Hypertension最新文献

Background: Hypotensive episodes detected by 24-hour ambulatory blood pressure (BP) monitoring capture daily cumulative hypotensive stress and could be clinically relevant to cognitive impairment, but this relationship remains unclear.

Methods: We included participants from the Systolic Blood Pressure Intervention Trial (receiving intensive or standard BP treatment) who had 24-hour ambulatory BP monitoring measured near the 27-month visit and subsequent biannual cognitive assessments. We evaluated the associations of hypotensive episodes (defined as systolic BP drops of ≥20 mm Hg between 2 consecutive measurements that reached <100 mm Hg) and hypotensive duration (cumulative time of systolic BP <100 mm Hg) with subsequent cognitive function using adjusted linear mixed models. We further assessed 24-hour average BP and variability.

Results: Among 842 participants with treated hypertension (mean age, 71±9 years; 29% women), the presence (versus absence) of recurrent hypotensive episodes (11%) was associated with lower digit symbol coding scores (difference in Z scores, -0.249 [95% CI, -0.380 to -0.119]) and their faster declines (difference in Z score changes, -0.128 [95% CI, -0.231 to -0.026]). A consistent dose-response association was also observed for longer hypotensive duration with worse Montreal Cognitive Assessment and digit symbol coding scores. The association with digit symbol coding scores remained significant after further adjusting for 24-hour average BP and variability and was not observed for hypotension defined by clinic, orthostatic, or 24-hour average BP. Intensive BP treatment increased 24-hour hypotensive episodes and modified its association with the decline in digit symbol coding score.

Conclusion: Twenty-four-hour hypotensive episodes were associated with worse cognitive function, especially in processing speed, and could be a novel marker for optimal BP control and dementia prevention.

Background: Ciliary neurotrophic factor (CNTF), mainly known for its neuroprotective properties, belongs to the IL-6 (interleukin-6) cytokine family. In contrast to IL-6, the effects of CNTF on the vasculature have not been explored. Here, we examined the role of CNTF in AngII (angiotensin II)-induced hypertension.

Methods: Hypertension was chronically induced with AngII (1000 ng/kg per minute, osmotic mini-pumps, 14 days) in CNTF-knockout and wild-type mice (with or without nephrectomy and 1% NaCl drinking water). Blood pressure was measured by tail-cuff and radiotelemetry. Effects of CNTF on vascular function and the JAK2/STAT3 pathway were measured in vivo, in the isolated perfused kidney, and in mouse and human vascular smooth muscle cells.

Results: At baseline, systolic blood pressure was similar between both groups. During AngII infusion, blood pressure increase was significantly attenuated and hypertensive heart and kidney damage was significantly attenuated in CNTF-knockout compared with wild-type mice. Accordingly, renal pressor response to AngII but not KCl or phenylephrine was significantly decreased in CNTF-knockout compared with wild-type mice. Acute CNTF (5 µmol/L) administration nearly restored the AngII-dependent renal pressor response. Chronic CNTF treatment in CNTF-knockout mice increased blood pressure response to AngII to levels observed in wild-type mice. CNTF augments AngII-induced activation of the JAK2/STAT3 pathway in vitro in vascular smooth muscle cells. The significance of this interaction was shown, as the increase in renal pressor response by CNTF was abolished by JAK2/STAT3 inhibitors.

Conclusions: Our results demonstrate a major impact of CNTF on blood pressure regulation by modulating AngII-induced pressor response via a JAK2/STAT3-dependent mechanism and indicate that CNTF is an important regulatory cytokine in hypertension.

Hypertension is a multifactorial condition influenced by the intricate interplay of biological and genetic determinants. The growing field of Environmental Hypertensionology endorses the outsized role of environmental factors in the pathogenesis and exacerbation of hypertension. It provides a clinical approach to address these factors at the individual and societal levels. Environmental stressors contributing to blood pressure levels can be viewed within the mosaic model of hypertension, which offers a comprehensive framework for understanding blood pressure regulation through its connection with multiple other nodes causally related to the pathogenesis of hypertension. This review synthesizes growing evidence supporting the impact of several factors in the physical environment and adverse stressors embedded in key provisioning systems, including air, noise, and chemical pollution, along with aspects of the built environment, green spaces, food systems, on the global burden of hypertension. Although many factors may not be directly in the causal cascade of hypertension, the web of connections between many behooves an understanding of the important nodes for intervention. Public health strategies emphasizing the redesign of environments present an unprecedented opportunity to enhance global hypertension control rates. Future research should thus focus on integrating environmental risk assessment and interventions into clinical practice, optimizing urban planning, and public policy to achieve meaningful reductions in the global burden of hypertension. By understanding hypertension as a mosaic of interconnected causes, healthcare professionals are better equipped to individualize treatment, combining lifestyle interventions and multiple drug classes to target environmental and genetic factors driving high blood pressure.

