一、Piezo1-Esm1通路介导盐敏感高血压血管平滑肌表型转化的机制研究

背景：盐敏感高血压涉及超58%的高血压患者，其特征是患者血压对盐摄入量高度敏感，更易出现靶器官损伤。高盐摄入诱导的血管炎症和血管平滑肌细胞（vascular smooth muscle cell, VSMC）表型转化是其关键病理机制。课题组前期转录组学测序结果显示Piezo1和ESM1在盐敏感高血压动物模型中表达上调且在炎症通路富集，并发现ESM1可以介导VSMC表型转化并导致血管炎症和血管重塑，但二者在盐敏感高血压中的具体调控机制尚不清楚。本研究旨在探讨Piezo1和ESM1在盐敏感高血压中对VSMC表型转化的调控机制。

方法：本研究通过构建DOCA盐敏感高血压小鼠模型并提取原代VSMC进行培养，采用siRNA转染技术、特异性激活剂或抑制剂干预信号通路中的各相关分子，运用Western Blot、免疫荧光染色、CCK8实验、细胞划痕实验等技术手段，检测Piezo1、ESM1、收缩型标志物（MHC11和TAGLN）、合成型标志物（PCNA）及该通路中各相关蛋白的表达水平，分析VSMC的表型变化，探究Piezo1对ESM1及下游信号通路的调控机制。所有数据分析采用GraphPad Prism、ImageJ软件完成，结果以均值±标准差表示，通过t检验和方差分析确定统计学显著性，以p<0.05作为判断标准。

结果：

1.盐敏感高血压小鼠VSMC中Piezo1表达上调，高盐环境可引起Piezo1和ESM1表达上调，VSMC发生表型转化；

2.在高盐环境下，Piezo1通过调控ESM1表达，介导VSMC的表型转化。激活Piezo1可使ESM1表达上调，而沉默Piezo1则可下调ESM1表达并部分逆转VSMC表型转化；

3.Piezo1通过Ca²⁺依赖的ATP外流激活P2Y2受体，进而调控ESM1和VSMC表型转化。螯合细胞外Ca²⁺、水解胞外ATP或抑制P2Y2受体均可下调ESM1表达，使VSMC表型转化部分逆转；

4.Piezo1-Ca²⁺-ATP-P2Y2通路通过激活HMGB1/RAGE-NF-κB通路上调ESM1表达，介导VSMC表型转化。

结论：在盐敏感高血压中，Piezo1通过Ca2+-ATP-P2Y2-HMGB1/RAGE-NF-κB途径激活血管炎症的重要分子ESM1，进而引起了VSMC的表型转化。

二、

中青年单纯收缩期高血压人群心血管疾病风险研究：一项基于开滦队列的单中心研究

目的: 单纯收缩期高血压（ISH）对中青年人群心血管预后的影响仍存在争议。本研究的旨在探究18-49岁中青年ISH与心血管疾病（CVD）发生风险的关系。

方法: 本研究基于开滦研究队列，纳入2006-2013年入组的73552 名18-49岁无CVD事件史及降压药服用史的参与者，主要研究终点为复合CVD事件的发生：心梗（MI）、心力衰竭（HF）和卒中（stroke）。参与者根据基线血压水平被分为五个互斥的血压组：正常血压组、正常高值血压组、ISH组、单纯舒张期高血压（IDH）组和收缩期-舒张期高血压（SDH）组。倾向性评分（PSM）匹配后分别比较ISH组与其他4个血压组人群的CVD风险，Cox比例风险模型被应用于计算CVD结局发生风险的HR和95%CI。

结果: 中青年ISH共1775人（2.4%），在12.1年的中位随访时间中发生102例CVD事件，其中stroke 71例，HF 24例，MI 13例。经过1：1的PSM匹配后，多因素cox回归结果显示，ISH的CVD风险显著高于正常血压（[HR (95% CIs): 0.374 (0.244-0.574)]和正常高值[0.621 (0.445-0.868)]人群，与IDH人群风险无显著差异[0.754 (0.556-1.021)]，显著低于SDH人群[1.540 (1.190-1.992)]。相比正常血压，ISH的stroke [0.239 (0.143-0.401)]和HF[0.198 (0.076-0.52)]发生风险显著上升，而MI[0.753 (0.33-1.719)]的发生风险上升不显著。

结论: 在这项基于开滦队列中青年人群的研究中，ISH人群的CVD事件发生风险较正常血压、正常高值人群显著升高，与IDH人群无显著差异，仅次于SDH人群。

(1) the Mechanism of Piezo1-Esm1 Pathway Mediating Phenotypic Transition of Vascular Smooth Muscle Cell in Salt-Sensitive Hypertension

