Antioxidant enzymes reduce DNA damage and early activation of valvular interstitial cells in aortic valve sclerosis.
Antioxidant enzymes reduce DNA damage and early activation of valvular interstitial cells in aortic valve sclerosis.
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DOI：
10.1161/atvbaha.112.300177
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发表时间：
2013-02
期刊：
影响因子：
--
通讯作者：
Ferrari G
中科院分区：
文献类型：
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作者：
Branchetti E;Sainger R;Poggio P;Grau JB;Patterson-Fortin J;Bavaria JE;Chorny M;Lai E;Gorman RC;Levy RJ;Ferrari G
活性氧（ROS）的积累和尖瓣微结构的重塑是主动脉瓣硬化的特征，这是钙化主动脉瓣疾病的早期阶段。这些事件与瓣膜间质细胞（VIC）向成骨样表型的激活有关。由于 ROS 会引起 DNA 损伤和转录激活，我们研究了 ROS、DNA 损伤反应和 VIC 转分化之间的关系。从 39 名患有或不患有钙化性主动脉瓣疾病的患者中收集了人主动脉瓣尖瓣和患者匹配的 VIC。用细胞外超氧化物歧化酶/过氧化氢酶腺病毒进行细胞转导后，将 VIC 暴露于过氧化氢 (0.1–1 mmol/L)，并表征 DNA 损伤反应、成骨转分化和钙化。 ROS 诱导磷酸化 γH2AX、MRE11 和 XRCC1 蛋白的重新定位，并通过 AKT 表达成骨信号分子 RUNX2。我们报告了主动脉瓣硬化衍生的 VIC 中 γH2AX 的持续激活，表明它们修复 DNA 损伤的能力受损。腺病毒超氧化物歧化酶/过氧化氢酶转导可减少主动脉瓣硬化衍生细胞中 ROS 诱导的 DNA 损伤和 VIC 转分化。最后，用过氧化氢酶进行腺病毒转导可恢复 ROS 介导的钙化和细胞转分化。我们的结论是，ROS 诱导的 DNA 损伤反应在钙化性主动脉瓣疾病的早期无症状阶段是功能失调的。我们揭示了 ROS、DNA 损伤反应和细胞转分化之间的关联，这种关联可以通过抗氧化酶的传递来逆转。
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. 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 γH2AX, MRE11, and XRCC1 proteins with expression of osteogenic signaling molecule RUNX2 via AKT. We report a sustained activation of γH2AX 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. 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.