Hypertension最新文献

Background: Chronic unfolded protein response due to endoplasmic reticulum stress has been proposed as a therapeutic target for hypertension. Here, we tested our hypothesis that inactivation of one of the central unfolded protein response effectors, inositol-requiring enzyme 1α, mitigates hypertension and vascular remodeling in mice infused with angiotensin II.

Methods: C57BL6 mice were infused with angiotensin II for 2 weeks with or without an inositol-requiring enzyme 1α inhibitor KIRA6 treatment to evaluate blood pressure and cardiovascular remodeling. Mouse small mesenteric arteries were used to assess vascular reactivity. Rat vascular smooth muscle cells were used to assess inositol-requiring enzyme 1α activation, intracellular Ca²⁺ concentration, and secretory phenotype via proteomics.

Results: KIRA6 treatment mitigated hypertension induced by angiotensin II infusion. KIRA6 treatment also prevented angiotensin II-induced vascular thickening and perivascular fibrosis. Immunohistochemical staining of aortas indicated that phosphorylated inositol-requiring enzyme 1α signal in vascular smooth muscle cells was elevated with angiotensin II infusion and attenuated with KIRA6 treatment. Vasoconstriction in small mesenteric arteries after incubation with angiotensin II was attenuated by KIRA6 coincubation. Angiotensin II-induced elevation in intracellular Ca²⁺ concentration was partially reduced by KIRA6 pretreatment in vascular smooth muscle cells. Proteomic analysis demonstrated that angiotensin II induced a unique secretory phenotype in vascular smooth muscle cells, which was mitigated by KIRA6.

Conclusions: Targeting inositol-requiring enzyme 1α is a potential therapy for hypertension and vascular remodeling by reducing vascular resistance, mitigating intracellular Ca²⁺ elevation, and protecting against secretory phenotype in vascular smooth muscle cells.

Background: The ambulatory arterial stiffness index (AASI) is increasingly used in clinical research and practice. This individual-participant meta-analysis aims to consolidate the prognostic accuracy of AASI in the general population and to derive an end point-based AASI risk threshold.

Methods: In 12 558 individuals enrolled in 14 population studies (48.8% women; mean age, 59.3 years), AASI was derived by regressing 24-hour diastolic on systolic blood pressure (mm Hg/mm Hg). Using Cox regression, the risk-carrying AASI threshold was established by examining stepwise increasing AASI levels and by determining the AASI level, yielding a 10-year risk similar to an office systolic pressure of 140 mm Hg.

Results: Over 10.7 years (median), 3027 all-cause deaths and 2183 cardiovascular end points occurred. In all participants, multivariable-adjusted hazard ratios expressing the all-cause deaths and cardiovascular end point risk per 1-SD AASI increment were 1.08 (95% CI, 1.04-1.13) and 1.13 (95% CI, 1.07-1.18). In a randomly defined subset of 8189 individuals, the risk-carrying AASI thresholds converged to 0.50 with hazard ratios (≥0.50 versus <0.50) of 1.14 (95% CI, 1.04-1.26) for all-cause deaths and 1.13 (95% CI, 1.01-1.26) for cardiovascular end point. In the replication sample (n=4369), these hazard ratios were 1.13 (95% CI, 1.01-1.26) and 1.19 (95% CI, 1.04-1.35). AASI continuous or per threshold significantly improved model performance. Analyses of secondary end points and subgroups stratified by sex, age, hypertension status and treatment, history of cardiovascular disease, and nocturnal dipping were confirmatory.

Conclusions: Over and beyond traditional risk factors, AASI improves risk stratification. Exceeding the risk-carrying 0.50 AASI threshold necessitates increased vigilance in managing risk factors before irreversible cardiovascular complications occur.

Background: uPA (urokinase-type plasminogen activator) inhibitors mitigate salt retention, plasmin, and complement activation in acute proteinuric kidney diseases. We hypothesized that in chronic kidney injury with albuminuria, uPA contributes to hypertension and complement-dependent tissue inflammation and injury.

Methods: Wild-type and uPA KO (knockout) mice underwent either sham surgery or unilateral nephrectomy, followed by insertion of deoxycorticosterone acetate (DOCA)- or sham pellets and a high (4%) or control (0.5%) sodium chloride diet for 21 days. Glomerular filtration rate was estimated by transcutaneous fluorescein-isothiocyanate-sinistrin, and arterial blood pressure was recorded continuously by indwelling femoral catheters. Urine was analyzed for albumin, plasmin(ogen), electrolytes, kidney injury markers (neutrophil gelatinase-associated lipocalin), and complement proteins (C3, C3a). Kidney tissue was examined for neutrophil gelatinase-associated lipocalin, epithelial sodium channel, C3, C3a, C5a, cytokines, inflammation, and macrophage polarization markers (CD16⁺CD32⁺, CD163⁺).

