Clinical and Experimental Hypertension最新文献

Objective: This study investigated the expression of TGF-β/Smad pathway-related indices in patients with isolated iliac artery aneurysms (IIAA) complicated with iliac arteriovenous fistula (IAVF) and their relationship with prognosis.

Methods: From January 2016 to June 2022, 83 patients with IIAA complicated with IAVF (Study group) and 54 patients with IIAA not complicated with IAVF (control group) were studied. The related indices of TGF-β/Smad pathway were evaluated, and the effects of each index on the formation of IAVF were analyzed. The patients were divided into the survival group (64 cases) and death group (19 cases), and the prognostic value of indices in combination was analyzed.

Results: TGF-β, p-Smad2, p-Smad3, p-JNK, and p-ERK in the study group were higher than those in the control group. Abnormal increase of pSmad3 expression was a risk factor for IAVF formation in patients with IIAA. TGF-β level in the death group was higher than that in the survival group, and p-Smad3 and p-JNK proteins were higher than those in the survival group. The AUC value of indices in the TGF-β/Smad pathway in combination was greater than that of each index alone. Abnormal increased expression of pSmad3 was a risk factor for prognosis of patients with IIAA complicated with IAVF.

Conclusion: The abnormal increase of TGF-β/Smad pathway-related indices is related to poor prognosis of patients with IIAA complicated with IAVF, and the combined detection of all indices has a predictive value for patients' prognosis.

Background: The present study aimed to investigate the effect of microRNA153 (miRNA153) on pulmonary hypertension (PH).

Methods: PH was induced by a single subcutaneous injection of sugen5416 (SU5416) combined with hypoxia exposure for 3 weeks (SuHx) in rats, while pulmonary arterial smooth muscle cells (PASMCs) obtained from rats were exposed to hypoxia to establish an in vitro model. Through observing the characteristic hemodynamic index in rats and by analyzing the physiological function, vascular remodeling and right ventricular hypertrophy were identified. The regulatory effects of miRNA153 on the nuclear factor of activated T cell isoform c3 (NFATc3) were measured by RT-qPCR, western blot, and immunofluorescence. Cell apoptosis was evaluated by flow cytometry.

Results: The miRNA153 expression was reduced and unclear translation of NFATc3 was increased in both the in vivo and in vitro models of PH. In vivo, the pulmonary arterial pressure, right ventricle/(left ventricle + interventricular septum) (RV/(LV+S)), and media vascular thickness were increased in rats with PH; however, all these parameters were suppressed by prophylactic administration of miRNA153agomir. The upregulation of NFATc3 and downregulation of the potassium voltage-gated channel subfamily A member 5 (Kv1.5) were also reversed by transfection with miRNA153agomir. In vitro, miRNA153 increased the level of Kv1.5 in hypoxic PASMCs by targeting NFATc3 and inhibiting their proliferation and apoptosis resistance.

Conclusion: Our results confirmed that the therapeutic administration of miRNA153 promotes apoptosis and inhibits the proliferation of PASMCs to ameliorate PH, and that the NFATc3/Kv1.5 channel pathway may be involved in this process.

Background and aims: To evaluate the association of Chinese visceral adiposity index (CVAI) and its dynamic trends with risk of renal damage, and to compare its prediction performance with that of other obesity indices.

Methods and results: A community-based population with 23 905 participants from Shantou city was included in the cross-sectional analysis. A total of 9,778 individuals from two separated cohort were included in the longitudinal portion. Five patterns of CVAI change were predefined (low-stable, decreasing, moderate, increasing, and persistent-high). Logistic and Cox regressions were used to evaluate the association between CVAI and renal damage. We explored potential mechanisms using the mediating effect method, and the prediction performance was determined by receiver operating characteristic curve analysis. Results from both cross-sectional and longitudinal data revealed a positive and linear association between CVAI and risk of renal damage. Pooled analysis of the two cohorts showed that per unit increase in Z score of CVAI induced 18% increased risk of renal damage (P = .008). Longitudinal trends of CVAI were also associated with renal damage, and the moderate, increasing, and persistent-high patterns showing a higher risk. Blood pressure and glucose had a mediating effect on renal damage induced by CVAI. Among several obesity indices, CVAI was the optimal for predicting renal damage.

