Triterpenoid dihydro-CDDO-trifluoroethyl amide protects against maladaptive cardiac remodeling and dysfunction in mice: a critical role of Nrf2.
Triterpenoid dihydro-CDDO-trifluoroethyl amide protects against maladaptive cardiac remodeling and dysfunction in mice: a critical role of Nrf2.
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DOI：
10.1371/journal.pone.0044899
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Cui T
中科院分区：
文献类型：
--
作者：
Xing Y;Niu T;Wang W;Li J;Li S;Janicki JS;Ruiz S;Meyer CJ;Wang XL;Tang D;Zhao Y;Cui T
核因子E2相关因子2（Nrf 2）似乎是治疗心脏疾病的一个有吸引力的治疗靶点。我们研究了一种新的Nrf 2激活剂二氢-CDDO-三氟乙基酰胺（dh 404）的合成三萜类衍生物是否可以保护小鼠免受血液动力学应激的病理性心脏反应。采用小鼠主动脉缩窄术（TAC）建立心脏适应性重构和功能障碍模型。用血管紧张素Ⅱ（Ang Ⅱ）诱导乳鼠心肌细胞肥大生长。用过氧化氢（H2 O2）诱导乳鼠心肌细胞死亡。用血管紧张素Ⅱ（Ang Ⅱ）、去甲肾上腺素（NE）和苯肾上腺素（PE）诱导新生大鼠心脏成纤维细胞增殖。通过免疫化学染色和Western印迹评估蛋白质表达。通过真实的时间反转录-聚合酶链反应（Q-PCR）测定基因表达。TAC抑制心肌Nrf 2表达，增加心肌4-羟基-2-壬烯醛和8-羟基脱氧鸟苷水平，并诱导小鼠心脏肥大、纤维化和凋亡，以及明显的心力衰竭和死亡。给予dh 404可抑制病理性心脏重构和功能障碍，降低死亡率。此外，dhd 404提高了心肌Nrf 2和Nrf 2核转位的水平，并显著抑制了心脏中的氧化应激。dh 404抑制原代培养的大鼠新生心肌细胞的肥大生长和死亡，并抑制原代培养的大鼠新生心脏成纤维细胞的增殖。然而，dh 404的这些作用通过敲低Nrf 2而减弱。这些发现表明，dh 404通过激活Nrf 2防止病理性心脏重塑和功能障碍，表明dh 404对心脏疾病的治疗潜力。
Nuclear factor E2-related factor 2 (Nrf2) appears to be an attractive therapeutic target for the treatment of cardiac disease. We investigated whether a synthetic triterpenoid derivative of dihydro-CDDO-trifluoroethylamide (dh404), a novel Nrf2 activator, protects against pathological cardiac responses to hemodynamic stress in mice. Cardiac maladaptive remodeling and dysfunction were established by transverse aortic constriction (TAC) in mice. Hypertrophic growth of rat neonatal cardiomyocytes was induced by angiotensin II (Ang II). Cell death of rat neonatal cardiomyocytes was induced with hydrogen peroxide (H2O2). Cellular proliferation of rat neonatal cardiac fibroblasts was induced by Ang II, norepinephrine (NE) and phenylephrine (PE). Protein expression was assessed by immunochemical staining and Western blots. Gene expression was determined by real time reverse transcription-polymerase chain reaction (Q-PCR). TAC suppressed myocardial Nrf2 expression, increased myocardial 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine levels, and induced cardiac hypertrophy, fibrosis and apoptosis, and overt heart failure and death in mice. Administration of dh404 inhibited the pathological cardiac remodeling and dysfunction, and reduced the mortality. Moreover, dhd404 elevated myocardial levels of Nrf2 and Nrf2 nuclear translocation with a dramatic suppression of the oxidative stress in the heart. Dh404 inhibited hypertrophic growth and death in primary culture of rat neonatal cardiomyocytes and suppressed proliferation in primary culture of rat neonatal cardiac fibroblasts. However, these effects of dh404 were blunted by knocking down of Nrf2. These findings demonstrate that dh404 prevents pathological cardiac remodeling and dysfunction by activating Nrf2, indicating a therapeutic potential of dh404 for cardiac disease.
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影响因子：
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作者：
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通讯作者：
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DOI：
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影响因子：
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DOI：
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影响因子：
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