Background: Salt-sensitive hypertension, affecting over 58% of hypertensive patients, is characterized by heightened blood pressure sensitivity to salt intake and increased susceptibility to target organ damage. The high-salt intake-induced vascular inflammation and the phenotypic switching of vascular smooth muscle cells (VSMC) are the key pathogenesis. Our previous transcriptomic sequencing showed that Piezo1 and ESM1 were up-regulated in salt-sensitive hypertensive animal model and enriched in inflammatory pathways.. ESM1 was also found to mediate VSMC phenotypic switching, which leading to vascular inflammation and remodeling. However, the specific regulatory mechanisms of Piezo1 and ESM1 in salt-sensitive hypertension remain unclear. This study aims to explore the regulatory mechanisms of Piezo1 and ESM1 on VSMC phenotypic switching in salt-sensitive hypertension.

Methods: The DOCA/salt/uninephrectomy model were established, and primary VSMC were isolated and cultured. siRNA transfection, specific activators, or inhibitors were used to interfere with related molecules in the signaling pathways. Western Blot, immunofluorescence staining, CCK8 assay, scratch assay and other techniques were employed to detect the expression levels of Piezo1, ESM1, contractile markers (MHC11 and TAGLN), synthetic markers (PCNA), and related proteins in the pathway, or to analyze VSMC phenotypic changes. The regulatory mechanism of Piezo1 on ESM1 and downstream signaling pathways was also explored. All data analyses were performed using GraphPad Prism and ImageJ, with results expressed as mean ± standard deviation. Statistical significance was determined using unpaired t test and one-way ANOVA, with p<0.05 considered statistically significant.

Results: 1. In VSMC of salt-sensitive hypertensive mice, the expression of Piezo1 was upregulated. The high-salt environment led to increased Piezo1 and ESM1 expression and VSMC phenotypic switching.

2. Under high-salt environment, Piezo1 regulated the expression of ESM1 to mediate VSMC phenotypic switching. The activation of Piezo1 upregulated ESM1 expression, whereas the silencing of Piezo1 downregulated ESM1 expression and partially reversed VSMC phenotypic switching.

3. Piezo1 regulated ESM1 and VSMC phenotypic switching by inducing Ca²⁺-dependent ATP efflux to activate P2Y2 receptors. Chelating extracellular Ca²⁺, hydrolyzing extracellular ATP, or inhibiting P2Y2 receptors could downregulate ESM1 and partially reverse VSMC phenotypic switching.

4. The Piezo1-Ca²⁺-ATP-P2Y2 pathway upregulated ESM1 via the HMGB1/RAGE-NF-κB pathways, mediating VSMC phenotypic switching.

Conclusion: In salt-sensitive hypertension, Piezo1 activates ESM1, a key molecule in vascular inflammation, through the Ca²⁺-ATP-P2Y2-HMGB1/RAGE-NF-κB pathway, thereby inducing VSMC phenotypic switching.

(2) Cardiovascular Risk of Isolated Systolic Hypertension in Young-to-Middle-Aged Adults: A single-center study based on the Kailuan cohort

Objective: The clinical significance of isolated systolic hypertension (ISH) among young-to-middle-aged adults is still controversial. We aimed to investigate the association between ISH and the risk of cardiovascular disease (CVD) in adults aged 18-49.

Method: Our study is based on Kailuan cohort, 73552 participants aged 18-49 without history of CVD and antihypertensive medication were included from 2006 to 2013. The outcome was the occurrence of composite CVD events: myocardial infarction (MI), heart failure (HF), and stroke. Participants were categorized into five groups based on baseline blood pressure (BP): normal BP, high-normal BP, ISH, isolated diastolic hypertension (IDH), and systolic-diastolic hypertension (SDH). The CVD risk of ISH was compared with the other four groups using Cox proportional hazards analysis after propensity score matching (PSM).

Result: There were 1775 (2.4%) participants with ISH, during a median follow-up time of 12.1 years, 102 CVD events occurred (71 of stroke, 24 of HF, and 13 of MI). Cox regression analysis showed that the CVD risk of ISH was significantly higher than normal BP [HR (95% CIs): 0.374 (0.244-0.574)] and high-normal BP [0.621 (0.445-0.868)], lower than SDH [1.540 (1.190-1.992)], and no significant difference was observed between ISH and IDH [0.754 (0.556-1.021)]. Compared to normal BP, the risk of stroke [0.239 (0.143-0.401)] and HF [0.198 (0.076-0.52)] in ISH were significantly increased, but not in MI [0.753 (0.33-1.719)].

Conclusion: In this study based on the young-to-middle-aged adults of the Kailuan cohort, the risk of CVD in ISH was significantly higher than normal BP and high-normal BP, similar to the IDH, and lower than SDH.