RamachandraRao Satish, Hench Christiana, Berrido Andrea, Auchus Richard J, Troost Jonathan, Darcy John, Byrd James Brian
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School.
Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine & Department of Pharmacology, University of Michigan Medical School.
medRxiv. 2025 Aug 14:2025.08.12.25333544. doi: 10.1101/2025.08.12.25333544.
While some individuals exhibit salt sensitivity, others demonstrate salt resistance or inverse salt sensitivity-blood pressure reduction during high sodium intake. The molecular mechanisms underlying heterogeneous blood pressure responses to dietary sodium remain poorly understood. Deep proteomics provides a new tool to identify molecular mediators of salt resistance and inverse salt sensitivity.
We conducted a randomized crossover trial in 20 normotensive adults comparing 8-day periods of low-sodium (10 mmol/day) versus high-sodium (300 mmol/day) diets. Comprehensive plasma proteomic analysis was performed using SomaLogic's 7k proteomics platform, which measures approximately 7,000 human proteins. The change in proteins between the high- and low-sodium diets was compared with the change in blood pressure.
Despite average weight difference of +1.4 kg during high- versus low-sodium intake (p=8.85×10), diastolic blood pressure and mean arterial pressure were significantly lower (67.0±7.5 vs 69.7±8.0 mm Hg, p=0.014 for diastolic blood pressure; 82.2±7.6 versus 84.8±8.3 mm Hg, p=0.029 for mean arterial pressure). Among approximately 7,000 proteins analyzed, SVEP1 demonstrated one of the most significant responses to sodium loading, with two independent aptamers (antibody-like DNA molecules) ranking 4th (p= 5.33×10) and 8th (p=2.19×10) in statistical significance. SVEP1 substantially outranked established sodium-regulatory hormones including renin (23rd) and NT-proBNP (16th). SVEP1 upregulation correlated inversely with blood pressure changes (R= -0.50, p=0.028), and individuals exhibiting inverse salt sensitivity demonstrated 2-fold higher SVEP1 responses. Changes in SVEP1 correlated strongly with changes in NT-ProBNP (R= 0.80, p<0.001). Reactome analysis revealed coordinated extracellular matrix remodeling as the dominant biological response to sodium loading.
SVEP1 emerges as a primary molecular correlate of blood pressure responses to dietary sodium, likely through a volume- or stretch-mediated stimulus. Given SVEP1's established functions in vascular smooth muscle relaxation and lymphangiogenesis, these findings suggest novel pathways mediating cardiovascular adaptation to sodium challenges and potential biomarkers for identifying salt-sensitive versus salt-resistant individuals.
虽然一些个体表现出盐敏感性，但另一些个体则表现出抗盐性或反向盐敏感性（高钠摄入期间血压降低）。饮食中钠摄入导致血压反应异质性的分子机制仍知之甚少。深度蛋白质组学为识别抗盐性和反向盐敏感性的分子介质提供了一种新工具。
我们对20名血压正常的成年人进行了一项随机交叉试验，比较了8天低钠（10 mmol/天）饮食和高钠（300 mmol/天）饮食的情况。使用SomaLogic的7k蛋白质组学平台进行了全面的血浆蛋白质组分析，该平台可测量约7000种人类蛋白质。比较了高钠饮食和低钠饮食之间蛋白质的变化与血压的变化。
尽管高钠摄入与低钠摄入期间平均体重相差 +1.4 kg（p = 8.85×10），但舒张压和平均动脉压显著更低（舒张压：67.0±7.5 与 69.7±8.0 mmHg，p = 0.014；平均动脉压：82.2±7.6 与 84.8±8.3 mmHg，p = 0.029）。在分析的约7000种蛋白质中，SVEP1对钠负荷的反应最为显著，两种独立的适体（类抗体DNA分子）在统计学意义上分别排名第4（p = 5.33×10）和第8（p = 2.19×10）。SVEP1的排名明显高于已确定的钠调节激素肾素（第23位）和N末端脑钠肽原（NT-proBNP，第16位）。SVEP1的上调与血压变化呈负相关（R = -0.50，p = 0.028），表现出反向盐敏感性的个体的SVEP1反应高出2倍。SVEP1的变化与NT-ProBNP的变化密切相关（R = 0.80，p <0.001）。Reactome分析显示，协调的细胞外基质重塑是对钠负荷的主要生物学反应。
SVEP1可能通过容量或拉伸介导的刺激，成为饮食中钠摄入导致血压反应的主要分子关联物。鉴于SVEP1在血管平滑肌舒张和淋巴管生成中已确定的功能，这些发现提示了介导心血管对钠挑战适应的新途径以及识别盐敏感和抗盐个体的潜在生物标志物。
