Clinical and Experimental Hypertension最新文献

Background: Mitsugumin 53 (MG53) is a membrane repair factor that is associated with acute myocardial infarction. This study aimed to investigate the effects of MG53 on cardiomyocyte injury and the posttranslational modification of MG53.

Methods: Cardiomyocyte injury was evaluated by enzyme-linked immunosorbent assay and flow cytometry. The succinylation and ubiquitination levels of MG53 were examined by immunoprecipitation (IP) and western blot. The relationship between MG53 and KAT3B or SIRT7 was assessed by co-IP and immunofluorescence.

Results: The results showed that overexpression of MG53 inhibited inflammation response and apoptosis of cardiomyocytes induced by hypoxia/reoxygenation (H/R). Succinylation and protein levels of MG53 were downregulated in H/R-induced cells, which was inhibited by SIRT7 and promoted by KAT3B. SIRT7 aggravated and KAT3B alleviated MG53-mediated cardiomyocyte injury. Moreover, MG53 was succinylated and ubiquitinated at K130.

Conclusion: SIRT7 inhibited/KAT3B promoted succinylation of MG53 at K130 sites, which suppressed ubiquitination of MG53 and upregulated its protein levels, thereby alleviating H/R-induced cardiomyocyte injury. The findings suggested that MG53 may be a potential therapy for myocardial infarction.

Objective: The quantification of cardiovascular health (CVH) was updated by the American Heart Association recently by using the "Life's Essential 8" (LE8) score. We aimed to investigate the associations of baseline and longitudinal CVH status measured by the new LE8 score (except for blood pressure) with the risk of hypertension.

Methods: A total of 52 990 participants with complete data on LE8 metrics and without hypertension were enrolled from the Kailuan study, Tangshan, China. The associations of incident hypertension with the overall baseline, time-updated, and time-varying CVH score (ranging 0 [lowest] to 100 [highest]), and each component of LE8, were assessed by Cox regressions.

Results: During a median follow-up of 10.73 years 28 380 cases of incident hypertension were identified. The risk of hypertension attenuated with increased CVH score (P_trend < 0.0001), the hazard ratios (HRs) in high CVH versus low CVH group was 0.54 (95% confidence interval [CI], 0.51-0.57) for baseline CVH, 0.47 (95% CI, 0.45-0.50) for time-updated CVH, and 0.59 (95% CI, 0.55-0.63) for time-varying CVH. The predictive value of CVH in predicting hypertension improved by using LE8 than using Life's Simple 7 metrics. Among LE8 components, body mass index score was the strongest risk factor for hypertension. Subgroup analyses showed that the benefit of a higher CVH score on hypertension was more prominent in young adults and in women (P_interaction < 0.05).

Conclusions: A higher CVH score assessed by new LE8 is associated with a lower risk of subsequent hypertension, especially young adults and women.

Pulmonary arterial hypertension (PAH) is a disease with a high mortality and few treatment options to prevent the development of pulmonary vessel remodeling, pulmonary vascular resistance, and right ventricular failure. Canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is originally used in diabetes patients which could assist the glucose excretion and decrease blood glucose. Recently, a few studies have reported the protective effect of SGLT2 inhibitor on monocrotaline-induced PAH. However, the effects of canagliflozin on hypobaric hypoxia-induced PAH as well as its mechanism still unclear. In this study, we used hypobaric hypoxia-induced PAH mice model to demonstrate if canagliflozin could alleviate PAH and prevent pulmonary vessel remodeling. We found that daily canagliflozin administration significantly improved survival in mice with hypobaric hypoxia-induced PAH compared to vehicle control. Canagliflozin treatment significantly reduced right ventricular systolic pressure and increased pulmonary acceleration time determined by hemodynamic assessments. Canagliflozin significantly reduced medial wall thickening and decreased muscularization of pulmonary arterioles compared to vehicle treated mice. In addition, canagliflozin inhibited the proliferation and migration of pulmonary arterial smooth muscle cells through suppressing glycolysis and reactivating AMP-activated protein kinase signaling pathway under hypoxia condition. In summary, our findings suggest that canagliflozin is sufficient to inhibit pulmonary arterial remodeling which is a potential therapeutic strategy for PAH treatment.

