Sodium pump inhibitors in blood pressure regulation and in profibrotic signaling in salt sensitive hypertension and aging

钠泵抑制剂在盐敏感性高血压和衰老中的血压调节和促纤维化信号传导中的作用

• 批准号: 10259328
• 负责人: Olga V Fedorova
• 金额: $ 185.1万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10259328
• 关键词: Adult; Age; Aging; Amlodipine; Animal Model; Animals; Blood Pressure; Blood Vessels; C-reactive protein; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Chronic Kidney Failure; Clinical; Clinical Research; Consumption; Dahl Hypertensive Rats; Data; Devices; Diabetes Mellitus; Disease model; Enrollment; Erythrocytes; Ethnic Origin; Excretory function; Exhibits; Female; Fibrosis; Future; Gender; Glucose; Heart Hypertrophy; Height; High Density Lipoprotein Cholesterol; Hour; Human; Hydrochlorothiazide; Infusion procedures; Left Ventricular Mass; Link; Lisinopril; Measures; Modeling; Na(+)-K(+)-Exchanging ATPase; Oxidative Stress; Participant; Pathway interactions; Patients; Physiologic pulse; Physiological; Play; Population; Rattus; Regression Analysis; Renal Tissue; Resistant Hypertension; Risk; Risk Marker; Role; Signal Transduction; Smooth Muscle Myocytes; Sodium; Sodium Chloride; Sprague-Dawley Rats; Steroids; Transferase; Transforming Growth Factor beta; Vascular Smooth Muscle; Woman; aged; arterial stiffness; blood pressure regulation; cardiovascular risk factor; dietary salt; early detection biomarkers; experimental study; inhibitor/antagonist; male; marinobufagenin; men; normotensive; older patient; potential biomarker; pressure; prevent; response; salt intake; salt sensitive hypertension; saluretic; urinary; young woman

There are two pro-fibrotic pathways, Fli1-dependent and TGF-beta-dependent, which are activated by MBG in animal chronic kidney disease models, diabetes and aging, and in the cultured rat vascular smooth muscle cells and cardiac myocytes. The TGF-beta-dependent pathway is activated by heightened MBG in the presence of a high salt intake in cardiovascular and renal tissues from hypertensive Dahl salt-sensitive rats and normotensive Sprague-Dawley rats. We demonstrated in the animal models and in cultured rat cardiac myocytes and vascular smooth muscle cells (i) that Fli1-dependent and TGF-beta-dependent pro-fibrotic pathways exhibit a crosstalk at the level of phosphorylated PKC-delta, (ii) that these pathways are activated either independently, or simultaneously, and (iii) that the activation of the profibrotic signaling is BP independent. Experiment 1. Thirty-four patients (18 males and 16 females; 568 years) with RH on a combined (lisinopril/amlodipine/hydrochlorothiazide) therapy and 11 healthy age-matched normotensive subjects (7 males and 4 females; 542 years) were enrolled in this study. Arterial stiffness was measured by Sphygmocor Px device with a calculation of PWV. Activity of Na pump was measured in erythrocytes. We demonstrated that the response of MBG on a moderate sodium chloride administration did not correlate with arterial BP and was associated with PWV in a gender- and age-specific fashion in RH patients vs. normotensive controls. Experiment 2. This clinical study included data of 711 participants (black 51%, men 42%, mean age 24.83.0 years). We measured the carotidfemoral pulse wave velocity (cfPWV), 24-h urinary MBG and sodium excretion. In single, partial and multivariable adjusted regression analyses, we found a persistent positive association between cfPWV and MBG excretion in young women, but not men. Multiple regression models were adjusted for ethnicity, age, waist-to-height ratio, mean arterial BP, high-density lipoprotein cholesterol, C-reactive protein, glutamyl transferase and glucose. In conclusion, already at a young age heightened endogenous MBG levels may contribute to large artery stiffness in women via pressure-independent mechanisms, increasing their risk for future cardiovascular disease. Recent findings demonstrated that 24-hour urinary MBG strongly associates with habitual salt intake in young healthy adults (aged 20-30 years). Furthermore, in young healthy adults free of detected cardiovascular disease, MBG associates with increased large artery stiffness and left ventricular mass independent of blood pressure. These findings in human studies corroborate mechanistic data from rat studies whereby stimulation of MBG by a high salt intake or MBG infusion increased vascular fibrosis and cardiac hypertrophy. Twenty-four-hour urinary MBG may be a potential biomarker of early cardiovascular risk. Adverse associations between MBG, which increases with salt consumption,and early cardiovascular risk markers support the global efforts to reduce population-wide salt intake in an effort to prevent and control the burden of non-communicable diseases. Conclusion: These findings in human studies corroborate mechanistic data from rat studies whereby stimulation of MBG by a high salt intake or MBG infusion increased vascular fibrosis and cardiac hypertrophy. MBG is a marker of salt-sensitivity and may be a potential biomarker of early cardiovascular risk.