Conclusion: A higher level of immediate CVAI and longitudinal increasing and persistent-high patterns of CVAI were independently associated with increased risk of renal damage. Monitoring immediate level and long-term trend of CVAI may contribute to the prevention of renal damage.

Background: The triglyceride and glucose (TyG) index has been found to be significantly associated with a higher risk of mortality. However, there has been a lack of studies exploring the specific relationship between the TyG index and all-cause and cardiovascular mortality among middle-aged and elderly with hypertension.

Methods: A total of 3,614 participants with hypertension were enrolled from the National Health and Nutrition Examination Survey. The TyG index was calculated using the formula log [fasting triglycerides (mg/dL) x fasting glucose (mg/dL)/2]. The Cox proportional hazard ratios were used to evaluate the association between the TyG index and the risk of mortality.

Results: Over a follow-up period of 7.87 years, 991 all-cause death and 189 cardiovascular deaths occurred. Compared with the reference quartile, the multivariate-adjusted hazard ratios and 95% confidence intervals were 1.28 (1.07-1.53; p = .006) in the fourth quartile for all-cause mortality and 0.63 (0.42-0.96; p = .031) in the second quartile for cardiovascular mortality. Dose-response analysis indicated an L-shaped relationship.

Conclusions: The TyG index exhibited an L-shaped association with the risk of all-cause mortality among middle-aged and elderly with hypertension.

Long non-coding RNAs (LncRNAs) have been found to play a regulatory role in the pathophysiology of vascular remodeling-associated illnesses through the lncRNA-microRNA (miRNA) regulation axis. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is thought to be involved in proliferation, migration, apoptosis, and calcification of vascular smooth muscle cells (VSMCs). The purpose of this study was to investigate the regulatory role of MALAT1 on vascular remodeling in hypertension. Our data indicate that the expression of MALAT1 is significantly upregulated in hypertensive aortic smooth muscle. Knockdown of MALAT1 inhibited the proliferation, migration, and phenotypic transition of VSMCs induced by Ang II. Bioinformatics analysis was used to predict the complementary binding of miR-145-5p to the 3'-untranslated region of MALAT1. Besides, the expressions of MALAT1 and miR-145-5p were negatively correlated, while luciferase reporter assays and RNA immunoprecipitation assay validated the interaction between miR-145-5p and MALAT1. The proliferation, migration and phenotypic transformation of VSMCs induced by overexpression of MALAT1 were reversed in the presence of miR-145-5p. Furthermore, we verified that miR-145-5p could directly target and bind to hexokinase 2 (HK2) mRNA, and that HK2 expression was negatively correlated with miR-145-5p in VSMCs. Knockdown of HK2 significantly inhibited the effects of overexpression of MALAT1 on Ang II-induced VSMCs proliferation, migration and phenotypic transformation. Taken together, the MALAT1/miR-145-5p/HK2 axis may play a critical regulatory role in the vascular remodeling of VSMCs in hypertension.