Background: Obesity, especially visceral obesity, plays an important role in the progression of cardiovascular disease (CVD). The body roundness index (BRI) is a new measure of obesity that is considered to reflect visceral obesity more comprehensively than other measures. This study aims to evaluate the relationship between BRI and CVD risk in hypertensive patients with obstructive sleep apnea (OSA) and explore its superiority in predicting CVD.

Methods: The Cox proportional hazards model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CVD. The area under the curve (AUC), continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to assess which measures of obesity had the best predictive value for CVD risk.

Results: During a median follow-up period of 6.8 years, 324 participants suffered a CVD event. After multivariable adjustment, compared with the reference group (the first tertile), the HRs (95% CI) of CVD were 1.25 (95% CI, 0.93-1.70) and 1.74 (95% CI, 1.30-2.33) for subjects in the tertile 2 and tertile 3 groups, respectively. Compared with other measurement indicators, BRI has the highest predictive value for CVD risk [AUC: 0.627, 95% CI: 0.593-0.661]. The addition of the BRI to the fully adjusted multivariate model improved the predictive power for CVD, which was validated in the continuous NRI and the IDI (all P < .05).

Conclusions: BRI was significantly associated with the risk of CVD in hypertensive patients with OSA. Furthermore, BRI may improve CVD risk prediction in hypertensive patients with OSA.

Background: The relationship of cumulative non high-density lipoprotein-cholesterol (Cum-non-HDL-C) concentration with the risk of cardiovascular disease (CVD) in individuals with hypertension remains unclear.

Methods: In total 27 234 participants for whom three consecutive total cholesterol and HDL-C concentrations were available, and who did not have CVD, comprising 13 617 with hypertension and 13 617 without from 2006 to 2010. Participants were placed into four groups according to Cum-non-HDL-C. Cox proportional hazards models were used to evaluate the relationship between Cum-non-HDL-C and the risk of CVD.

Results: Over a median 11 years, 1,298 participants with hypertension developed CVD. After adjustment for multiple potential confounding factors, compared with participants with hypertension and Cum-non-HDL-C < 130 mg/dl, the fully adjusted hazard ratios and 95% confidence intervals of CVD associated with Cum-non-HDL-C values of 130-159 mg/dl, 160-189 mg/dl, and ≥ 190 mg/dl were 1.23 (1.01, 1.34), 1.27 (1.04, 1.56), and 1.51 (1.13, 2.01), respectively. Compared with participants without hypertension and a Cum-non-HDL-C < 130 mg/dl, the fully adjusted hazard ratios (95% confidence intervals) for the participants with hypertension and Cum-non-HDL-Cs < 130 mg/dl, 130-159 mg/dl, 160-189 mg/dl, and ≥ 190 mg/dl were 1.84 (1.55, 2.18), 2.16 (1.81, 2.59), 2.17 (1.73, 2.70), and 2.45 (1.12, 3.29), respectively.

Conclusions: A consistently high non-HDL-C concentration increases the risk of CVD in individuals with hypertension, as does prolonged exposure to a high non-HDL-C concentration. Thus, the achievement of target blood pressure and non-HDL-C concentrations should help reduce the risk of CVD in individuals with hypertension.