在慢性肾脏疾病动物模型、糖尿病和衰老动物模型中，以及在培养的大鼠血管平滑肌细胞和心肌细胞中，有两条促纤维化的途径，即依赖于FLI1和依赖于转化生长因子-β的途径。在高血压Dahl盐敏感大鼠和正常血压的SpragueDawley大鼠的心血管和肾脏组织中，高盐摄入量增加的MBG激活了转化生长因子-β依赖的途径。我们在动物模型和培养的大鼠心肌细胞和血管平滑肌细胞中证实：(I)依赖于FLI1和依赖于转化生长因子-β的促纤维化通路在磷酸化的PKC-Delta水平上表现出串扰，(Ii)这些通路被独立或同时激活，(Iii)促纤维化信号的激活不依赖于BP。 实验1.34例接受赖诺普利/氨氯地平/氢氯噻嗪联合治疗的RH患者(男18例，女16例；年龄568岁)和11例年龄匹配的健康血压正常者(男7例，女4例；年龄542岁)纳入本研究。用SPhygmoCor PX血流仪测量动脉硬度，计算PWV。测定红细胞钠泵活性。我们证明，在RH患者和正常血压对照组中，MBG对中等剂量氯化钠的反应与动脉血压无关，而与PWV以性别和年龄特定的方式相关。 实验2.这项临床研究包括711名参与者的数据(黑人占51%，男性占42%，平均年龄24.83.0岁)。测定颈动脉-股动脉脉搏波传导速度(CfPWV)、24小时尿MBG和钠排泄量。在单因素、部分因素和多变量调整的回归分析中，我们发现年轻女性的cfPWV与MBG排泄量之间存在持续的正相关，而男性则不然。调整了种族、年龄、腰高比、平均动脉压、高密度脂蛋白胆固醇、C反应蛋白、谷氨酰转移酶和血糖的多元回归模型。总而言之，在年轻时，内源性MBG水平升高可能通过压力非依赖性机制导致女性大动脉僵硬，增加她们未来患心血管疾病的风险。 最近的研究表明，年轻健康成年人(20-30岁)24小时尿MBG与习惯性食盐摄入量密切相关。此外，在没有检测到心血管疾病的年轻健康成年人中，MBG与大动脉僵硬和独立于血压的左心室质量增加有关。这些在人类研究中的发现证实了来自大鼠研究的机制数据，即高盐摄入或注射MBG刺激MBG会增加血管纤维化和心肌肥厚。24小时尿MBG可能是早期心血管风险的潜在生物标志物。随着食盐消费而增加的MBG与早期心血管风险标记物之间的不利关联支持了全球减少全人口食盐摄入量的努力，以努力预防和控制非传染性疾病的负担。 结论：在人类研究中的这些发现证实了来自大鼠研究的机制数据，即高盐摄入或输注MBG刺激MBG可增加血管纤维化和心肌肥厚。MBG是盐敏感性的标志物，可能是早期心血管风险的潜在生物标志物。