Effect of an Isolevuglandin Scavenger on Salt Sensitivity of Blood Pressure and Immune Cell Activation in Humans

Summary

Hypertension is the leading cause of preventable deaths globally, driven by complications such as myocardial infarction, stroke, heart failure, and kidney disease. Recent updates in hypertension classification by the American Heart Association (AHA) place nearly half of the U.S. population in the hypertensive category. Excess dietary salt is a major risk factor for hypertension, with 50% of hypertensive individuals exhibiting salt-sensitivity of blood pressure (SSBP). SSBP is an independent predictor of cardiovascular events and death. While kidney mechanisms in salt-sensing have been extensively studied, emerging evidence suggests that immune cells can also sense sodium (Na+). This trial hypothesizes that myeloid cell-derived isolevuglandins (IsoLGs) drive endothelial dysfunction, perpetuating the salt-sensitive phenotype. Preliminary data indicate that targeting IsoLGs with the IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) may interrupt this immune-vascular axis, reducing salt sensitivity and associated cardiovascular risks. This phase 2 clinical trial aims to investigate the role of 2-HOBA in modulating immune cell function within blood vessels in hypertensive patients. The study will explore the impact of immunity on salt sensitivity and assess 2-HOBA's potential to reduce endothelial dysfunction, improve immune cell activation, and alleviate SSBP.

Timeline

Start

2026-07

Primary completion

2031-07

Completion

2031-07

Publications

• Results Weinberger MH. Salt sensitivity is associated with an increased mortality in both normal and hypertensive humans. J Clin Hypertens (Greenwich). 2002 Jul-Aug;4(4):274-6. doi: 10.1111/j.1524-6175.2002.00924.x.
• Results Ertuglu LA, Pitzer Mutchler A, Jamison S, Laffer CL, Elijovich F, Saleem M, Blackwell DJ, Kryshtal DO, Egly CL, Sahinoz M, Sheng Q, Wanjalla CN, Pakala S, Yu J, Gutierrez OM, Kleyman TR, Knollmann BC, Ikizler TA, Kirabo A. Eicosanoid-Regulated Myeloid ENaC and Isolevuglandin Formation in Human Salt-Sensitive Hypertension. Hypertension. 2024 Mar;81(3):516-529. doi: 10.1161/HYPERTENSIONAHA.123.21285. Epub 2023 Sep 7.
• Results Weinberger MH. Salt sensitive human hypertension. Endocr Res. 1991;17(1-2):43-51. doi: 10.1080/07435809109027188.
• Results Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M. Salt sensitivity, pulse pressure, and death in normal and hypertensive humans. Hypertension. 2001 Feb;37(2 Pt 2):429-32. doi: 10.1161/01.hyp.37.2.429.
• Results Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension. 1986 Jun;8(6 Pt 2):II127-34. doi: 10.1161/01.hyp.8.6_pt_2.ii127.
• Results Luft FC, Miller JZ, Grim CE, Fineberg NS, Christian JC, Daugherty SA, Weinberger MH. Salt sensitivity and resistance of blood pressure. Age and race as factors in physiological responses. Hypertension. 1991 Jan;17(1 Suppl):I102-8. doi: 10.1161/01.hyp.17.1_suppl.i102.
• Results Weinberger MH, Fineberg NS. Sodium and volume sensitivity of blood pressure. Age and pressure change over time. Hypertension. 1991 Jul;18(1):67-71. doi: 10.1161/01.hyp.18.1.67.
• Results Ertuglu LA, Demirci M, Mutchler AL, Laffer CL, Saleem M, Ikizler TA, Kirabo A. Antigen-Presenting Cell Isolevuglandins Link Salt Sensitivity of Blood Pressure to Insulin Resistance. J Clin Endocrinol Metab. 2026 Mar 17;111(4):1091-1097. doi: 10.1210/clinem/dgaf556.
• Results Ertuglu LA, Pitzer Mutchler A, Elijovich F, Laffer CL, Sheng Q, Wanjalla CN, Kirabo A. Regulation of human salt-sensitivite hypertension by myeloid cell renin-angiotensin-aldosterone system. Front Physiol. 2023 Jul 18;14:1208270. doi: 10.3389/fphys.2023.1208270. eCollection 2023.

Drugs

Indications