Objective: Excessive proliferation and migration of pulmonary arterial smooth muscle cell (PASMC) is a core event of pulmonary hypertension (PH). Regulators of G protein signaling 10 (RGS10) can regulate cellular proliferation and cardiopulmonary diseases. We demonstrate whether RGS10 also serves as a regulator of PH.Methods: PASMC was challenged by hypoxia to induce proliferation and migration. Adenovirus carrying Rgs10 gene (Ad-Rgs10) was used for external expression of Rgs10. Hypoxia/SU5416 or MCT was used to induce PH. Right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) were used to validate the establishment of PH model.Results: RGS10 was downregulated in hypoxia-challenged PASMC. Ad-Rgs10 significantly suppressed proliferation and migration of PASMC after hypoxia stimulus, while silencing RGS10 showed contrary effect. Mechanistically, we observed that phosphorylation of S6 and 4E-Binding Protein 1 (4EBP1), the main downstream effectors of mammalian target of rapamycin complex 1 (mTORC1) as well as phosphorylation of AKT, the canonical upstream of mTORC1 in hypoxia-induced PASMC were negatively modulated by RGS10. Both recovering mTORC1 activity and restoring AKT activity abolished these effects of RGS10 on PASMC. More importantly, AKT activation also abolished the inhibitory role of RGS10 in mTORC1 activity in hypoxia-challenged PASMC. Finally, we also observed that overexpression of RGS10 in vivo ameliorated pulmonary vascular wall thickening and reducing RVSP and RVHI in mouse PH model.Conclusion: Our findings reveal the modulatory role of RGS10 in PASMC and PH via AKT/mTORC1 axis. Therefore, targeting RGS10 may serve as a novel potent method for the prevention against PH."

Background: Cardiovascular disease (CVD) is the leading cause of death. Oxidative stress is an important pathological process of a variety of CVDs. Xinshuaining preparation has a therapeutic effect on the heart failure. However, the anti-oxidative stress role of Xinshuaining preparation in H9c2 cells is still unclear.

Methods: The medicated serum of Xinshuaining preparation was acquired and utilized to hatch with H₂O₂-induced H9c2 cells. Main components in the Xinshuaining preparation were analyzed by liquid chromatography-mass spectrometry (LC/MS). The effect of medicated serum on the cell viability, apoptosis rate, the oxidative stress indicators (SOD, GSH-Px, and MDA), mitochondrial membrane potential (MMP), and ROS level was evaluated by CCK-8, flow cytometry, commercial biochemical detection kits, and JC-1 staining. Additionally, the associated mechanism was determined by the detection of the protein levels (PI3K, phosphorylated PI3K, Akt, phosphorylated Akt, and Nrf-2) through western blot assays, which was also further assessed with the application of LY294002.

Results: The medicated serum of Xinshuaining preparation notably increased the H₂O₂-reduced, the cell viability, the concentration of SOD and GSH-Px, MMP level and the relative protein expression level of phosphorylated PI3K and Akt and Nrf-2, while dampened the H₂O₂-elevated the level of the cell apoptosis rate, MDA, and ROS. However, Xinshuaining preparation on the cell viability, apoptosis, and oxidative stress was notably antagonized by LY294002 pre-treatment.

Conclusions: The medicated serum of Xinshuaining preparation increased the cell viability and suppressed apoptosis and oxidative stress via the PI3K/Akt/Nrf-2 signaling pathway.

Background: The vitamin D level in the blood is associated with the incidence of hypertension. The present study investigated whether or not calcitriol, an active form of vitamin D, reverses age-related hypertension.

Methods: Young (3-month-old) and aged (12-month-old) C57BL/6 male mice were administered with or without calcitriol at 150 ng/kg per day by oral gavage for 8 weeks. Blood pressure was measured by tail-cuff plethysmography and telemetry, and superoxide production in renal tissue was assessed by fluorescence imaging, and the protein expression of AP1/AT₁R signaling pathway was examined by Western blot.

