부산대학교 도서관

R4173 --> Background: Myxomatous valve degeneration (MVD) is the most common cause of mitral regurgitation, characterized by valve leaflet thickening and progressive valve degeneration, leading to impaired cardiac function and heart failure. MVD in a mouse model of Marfan syndrome (MFS) is characterized leaflet thickening and increased macrophage infiltration which are reduced with loss of C‐C chemokine receptor type 2 (CCR2). However, the specific contributions of macrophages to pathological extracellular matrix (ECM) remodeling and the underlying mechanisms are unknown. Methods: Mice with the mutation of Fibrillin 1 (Fbn1C1039G/+) recapitulate histopathological features of MFS. ECM remodeling in mitral valves was assessed by detecting collagen and proteoglycan in Fbn1C1039G/+; CCR2RFP/RFP mice. Here, we tested the efficacy of a selective CCR2 antagonist RS504393 in the valves of MFS model in the initiation (1‐month‐old) and the progression (2‐month‐old) of MVD, respectively. MFS mice were intraperitoneally injected with RS504393 at 2 mg/kg/d for 1 month. Histological evaluation and immunofluorescence for macrophages and ECM were performed. Results: MFS valves revealed ECM abnormalities characterized by collagen fragmentation and proteoglycan accumulation. Deficiency of CCR2 inhibited ECM abnormalities in MFS mitral valves. RS504393 treatment reduced infiltrating macrophages (MHCII+, CCR2+) in myxomatous valves. Remarkably, RS504393 was protective against both the initiation and the progression of MVD, detected by decreased mitral valve thickness and prevented pathological ECM remodeling in MFS mice. Conclusion: Our results suggest the deficiency of CCR2 inhibits macrophage infiltration and abnormal ECM remodeling. In addition, the CCR2 inhbitor RS504393 is a potential pharmacological candidate to treat MVD in MFS. [ABSTRACT FROM AUTHOR]