Results: DOCA-salt increased diuresis, Na⁺ excretion, albuminuria, tubular injury markers, and single-kidney glomerular filtration rate, with no genotype-dependent differences. Blood pressure increased by ≈30 mm Hg within 2 days and then stabilized, with no genotype difference for up to 15 days. DOCA-salt wild-type mice showed elevated urinary protease activity, plasmin, C3, and C3a, while these were mitigated in KO mice. In the kidney, DOCA-salt increased IL-6 (interleukin 6), MCP-1 (monocyte chemoattractant protein-1), MIP-1α (macrophage inflammatory protein 1 alpha), and TNF (tumor necrosis factor), while TNF and IP-10 (interferon gamma-induced protein-10) were reduced in KO mice. CD16⁺CD32⁺ macrophages predominated over CD163⁺ macrophages in DOCA-salt kidney tissue across genotypes.

Conclusions: While not essential for filtration barrier injury, glomerular filtration rate decline, and hypertension in DOCA-salt-induced kidney injury, uPA, through plasmin, generates anaphylatoxins with effects on specific cytokines.

Background: Time in target range (TTR) reflects the proportion of time blood pressure (BP) remains within a defined range, integrating BP variability and control. We examined associations of systolic BP (SBP) TTR during ambulatory BP monitoring with cardiovascular and all-cause mortalities.

Methods: Patients from the Spanish Ambulatory BP Monitoring Registry who were receiving antihypertensive medications or who had sustained or masked hypertension without treatment, defined by office BP ≥140/90 mm Hg and 24-hour BP ≥130/80 mm Hg. TTR was estimated by linear interpolation between consecutive SBP recordings obtained from ambulatory BP monitoring and expressed as the proportion of time SBP remained within 120 to 134 mm Hg during daytime and 110 to 119 mm Hg during nighttime, from which 24-hour TTR was derived. Associations with mortality were assessed by Cox regression adjusted for demographic and clinical variables.

Results: A total of 48 687 patients (46% women) were analyzed. Over a median follow-up of 9.7 years, 6502 deaths occurred, including 2185 cardiovascular deaths. Higher 24-hour TTR was associated with lower all-cause mortality (hazard ratio, 0.83 per 1-SD increment [95% CI, 0.80-0.85]). Similarly, higher 24-hour TTR was associated with lower cardiovascular mortality (hazard ratio, 0.80 per 1-SD increment [95% CI, 0.76-0.84]). Both associations remained significant after adjusting for the mean 24-hour SBP and SBP variability.

Conclusions: Higher 24-hour SBP TTR derived from ambulatory BP monitoring was independently associated with lower all-cause and cardiovascular mortalities.

Background: Angiotensin-(1-7) lowers blood pressure and improves metabolic outcomes in animal models of obesity and hypertension. Whether central mechanisms are involved in these protective cardiometabolic effects is poorly understood. In this study, we hypothesized that angiotensin-(1-7) engages central neurocircuits originating in the arcuate nucleus of the hypothalamus under normal conditions and in diet-induced obesity.

Methods: Male mice were placed on a control diet or 60% high-fat diet for 12 weeks. Immunohistochemistry, in situ hybridization, electrophysiology, and physiological approaches were employed to determine whether angiotensin-(1-7) activates arcuate neurocircuits, characterizes the molecular identity of activated arcuate cells, and assesses the functional importance of this neurocircuit in blood pressure regulation.

Results: Under control diet conditions, systemic angiotensin-(1-7) administration (2 mg/kg, SC) increased the number of c-fos positive cells in the arcuate nucleus. Angiotensin-(1-7) mas receptors were highly localized to proopiomelanocortin neurons containing markers of gamma-aminobutyric acid transmission in the arcuate, with angiotensin-(1-7) increasing the firing activity of proopiomelanocortin neurons in a mas receptor-dependent manner. Acute intra-arcuate angiotensin-(1-7) administration lowered blood pressure. This effect was prevented by gamma-aminobutyric acid receptor antagonism in the downstream hypothalamic paraventricular nucleus, suggesting that angiotensin-(1-7) engages inhibitory arcuate-paraventricular circuits to lower blood pressure. Acute angiotensin-(1-7) could not activate proopiomelanocortin neurons or engage this arcuate-paraventricular neurocircuit in obese mice.