Results: We showed that 24-hour renal sodium excretion was impaired and blood pressure was increased in aged mice, which was related to the enhancement of renal AT₁R expression and function. In addition, the expression of transcription factor AP1 (a dimer of c-Fos and c-Jun) and the binding of AP1 to the AT₁R promoter region was significantly enhanced, accompanied by decreased nuclear translocation of Nrf2, abnormal mitochondrial function including decreased ATP production, NAD⁺/NADH ratio and mtDNA copy numbers, and increased reactive oxygen species. Calcitriol increased 24-hour urinary sodium excretion and reduced blood pressure in aged mice. Mechanically, calcitriol increased the nuclear translocation of Nrf2, improved mitochondrial function, reduced AP1 binding ability to AT₁R promoter, which reversed enhanced AT₁R expression and function, and lowered blood pressure in aged mice.

Conclusions: Our findings indicated that calcitriol reversed age-related hypertension via downregulating renal AP1/AT₁R pathway through regulating mitochondrial function. Thus, calcitriol may be a valuable therapeutic strategy for age-related hypertension.

Objective: Endothelial dysfunction is a critical initiating factor in the development of hypertension and related complications. Follistatin-like 1 (FSTL1) can promote endothelial cell function and stimulates revascularization in response to ischemic insult. However, it is unclear whether FSTL1 has an effect on ameliorating endothelial dysfunction in spontaneously hypertensive rats (SHRs).

Methods: Wistar Kyoto (WKY) and SHRs were treated with a tail vein injection of vehicle (1 mL/day) or recombinant FSTL1 (100 μg/kg body weight/day) for 4 weeks. Blood pressure was measured by tail-cuff plethysmograph, and vascular reactivity in mesenteric arteries was measured using wire myography.

Results: We found that treatment with FSTL1 reversed impaired endothelium-dependent relaxation (EDR) in mesenteric arteries and lowered blood pressure of SHRs. Decreased AMP-activated protein kinase (AMPK) phosphorylation, elevated endoplasmic reticulum (ER) stress markers, increased reactive oxygen species (ROS), and reduction of nitric oxide (NO) production in mesenteric arteries of SHRs were also reversed by FSTL1 treatment. Ex vivo treatment with FSTL1 improved the impaired EDR in mesenteric arteries from SHRs and reversed tunicamycin (ER stress inducer)-induced ER stress and the impairment of EDR in mesenteric arteries from WKY rats. The effects of FSTL1 were abolished by cotreatment of compound C (AMPK inhibitor).

Conclusions: These results suggest that FSTL1 prevents endothelial dysfunction in mesenteric arteries of SHRs through inhibiting ER stress and ROS and increasing NO production via activation of AMPK signaling.

Background: Microcirculatory endothelial dysfunction is a complex phenomenon that contributes to the development of cardiovascular disease. However, the relationship between microcirculatory endothelial dysfunction and macrovascular disease remains incompletely understood. Fluid overload is a risk factor for cardiovascular mortality in patients undergoing peritoneal dialysis. Therefore, we investigated the effects of chronic fluid overload on both the microcirculation and macrocirculation in these patients.

Methods: Thirty patients undergoing peritoneal dialysis were included in this cross-sectional study. We measured their central blood pressure and pulse wave velocity, assessed their microvascular endothelial function using drug-induced iontophoresis with laser Doppler flowmetry, and determined the amount of fluid overload using bioimpedance. We conducted a Spearman correlation analysis, univariate analysis, and stepwise multivariate regression models to determine the associations among the hemodynamic parameters.

Results: Acetylcholine-induced iontophoresis with laser Doppler flowmetry showed a correlation with both brachial and central pulse pressure (PP), but not with pulse wave velocity. Fluid overload was associated with both central and brachial PP and remained an independent predictor of central PP even after adjusting for multiple factors. However, fluid overload was not associated with microcirculatory endothelial function.

Conclusion: In peritoneal dialysis patients, we observed a significant association between central PP and microvascular endothelial function, indicating a connection between macrocirculation and microcirculation. However, conclusive evidence regarding fluid overload as a mediator between these circulatory systems is lacking. Further research is needed to investigate this relationship.