Abstract P3006: Inhibition Of Tnfα Signaling Delay CAVD Progression In Mice

Abstract

Background: Inflammation is a prominent feature of calcific aortic valve disease (CAVD), a leading cause of aortic stenosis. Inflammation can activate surface valvular endothelial cells (VEC) to produce pathogenic signaling such as Tumor Necrosis Factor-alpha (TNFα), to valvular interstitial cells (VIC) in aortic valve leaflets, leading to pathological valve remodeling through increased extracellular matrix synthesis, calcium deposition, and cell death which underlies CAVD. Thus, TNFα inflammatory signaling maybe a major candidate therapeutic target for alleviating CAVD progression. Hypothesis: We hypothesized that inhibition of TNFα signaling may delay CAVD progression. Results: We compared CAVD progression in a mouse model of CAVD with deletion of Ldlr, low-density lipoprotein receptor, and fed with standard or high fat diet. We inhibited the TNFα inflammatory signaling in this CAVD model by crossing the Ldlr -/- mice with the Tnfr1 and Tnfr2 double null mice. The aortic valve functions were measured by echocardiogram and the results showed that aortic valve velocity was significantly decreased in the triple null ( Ldlr -/- ;Tnfr1 -/- ;Tnfr2 -/- ) group compared to the Ldlr -/- group, both fed with high fat diet. Contractile function (systole to diastole ratio) at the aortic root was significantly increased in the triple null group. Aortic valve histopathology was examined by various staining methods. In the triple null mice, Hematoxylin and Eosin (H&E) showed significantly reduced the thickness of aortic valve leaflets; Masson’s Trichrome, Picrosirius Red, and Rusell-Movat staining revealed significantly reduced fibrosis and collagen deposition, and Von Kossa and Alizarin Red staining showed significantly decreased calcium deposition. Furthermore, immunofluorescence staining demonstrated significantly decreased DNA damage and cell death, as well as cell proliferation in aortic valve leaflets of the triple null mice. Conclusion: Our findings demonstrate a promising role of inhibiting TNFα signaling in slowing CAVD progression in mice, suggesting pharmacological or immunological inhibition of TNFα signaling as a non-invasive therapeutic option to treat CAVD patients.