Conclusions: These findings suggest that angiotensin-(1-7) activates arcuate proopiomelanocortin neurons and engages arcuate-paraventricular inhibitory neurocircuits to lower blood pressure under normal conditions. In obesity, this circuit appears disrupted, which could contribute to the elevated blood pressure in this model.

Background: Preeclampsia is a pregnancy-specific disorder characterized by placental hypoxia and superficial invasion of trophoblast cells. However, the precise mechanisms by which hypoxia induces lactate and lactylation remain unclear.

Methods: Pan lysine lactylation levels were analyzed in the placentae of 36 patients with severe preeclampsia (sPE) and 36 normotensive pregnancies. A global lactylome analysis was performed, and BCAT2 (branched-chain aminotransferase 2)-K377 was selected for further investigation. The BCAT2-377R mutant was constructed to evaluate the effect on trophoblast migration, invasion, tube formation, and oxidative stress. The impact of the BCAT2-377R mutant on BCAT2 ubiquitination and degradation was further examined using MG132 and cycloheximide supplementation. Co-immunoprecipitation and double-immunofluorescence staining were conducted to identify the lactyltransferase of BCAT2. The specialized antibody was developed to validate BCAT2-K377la (branched-chain amino acid transaminase 2-lysine 377 lactylation) abundance in tissues and treated cells. A preeclampsia-like rat model was constructed to further verify whether the results were consistent with the clinical findings.

Results: Lactylation levels were elevated in the placentae of sPE. High lactate concentration enhanced Pan lysine lactylation and reduced BCAT2 protein levels while inhibiting cell migration, invasion, and tube formation. BCAT2-K377la impaired cell biological behaviors, increased oxidative stress, and promoted BCAT2 ubiquitination. The p300 acted as a lysine lactylation writer of BCAT2. BCAT2-K377la abundance was upregulated in sPE placentae and cells treated with hypoxia and lactate. In the rat model, elevated placental Pan lysine lactylation and BCAT2-K377la levels mirrored findings in clinical samples.

Conclusions: Our findings emphasized the role of nonhistone lactylation in sPE pathogenesis. Targeting BCAT2-K377la may serve as a potential intervention strategy for sPE.

Background: Patients with chronic kidney disease (CKD) are at high risk of cardiovascular complications. We have shown that Ngal (neutrophil gelatinase-associated lipocalin)/lcn2 is involved in aldosterone-induced cardiac remodeling and inflammation. Here, we investigated the role of Ngal in the progression of cardiorenal syndrome.

Methods: CKD was induced in rats via 5/6 nephrectomy in wild-type and Ngal knockout rats. Cardiorenal functions were assessed 3 months after subtotal nephrectomy or sham operation. Cardiac fibroblasts were isolated from wild-type rats and incubated with or without rNgal (recombinant Ngal) and Gal-3 (galectin-3).

Results: Cardiac perfusion was less impaired in CKD Ngal knockout than in CKD wild type. Left ventricle interstitial fibrosis was more severe in CKD wild type than in sham but was blunted in CKD Ngal knockout rats. Levels of Gal-3, Col1 (collagen 1), Ccl2 (C-C motif chemokine ligand 2), and IL-6 (interleukin-6) were high in cardiac fibroblasts incubated with rNgal. A similar pattern was observed in cells treated with recombinant Gal-3. Both Ngal and Gal-3 induced activation of the Tlr4 (toll-like receptor 4)-Myd88 (myeloid differentiation primary response 88) pathway. The effects of rNgal were blunted by concomitant treatment with Gal-3 or Tlr4 inhibitors, suggesting that Gal-3 contributes to Ngal-induced cardiac fibrosis and inflammation by activating the Tlr4-Myd88 pathway. In both MEDIA-DHF (Metabolic Road to Diastolic Heart Failure) and BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) cohorts, elevated levels of Ngal and Gal-3 were associated with advanced diastolic dysfunction and adverse clinical outcomes, particularly among patients with impaired renal function.

Conclusions: In CKD rats, Ngal was involved in cardiac remodeling via a Gal-3/Tlr4-dependent pathway, increasing inflammation and fibrosis, and correlated to cardiac outcomes in the MEDIA-DHF and BIOSTAT-CHF cohorts.