Hypertension is well-known to be influenced by genetic and environmental factors. Managing stress is one of the non-pharmacologic approaches to treating hypertension. It is, therefore, imperative to unravel the molecular mechanism by which stress conditions influence hypertension. In this study, TIP60 expressions in human blood samples and cell lines, glutamate^{dmPFC-to-vCA1} release, and receptor expressions in the Stress-induced hypertension mice were determined using western blotting, CSF (obtained by microdialysis), and ELISA. The study reports increased protein expressions of TIP60 in the peripheral blood of hypertensive patients and in cell lines representing hypertension. In Chronic restraint stress (CRS) conditions TIP60 expression and vCA1 glutamate release were found to be up-regulated, with high SBP and DSP indicating hypertension was induced. After electrical stimulation at the dmPFC, release of glutamate in the vCA1 increased, indicating that activity within the dmPFC drives the release of glutamate in the vCA1, which was blocked by injecting MG149 (a TIP60 inhibitor) into dmPFC. To further determine whether TIP60 was involved in glutamate release and eventually results in hypertension, MG149 was also injected i.p. alongside CRS modeling. The increased glutamate release, NR2B, and IL-18 expressions as well as the CRS-induced hypertension was therefore reversed by chronic application with MG149. Altogether, these results suggest that TIP60 influences the glutamate^{dmPFC-to-vCA1} release and receptor expressions. This study, therefore, proposes that stressful condition induces increased expression of TIP60 which lead to the transcription of genes that result in conditions that favors glutamate release and receptor expressions hence triggering hypertension.

Circular RNAs (circRNAs) regulate the function of vascular smooth muscle cells (VSMCs) in atherosclerosis (AS) progression. We aimed to explore the role of circUSP9X in oxidized low-density lipoprotein (ox-LDL)-induced VSMCs. Cell proliferation was assessed using cell counting kit-8 and EDU assays. Cell migration was evaluated using Transwell and wound healing assays. The interaction between circUSP9X or STIM1 and miR-599 was analyzed using dual-luciferase reporter and RNA pull-down assays. Their levels were examined using quantitative real-time PCR. CircUSP9X and STIM1 expression was increased, whereas miR-599 expression was reduced in the serum of patients with AS and ox-LDL-stimulated VSMCs. Overexpression of circUSP9X facilitated the proliferation and migration of VSMCs induced by ox-LDL. CircUSP9X sponged miR-599, which targeted STIM1. MiR-599 reversed the effects induced by circUSP9X, and STIM1 reversed the effects induced by miR-599. Taken together, CircUSP9X promoted proliferation and migration in ox-LDL-treated VSMCs via the miR-599/STIM1 axis, providing a theoretical basis for the role of circUSP9X/miR-599/STIM1 axis in AS.

Background and purpose: Substitution of Cys⁶⁷⁴ (C674) in the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2 (SERCA2) causes SERCA2 dysfunction which leads to activated inositol requiring enzyme 1 alpha (IRE1α) and spliced X-box binding protein 1 (XBP1s) pathway accelerating cell proliferation of pulmonary artery smooth muscle cells (PASMCs) followed by significant pulmonary vascular remodeling resembling human pulmonary hypertension. Based on this knowledge, we intend to investigate other potential mechanisms involved in SERCA2 dysfunction-induced pulmonary vascular remodeling.

Experimental approach: Heterozygous SERCA2 C674S knock-in (SKI) mice of which half of cysteine in 674 was substituted by serine to mimic the partial irreversible oxidation of C674 were used. The lungs of SKI mice and their littermate wild-type mice were collected for PASMC culture, protein expression, and pulmonary vascular remodeling analysis.

Results: SERCA2 dysfunction increased intracellular Ca²⁺ levels, which activated Ca²⁺-dependent calcineurin (CaN) and promoted the nuclear translocation and protein expression of the nuclear factor of activated T-lymphocytes 4 (NFAT4) in an IRE1α/XBP1s pathway-independent manner. In SKI PASMCs, the scavenge of intracellular Ca²⁺ by BAPTA-AM or inhibition of CaN by cyclosporin A can prevent PASMC phenotypic transition. CDN1163, a SERCA2 agonist, suppressed the activation of CaN/NFAT4 and IRE1α/XBP1s pathways, reversed the protein expression of PASMC phenotypic transition markers and cell cycle-related proteins, and inhibited cell proliferation and migration when given to SKI PASMCs. Furthermore, CDN1163 ameliorated pulmonary vascular remodeling in SKI mice.

Conclusions and implications: SERCA2 dysfunction promotes PASMC phenotypic transition and pulmonary vascular remodeling by multiple mechanisms, which could be improved by SERCA2 agonist CDN1163.