Background: Mechanosensitive Piezo1 (Piezo Type Mechanosensitive Ion Channel Component 1) channel plays a key role in pulmonary hypertension (PH). However, the role of Piezo2 in PH remains unclear.

Methods: Endothelial cell (EC)-specific Piezo2 knockout (Piezo2^flox/flox, Tek-Cre⁺; Piezo2^EC-/-) rats and primarily cultured pulmonary microvascular ECs were used to determine the role of Piezo2 in PH.

Results: Data analysis of publicly accessible single-cell RNA-sequencing data sets uncovered significant downregulation of Piezo2 in lung ECs from patients with idiopathic pulmonary arterial hypertension, which was verified in the lungs/ECs from PH rat models induced by hypoxia or monocrotaline. Comparing to wild-type rats, Piezo2^EC-/- rats exhibited exacerbated PH in both hypoxia-induced PH and monocrotaline-induced PH, characterized by the worsened hemodynamical and histological changes. Piezo2^EC-/- rats showed dramatic loss of pulmonary microvessels, in association with the decreased intracellular free calcium concentration ([Ca²⁺]_i) and downregulation of VEGFR2 (vascular endothelial growth factor receptor 2) and phosphorylated SRF (serum response factor) in pulmonary microvascular ECs. Knockout of Piezo2 or treatment with a calcium chelator, EDTA, impaired the ability of tube formation and migration in pulmonary microvascular ECs, which was restored by supplementation of extra calcium. A safflower oil diet rich in linoleic acid, which can enhance the stability and function of Piezo2, effectively alleviated PH development in a hypoxia-induced PH rat model.

Conclusions: This study demonstrates that EC-specific knockout of Piezo2 exacerbates PH pathogenesis, at least partially, through the suppression of [Ca²⁺]_i/phosphorylated SRF/VEGFR2 signaling axis in pulmonary vascular ECs. Targeted activation of Piezo2 could be a novel effective strategy for the treatment of PH.

Background: Our previous findings that arachidonic acid-12/15-lipoxygenase (LOX)-generated metabolite 12(S)-HETE contributes to angiotensin II (AngII)-induced hypertension and 17β-estradiol protects from AngII-induced hypertension via its cytochrome P450 (CYP)1B1-generated metabolite 2-methoxyestradiol in the paraventricular nucleus (PVN) in female mice led us to test the hypothesis that 2-methoxyestradiol acts by inhibiting the LOX/12(S)-HETE in the PVN.

Methods: AngII was infused subcutaneously by osmotic pumps for 2 weeks in wild-type, LOX-knockout (LOXKO), and CYP1B1KO female mice. The blood pressure was measured by tail-cuff/radiotelemetry. Adenovirus (Ad)-GFP (green fluorescence protein)-LOX-short hairpin RNA, Ad-GFP-LOX-DNA, 12(S)-HETE, and 2-methoxyestradiol were injected selectively in PVN or intracerebroventricularly. Histological, immunohistochemical, and biochemical techniques were used to determine pathophysiological changes caused by various interventions.

Results: AngII-induced hypertension that was exaggerated in CYP1B1KO compared with wild-type mice was minimized by PVN-LOX knockdown with Ad-LOX-short hairpin RNA and restored by PVN-LOX reconstitution with Ad-LOX-DNA in intact-LOXKO mice and exacerbated in ovariectomized-LOXKO mice. Furthermore, intracerebroventricular-12(S)-HETE restored AngII-induced increases in blood pressure, autonomic impairment, neuroinflammation, and renal pathogenesis in intact-LOXKO mice, which were exacerbated in ovariectomized-LOXKO mice. Intracerebroventricular-2-methoxyestradiol that reduced the LOX expression and 12(S)-HETE content in PVN minimized AngII effects mentioned above in ovariectomized-LOXKO mice transduced with intracerebroventricular-Ad-LOX-DNA.

