Piperine Attenuates Pathological Cardiac Fibrosis Via PPAR-γ/AKT Pathways.
Piperine Attenuates Pathological Cardiac Fibrosis Via PPAR-γ/AKT Pathways.
复制标题
胡椒碱通过 PPAR-gamma/AKT 途径减轻病理性心脏纤维化
DOI：
10.1016/j.ebiom.2017.03.021
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发表时间：
2017-04
期刊：
影响因子：
11.1
通讯作者：
Tang QZ
中科院分区：
文献类型：
--
作者：
Ma ZG;Yuan YP;Zhang X;Xu SC;Wang SS;Tang QZ
丝裂原活化蛋白激酶（Mitogen-activated protein kinases，MAPKs）和腺苷酸活化蛋白激酶α（AMPKα）在心肌肥厚过程中起重要作用。已有研究表明胡椒碱可激活AMPKα并降低细胞外信号调节激酶（ERK）的磷酸化水平。然而，胡椒碱对心脏肥大的影响仍然完全未知。在这里，我们表明，胡椒碱治疗的小鼠有类似的肥大反应与车辆处理的小鼠，但表现出显着减弱后，压力超负荷或异丙肾上腺素（ISO）注射心脏纤维化。在体外实验中，苦参碱可抑制转化生长因子-β（TGF-β）或血管紧张素II（Ang II）诱导的心肌成纤维细胞向肌成纤维细胞的转化。这种抗纤维化作用不依赖于AMPKα和MAPK通路。苦参碱阻断蛋白激酶B（AKT）和下游糖原合成酶激酶3β（GSK 3 β）的激活。组成型活性AKT的过表达或GSK 3 β的敲低完全消除了胡椒碱介导的心脏成纤维细胞保护作用。胡椒碱的心脏保护作用在具有组成性活性AKT的小鼠中被阻断。过氧化物酶体增殖物激活受体-γ（peroxisome proliferator activated receptor-γ，PPAR-γ）的特异性抑制剂GW 9662可逆转胡椒碱的作用。总之，胡椒碱通过激活PPAR-γ和抑制AKT/GSK 3 β来减轻心脏纤维化。苦参碱对压力超负荷或异丙肾上腺素诱导的小鼠心肌纤维化有明显的保护作用。苦参碱通过减弱AKT/GSK 3 β途径抑制心脏成纤维细胞向肌成纤维细胞的转化。在心肌成纤维细胞中，马槟榔碱作为PPAR-γ的激动剂。心脏纤维化在心脏重塑和心力衰竭过程中起着关键作用。缺乏针对心脏纤维化的治疗有助于HF引起的高发病率和死亡率。我们发现胡椒碱通过激活PPAR-γ和抑制AKT/GSK 3 β来减轻心脏纤维化。本研究为胡椒碱治疗心肌纤维化提供了实验依据。
Mitogen-activated protein kinases (MAPKs) and AMPactivated protein kinase α (AMPKα) play critical roles in the process of cardiac hypertrophy. Previous studies have demonstrated that piperine activates AMPKα and reduces the phosphorylation of extracellular signal-regulated kinase (ERK). However, the effect of piperine on cardiac hypertrophy remains completely unknown. Here, we show that piperine-treated mice had similar hypertrophic responses as mice treated with vehicle but exhibited significantly attenuated cardiac fibrosis after pressure overload or isoprenaline (ISO) injection. Piperine inhibited the transformation of cardiac fibroblasts to myofibroblasts induced by transforming growth factor-β (TGF-β) or angiotensin II (Ang II) in vitro. This anti-fibrotic effect was independent of the AMPKα and MAPK pathway. Piperine blocked activation of protein kinase B (AKT) and, downstream, glycogen synthase kinase 3β (GSK3β). The overexpression of constitutively active AKT or the knockdown of GSK3β completely abolished the piperine-mediated protection of cardiac fibroblasts. The cardioprotective effects of piperine were blocked in mice with constitutively active AKT. Pretreatment with GW9662, a specific inhibitor of peroxisome proliferator activated receptor-γ (PPAR-γ), reversed the effect elicited by piperine in vitro. In conclusion, piperine attenuated cardiac fibrosis via the activation of PPAR-γ and the resultant inhibition of AKT/GSK3β. Piperine attenuated cardiac fibrosis induced by pressure overload or isoprenaline in mice. Piperine inhibited the transformation of cardiac fibroblasts to myofibroblasts via the attenuation of the AKT/GSK3β pathway. Piperine acted as an agonist of PPAR-γ in cardiac fibroblasts. Cardiac fibrosis plays key roles in the processes of cardiac remodeling and heart failure. The lack of therapy against cardiac fibrosis contributes to the high morbidity and mortality caused by HF. We found that piperine attenuates cardiac fibrosis via the activation of PPAR-γ and the resultant inhibition of AKT/GSK3β. Our study provides evidence for the application of piperine in the treatment of cardiac fibrosis.