All-trans retinoic acid prevents angiotensin II- and mechanical stretch-induced reactive oxygen species generation and cardiomyocyte apoptosis
All-trans retinoic acid prevents angiotensin II- and mechanical stretch-induced reactive oxygen species generation and cardiomyocyte apoptosis
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DOI：
10.1002/jcp.21297
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发表时间：
2008-04-01
影响因子：
5.6
通讯作者：
Pan, Jing
中科院分区：
文献类型：
--
作者：
Choudhary, Rashmi;Baker, Kenneth M.;Pan, Jing
心肌细胞凋亡在代偿性心脏重构向心力衰竭转变过程中起重要作用。全反式维甲酸（RA）是一种生物活性维生素A衍生物，可预防牵张和血管紧张素II（Ang II）诱导的心肌肥厚。然而，RA在心脏中的抗凋亡潜力仍然未被探索。在这里，我们表明，拉伸和血管紧张素II诱导的细胞凋亡是防止RA在新生儿心肌细胞。RA通过抑制拉伸和Ang II诱导的线粒体膜电位降低、细胞色素c释放和增加Bcl 2/Bax比值来改善线粒体功能。RA抑制拉伸和血管紧张素II诱导的细胞内活性氧（ROS）的产生和上调SOD 2水平。RA剂量依赖性地抑制过氧化氢诱导的TUNEL阳性细胞数量和Annexin V阳性细胞百分比的增加。巯基抗氧化剂，N-乙酰半胱氨酸（NAC），完全抑制拉伸和血管紧张素II诱导的细胞凋亡。使用二氮嗪（线粒体ATP敏感性K+通道开放剂）和SIDS（NADPH氧化酶激活剂），我们证实，RA抑制线粒体和NADPH氧化酶衍生的ROS。我们还观察到，RAR和RXR参与预防血管紧张素II和牵张诱导的ROS的产生和凋亡，通过使用选择性类维生素A受体激动剂和拮抗剂。我们的数据提供了第一个证据表明，RA通过抑制ROS的产生和增加抗氧化防御系统来防止Ang II和牵张诱导的细胞凋亡，这表明RA介导的信号传导可能为预防心脏重塑过程提供新的治疗靶点。
Cardiomyocyte apoptosis has an important role in the transition from compensatory cardiac remodeling to heart failure. All-trans retinoic acid (RA), a bioactive vitamin A derivative, prevents stretch- and angiotensin II (Ang II)-induced cardiac hypercrophy. However, the anti-apoptotic potential of RA in the heart remains unexplored. Here, we demonstrate that stretch- and Ang II-induced apoptosis is prevented by RA in neonatal cardiomyocytes. RA improved mitochondrial function by inhibiting the stretch- and Ang II-induced reduction in mitochondrial membrane potential, cytochrome c release and by increasing the Bcl2/Bax ratio. RA inhibited stretch- and Ang II-induced intracellular reactive oxygen species (ROS) generation and upregulated the SOD2 level. Hydrogen peroxide-induced increases in the number of TUNEL-positive cells and percentage of Annexin V positive cells, were dose-dependently inhibited by RA. The thiol antioxidant, N-acetyl cysteine (NAC), completely inhibited stretch- and Ang II-induced apoptosis. Using diazoxide (mitochondrial ATP-sensitive K+ channel opener) and SIDS (NADPH oxidase activator), we confirmed that RA suppressed both mitochondrial- and NADPH oxidase-derived ROS. We also observed that both RAR and RXR were involved in preventing Ang II- and stretch-induced ROS production and apoptosis, by using selective retinoid receptor agonists and antagonists. Our data provide the first evidence that RA prevents Ang II and stretch induced apoptosis, by inhibiting ROS generation and increasing the anti-oxidant defense system, suggesting that RA-mediated signaling may provide a, new therapeutic target for the prevention of the cardiac remodeling process.