Microbial metabolite 4-ethylphenylsulfate (4EPS) interacts with AT1R, reduces blood pressure and outcome of AngII-induced aortic aneurysm

BACKGROUND Plasma accumulation of the gut microbial metabolite, 4-ethylphenylsulfate (4EPS), produced from dietary protein aromatic amino acids has been observed in correlative and associative studies of cardiovascular, renal, metabolic and neurological diseases. 4EPS level increases upon AngII infusion in mice. How 4EPS alters host physiology to contribute to progression of any disease state is currently unknown.

METHODS To test the hypothesis that 4EPS interferes with angiotensin binding to AT1R, we used multiple approaches: AT1R pharmacology, cell-signaling, ex vivo vascular contraction and a mouse model of angiotensin-induced aortic aneurysm (AA) disease. ApoE-null mice were fed high-fat diet and infused with AngII, or co-infused with 4EPS and Olmesartan. BP was recorded. At the end of infusion, aortas were assessed for severity of AA, contractile response and histopathology. To evaluate signaling associated with different AA outcomes plasma proteomics analysis was done.

RESULTS In vitro, 4EPS reduced the binding of angiotensin and Candesartan to AT1R and calcium signaling. Ex vivo, 4EPS decreased vasomotor response of the aorta to AngII. In vivo, 4EPS inhibited AngII-mediated increase of BP and reduced mortality from AA. Abdominal aorta remodeling in 4EPS+AngII co-infused mice showed an increase of elastin area and reduced thickening of intimal/medial layers. Plasma proteome analysis indicated significant change in actin-cytoskeletal signaling associated with reduced ERK1/2 and Filamin-A activation, and cell motility.

CONCLUSIONS Benign antagonism of AT1R by 4EPS involves direct interaction with AT1R. Molecular mechanisms of 4EPS responsible for reduced AA associated mortality in mice are distinct from those of AT1R blocker, Olmesartan.