Arjunolic acid, a peroxisome proliferator-activated receptor α agonist, regresses cardiac fibrosis by inhibiting non-canonical TGF-β signaling
Arjunolic acid, a peroxisome proliferator-activated receptor α agonist, regresses cardiac fibrosis by inhibiting non-canonical TGF-β signaling
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DOI：
10.1074/jbc.m117.788299
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发表时间：
2017-10-06
影响因子：
4.8
通讯作者：
Sarkar, Sagartirtha
中科院分区：
文献类型：
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作者：
Bansal, Trisha;Chatterjee, Emeli;Sarkar, Sagartirtha
心脏肥大和相关的心脏纤维化仍然是世界范围内死亡的主要原因。植物化学物质作为治疗心血管疾病的替代疗法已引起人们的关注。其中包括从植物阿朱那末提取的提取物，这是一种流行的心脏保护剂，可以防止或减缓病理性肥厚到心力衰竭的进展。在这里，我们研究了一种主要的生物活性化合物arjunolic acid （AA）在改善血流动力学负荷引起的心脏纤维化中的作用模式，并确定了其细胞内靶点。我们的数据显示，AA可显著抑制心肌肥厚时胶原蛋白的表达，改善心功能。我们发现，AA结合并稳定过氧化物酶体增殖激活受体α (PPAR α)的配体结合域，并增加其在心肌肥厚过程中的表达。在AA处理的肥厚样本中，包括血管紧张素ii处理的成人心脏成纤维细胞和肾动脉结扎的大鼠心脏中，PPAR α敲低表明AA驱动的心脏保护主要来自PPAR α激动作用。此外，aa诱导的PPAR α上调导致tgf - β信号传导的抑制，特别是通过抑制tgf - β活化激酶1 （TAK1）的磷酸化。我们观察到PPAR α直接与TAK1相互作用，主要通过PPAR α n端转激活结构域（AF-1），从而掩盖TAK1激酶结构域。因此，aa诱导的PPAR α结合的TAK1水平与TAK1的磷酸化水平以及随后p38 MAPK和NF-kappa Bp65激活的降低呈负相关，最终导致心脏肥厚中过量胶原合成的改善。总之，我们的研究结果揭示了AA作为PPAR α激动剂灭活非典型tgf - β信号的作用，揭示了AA在肥厚相关心脏纤维化消退中的作用机制。
Cardiac hypertrophy and associated heart fibrosis remain a major cause of death worldwide. Phytochemicals have gained attention as alternative therapeutics for managing cardiovascular diseases. These include the extract from the plant Terminalia arjuna, which is a popular cardioprotectant and may prevent or slow progression of pathological hypertrophy to heart failure. Here, we investigated the mode of action of a principal bioactive T. arjuna compound, arjunolic acid (AA), in ameliorating hemodynamic load-induced cardiac fibrosis and identified its intracellular target. Our data revealed that AA significantly represses collagen expression and improves cardiac function during hypertrophy. We found that AA binds to and stabilizes the ligand-binding domain of peroxisome proliferator-activated receptor alpha (PPAR alpha) and increases its expression during cardiac hypertrophy. PPAR alpha knockdown during AA treatment in hypertrophy samples, including angiotensin II-treated adult cardiac fibroblasts and renal artery-ligated rat heart, suggests that AA-driven cardioprotection primarily arises from PPAR alpha agonism. Moreover, AA-induced PPAR alpha up-regulation leads to repression of TGF-beta signaling, specifically by inhibiting TGF-beta-activated kinase1 (TAK1) phosphorylation. We observed that PPAR alpha directly interacts with TAK1, predominantly via PPAR alpha N-terminal transactivation domain (AF-1) thereby masking the TAK1 kinase domain. The AA-induced PPAR alpha bound TAK1 level thereby shows inverse correlation with the phosphorylation level of TAK1 and subsequent reduction in p38 MAPK and NF-kappa Bp65 activation, ultimately culminating in amelioration of excess collagen synthesis in cardiac hypertrophy. In conclusion, our findings unravel the mechanism of AA action in regressing hypertrophy-associated cardiac fibrosis by assigning a role of AA as a PPAR alpha agonist that inactivates non-canonical TGF-beta signaling.