) and a high-salt diet for 7 days (18 g/day, NaCl). Those who exhibited a BP increase of 10% from low-salt period to high-salt period were diagnosed as salt-sensitive subjects. The concentration of plasma VEGF-C was measured by an immunoenzyme method (ELISA). RESULT: High salt intake significantly increased the plasma VEGF-C level. It was higher in the salt-sensitive subjects (3642.2 ± 406.1 pg/ml) than in the salt-resistant subjects (2249.8 ± 214.6 pg/ml). The comparison of VEGF-C levels between the 2 groups had significant statistical difference (P<0.01). CONCLUSIONS: The VEGF-C level increases significantly in the salt-sensitive subjects after high salt intake. VEGF-C could be used as a biomarker of salt sensitivity.

Integration of partial least squares and Monte Carlo gene expression analysis in coronary artery disease.

Coronary artery disease (CAD) is the most common type of cardiovascular disease and leading cause of mortality worldwide. Microarray technology for gene expression analysis has facilitated the identification of the molecular mechanism that underlies the pathogenesis of CAD. Previous studies have primarily used variance or regression analysis, without considering array specific factors. Thus, the aim of the present study was to investigate the mechanism of CAD using partial least squares (PLS)-based analysis, which was integrated with the Monte Carlo technique. Microarray analysis was performed with a data set of 110 CAD patients and 111 controls obtained from the Gene Expression Omnibus database. A total of 390 dysregulated genes were acquired. Significantly increased representations of dysregulated genes in Gene Ontology items, including transforming growth factor ß-activated receptor activity and acyl-CoA oxidase activity, were identified. Network analysis revealed three hub genes with a degree of >10, including ESR1, ITGA4 and ARRB2. The results of the present study provide novel information on the gene expression signatures of CAD patients and offer further theoretical support for future therapeutic study.

High salt intake fails to enhance plasma adiponectin in normotensive salt-sensitive subjects.

OBJECTIVE: Evidence shows that salt can modulate adiponectin and inflammation levels in normal individuals. Therefore, we hypothesized that abnormalities in adiponectin and inflammation might be the potential mechanism of salt sensitivity. The aim of this study was to investigate whether different alterations of adiponectin and inflammation levels in response to a high-salt intake were exhibited between normotensive salt-sensitive and salt-resistant subjects. METHODS: Thirty normotensive subjects (25 to 50 y old) were selected from a rural community of northern China. They were sequentially maintained on a normal diet for 3 d at baseline, a low-salt diet for 7 d (NaCl 3 g/d), and then a high-salt diet for 7 d (18 g/d). RESULTS: Salt sensitivity was diagnosed in 10 subjects who exhibited an increase of at least 10% in mean blood pressure from the low-salt to the high-salt periods. Plasma adiponectin was significantly higher with the high-salt intake than with the low-salt intake (6.1 ± 1.3 versus 7.1 ± 1.7 µg/mL, P = 0.047) in normotensive salt-resistant subjects but not in the normotensive salt-sensitive subjects (6.4 ± 2 versus 5.9 ± 2.1 µg/mL, P = 0.481). The high-salt intake markedly increased plasma tumor necrosis factor-α (P < 0.0001) and monocyte chemoattractant protein-1 (P < 0.0001) in normotensive salt-sensitive and salt-resistant subjects. No significant change in plasma high-sensitivity C-reactive protein was observed. CONCLUSIONS: Our data indicate that the disturbance of adiponectin exists in normotensive salt-sensitive subjects during a high-salt diet, which may be a novel underlying mechanism of salt sensitivity.