The beneficial effect of SCFAs on the cardiovascular system during hypertension

Abstract

Hypertension, which is associated with gut dysbiosis, is an independent and preventable risk factor for the development of cardiovascular diseases. The gut microbiota and its metabolites such as short‐chain fatty acids (SCFAs) play an important role in host physiology. SCFAs can regulate blood pressure in both rodent models and humans. However, the exact mechanism by which SCFA regulates hypertension is unknown. Our data showed that SCFAs can regulate miR‐204, a non‐coding RNA that is expressed in vessels. We recently showed that miR‐204, is reduced in vessels during hypertension. Additionally, miR‐204 targets inositol 1, 4, 5‐triphosphate receptor type1 (IP3R1) and therefore disrupt the calcium release into the cytosol leading to exacerbated vascular constriction. Thus, we hypothesize that SCFAs can regulate blood pressure and vascular constriction through miRNA‐204/IP3R1/Ca2+ axis. To test our hypothesis, we treated hypertensive mice with SCFAs cocktail (67.5 mM acetate, 40 mM butyrate, 25.9 mM propionate) in drinking water for 21 days. Increased blood pressure from hypertensive mice was reduced after SCFAs intake. Aortas and mesenteric arteries from hypertensive mice display increased vasoconstriction in response to phenylephrine, U46619, and angiotensin II. Treatment with SCFAs reduced vasoconstriction in response to all agonists. During hypertension, aortas display low levels of miR‐204 expression which was recovered after SCFAs intake. Additionally, IP3R1 was significantly up‐regulated in hypertensive mice and decreased after SCFAs supplementation. Furthermore, our in vitro data showed that SCFAs can directly affect the vascular miRNA‐204/IP3R1/Ca2+ axis. Our results suggest that SCFAs can regulate Ca2+ homeostasis and vascular contraction through the miR‐204/IP3R1 axis. The outcome of this study will establish novel treatment strategies conferring the benefits of SCFA control while circumventing the potential risks of delivering live biologics.