Targeting cytokine-like protein FAM3D lowers blood pressure in hypertension

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Hypertension Research

Background:

• Current antihypertensive treatments remain insufficient, indicating unknown mechanisms driving hypertension.
• The role of cytokine-like protein family with sequence similarity 3, member D (FAM3D) in hypertension pathogenesis is unexplored.

Purpose of the Study:

• To investigate the involvement of FAM3D in the etiology of hypertension.
• To elucidate the molecular mechanisms by which FAM3D influences blood pressure regulation.

Main Methods:

• Case-control study in human patients and angiotensin II (AngII)-induced hypertension mouse models.
• Assessment of endothelial nitric oxide synthase (eNOS) uncoupling, vasorelaxation, oxidative stress, and formyl peptide receptor (FPR) signaling.
• Therapeutic interventions targeting endothelial FAM3D using adeno-associated virus and neutralizing antibodies.

Main Results:

• FAM3D levels are elevated in hypertensive patients, correlating positively with hypertension risk.
• FAM3D deficiency protects against AngII-induced hypertension in mice by preventing eNOS uncoupling and improving vasorelaxation.
• FAM3D induces eNOS uncoupling via formyl peptide receptor 1 (FPR1) and FPR2, involving oxidative stress.
• Targeting endothelial FAM3D ameliorates AngII- or deoxycorticosterone acetate (DOCA)-salt-induced hypertension.

Conclusions:

• FAM3D promotes hypertension by inducing eNOS uncoupling through FPR1/FPR2-mediated oxidative stress, leading to endothelial dysfunction.
• FAM3D represents a promising therapeutic target for managing hypertension.