Conclusions: These data suggest that 2-methoxyestradiol protects against AngII-induced hypertension and associated pathogenesis, most likely by inhibiting LOX/12(S)-HETE actions in the PVN of female mice. Therefore, the selective LOX inhibitors or 12(S)-HETE receptor antagonists could be useful in treating hypertension and its pathogenesis in postmenopausal, hypoestrogenic women or females with ovarian failure.

Background: Cardiac hypertrophy constitutes the primary pathological basis for heart failure and exerts a considerable influence on morbidity and mortality. Deubiquitinating enzymes are crucial regulators of protein degradation and play a pivotal role in cardiac pathophysiology. This study aimed to clarify the involvement of a deubiquitinating enzyme, MYSM1 (Myb-like, SWIRM [Swi3p, Rsc8p and Moira], and MPN [Mpr1/Pad1 N-terminal] domains 1), in cardiac hypertrophy and to explore the underlying mechanism.

Methods: Cardiac hypertrophy was developed by angiotensin II or transverse aortic constriction surgery. Cardiomyocyte-specific knockdown of MYSM1 was accomplished using the adeno-associated virus serotype 9-cTNT-Mysm1-shRNA. Co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry analysis was utilized to identify potential substrates of MYSM1.

Results: First, we discovered that the expression of MYSM1 increases during cardiac hypertrophy. MYSM1 knockdown mitigated cardiac dysfunction and hypertrophy after angiotensin II administration. Cardiomyocyte-specific knockdown of MYSM1 with adeno-associated virus serotype 9 alleviated myocardial dysfunction and hypertrophy caused by transverse aortic constriction surgery. Through co-immunoprecipitation and LC-MS, poly (ADP-ribose) polymerase 1 (PARP1) was identified as a potential substrate protein of MYSM1. PARP1 initiates a novel form of programmed cell death termed parthanatos, which is characterized by excessive PARylation, nuclear translocation of AIF, and depletion of nicotinamide adenine dinucleotide. MYSM1 deubiquitinates and stabilizes PARP1 in an MPN domain-dependent manner. In addition, MYSM1 mediates cardiac hypertrophy through PARP1-dependent cardiomyocyte parthanatos.

Conclusions: This study identified the role of the MYSM1-PARP1 axis in mediating cardiac hypertrophy and suggested that MYSM1 is a promising pharmacological target for the treatment of cardiac hypertrophy.

Background: Primary aldosteronism is the most common form of secondary hypertension. The most frequent genetic cause of aldosterone-producing adenomas is somatic mutations in the potassium channel KCNJ5. They affect the ion selectivity of the channel, with sodium influx leading to cell membrane depolarization and activation of calcium signaling, the major trigger for aldosterone biosynthesis.

Methods: To investigate how KCNJ5 mutations lead to the development of aldosterone-producing adenomas, we established an adrenocortical cell model in which sodium entry into the cells can be modulated on demand using chemogenetic tools [H295R-S2 α7-5HT3-R (α7-5HT3 receptor) cells]. We investigated their functional and molecular characteristics with regard to aldosterone biosynthesis and cell proliferation.

Results: A clonal cell line with stable expression of the chimeric α7-5HT3-R in H295R-S2 (human adrenocortical carcinoma cell line, Strain 2) cells was obtained. Increased sodium entry through α7-5HT3-R upon stimulation with uPSEM-817 (uPharmacologically Selective Effector Molecule-817) led to cell membrane depolarization, opening of voltage-gated Ca²⁺ channels, and increased intracellular Ca²⁺ concentrations, resulting in the stimulation of CYP11B2 expression and increased aldosterone biosynthesis. Increased intracellular sodium influx did not increase proliferation but rather induced apoptosis. RNA sequencing and steroidome analyses revealed unique profiles associated with Na⁺ entry, with only partial overlap with Ang II (angiotensin II) or potassium-induced changes.

Conclusions: H295R-S2 α7-5HT3-R cells are a new model reproducing the major features of cells harboring KCNJ5 mutations. Increased expression of CYP11B2 and stimulation of the mineralocorticoid biosynthesis pathway are associated with a decrease of cell proliferation and an increase of apoptosis, indicating that additional events may be required for the development of aldosterone-producing adenomas.