Investigating the Impact of a Gut metabolite on Valvular Interstitial Cell Activation

Calcified Aortic Valve Disease (CAVD) affects up to 13% of the U.S. population and is linked to diet-induced changes in metabolism. Recent studies suggest that the gut metabolite trimethyl amine oxide (TMAO) may be a biomarker for atherosclerosis. Given the shared risk factors between atherosclerosis and CAVD, we hypothesize that TMAO may contribute to CAVD by activating the primary cell type in the valve, valve interstitial cells (VIC). VICs are usually found in a quiescent phenotype in healthy valves; however, VICs isolated from porcine aortic valves exhibit spontaneous activation in traditional culture. Thus, to study VIC activation induced by exposure to TMAO, we first applied our lab-engineered protocol to generate quiescent VICs (qVICs). TMAO treatment led to qVIC activation, demonstrated by increased αSMA expression, proliferation, and angiogenic cytokine secretion after 3 days in culture. The response to TMAO was not sex-specific with both male and female VICs responding to treatment with this metabolite. These results demonstrate that TMAO, a gut microbiome-derived metabolite, promotes the activation of quiescent VICs toward a myofibroblastic phenotype in vitro, potentially contributing to the initiation of CAVD. Overall, these findings underscore the significance of host-microbe interactions in the progression of cardiovascular disease.