Secreted Klotho Attenuated Inflammation-Associated Aortic Valve Fibrosis in Senescence Accelerated Mice P1 (SAMP1)

摘要

Senescence accelerated mice P1 (SAMP1) is an aging model characterized by shortened lifespan and early signs of senescence. Klotho is an aging-suppressor gene. The purpose of this study is to investigate whether in vivo expression of secreted klotho (Skl) gene attenuates aortic valve fibrosis in SAMP1 mice. SAMP1 mice and age-matched (AKR/J) control mice were used. SAMP1 mice developed obvious fibrosis in aortic valves, namely fibrotic aortic valve disease (FAVD). Serum level of Skl was decreased drastically in SAMP1 mice. Expression of MCP-1, ICAM-1, F4/80, and CD68 was increased in aortic valves of SAMP1 mice, indicating inflammation. An increase in expression of α-SMA (myofibroblast marker), TGFβ-1 and scleraxis (a transcription factor of collagen synthesis) was also found in aortic valves of SAMP1 mice, suggesting that accelerated aging is associated with myofiborblast transition and collagen gene activation. We constructed adeno-associated virus 2 (AAV2) carrying mouse Skl cDNA (AAV2-Skl) for in vivo expression of Skl. Skl gene delivery effectively increased serum Skl of SAMP1 mice to the control level. Skl gene delivery inhibited inflammation and myofibroblastic transition in aortic valves and attenuated FAVD in SAMP1 mice. It is concluded that senescence-related FAVD in SAMP1 mice is associated with a decrease in serum klotho leading to inflammation including macrophage infiltration and TGFβ-1/Scleraxis-driven myofibroblast differentiation in aortic valves. Restoration of serum Skl levels by AAV2-Skl effectively suppresses inflammation and myofibroblastic transition and attenuates aortic valve fibrosis. Skl may be a potential therapeutic target for FAVD.