Antioxidant Enzymes Reduce DNA Damage and Early Activation of Valvular Interstitial Cells in Aortic Valve Sclerosis

作者：Branchetti Emanuela; Sainger Rachana; Poggio Paolo; Grau Juan B; Patterson Fortin Jeffrey; Bavaria Joseph E; Chorny Michael; Lai Eric; Gorman Robert C; Levy Robert J; Ferrari Giovanni^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2013, 33(2): E66-+.

DOI：10.1161/ATVBAHA.112.300177

• aortic valve sclerosis
• DNA-damage response
• reactive oxygen species
• valvular interstitial cells

Objective-Accumulation of reactive oxygen species (ROS) and remodeling of the microstructure of the cusp characterize aortic valve sclerosis, the early phase of calcific aortic valve disease. These events are associated with activation of valvular interstitial cells (VICs) toward an osteogenic-like phenotype. Because ROS cause DNA damage and transcriptional activation we investigated the relationship between ROS, DNA damage response, and transdifferentiation of VICs. %26lt;br%26gt;Methods and Results-Human aortic valve cusps and patient-matched VICs were collected from 39 patients both with and without calcific aortic valve disease. VICs were exposed to hydrogen peroxide (0.1-1 mmol/L) after cell transduction with extracellular superoxide dismutase/catalase adenoviruses and characterized for DNA-damage response, osteogenic transdifferentiation, and calcification. ROS induce relocalization of phosphorylated gamma H2AX, MRE11, and XRCC1 proteins with expression of osteogenic signaling molecule RUNX2 via AKT. We report a sustained activation of gamma H2AX in aortic valve sclerosis-derived VICs suggesting their impaired ability to repair DNA damage. Adenovirus superoxide dismutase/catalase transduction decreases ROS-induced DNA damage and VIC transdifferentiation in aortic valve sclerosis-derived cells. Finally, adenoviral transduction with catalase reverts ROS-mediated calcification and cellular transdifferentiation. %26lt;br%26gt;Conclusion-We conclude that the ROS-induced DNA damage response is dysfunctional in early asymptomatic stages of calcific aortic valve disease. We unveiled an association among ROS, DNA-damage response, and cellular transdifferentiation, reversible by antioxidant enzymes delivery. (Arterioscler Thromb Vasc Biol. 2013;33:e66-74.)

• 出版日期2013-2