Crosstalk between AMPK activation and angiotensin II-induced hypertrophy in cardiomyocytes: the role of mitochondria.
Crosstalk between AMPK activation and angiotensin II-induced hypertrophy in cardiomyocytes: the role of mitochondria.
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DOI：
10.1111/jcmm.12220
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发表时间：
2014-04
影响因子：
5.3
通讯作者：
Javadov S
中科院分区：
文献类型：
--
作者：
Hernández JS;Barreto-Torres G;Kuznetsov AV;Khuchua Z;Javadov S
AMP激酶（AMPK）激活可减少心肌肥大，但其潜在的分子机制尚不清楚。在这项研究中，我们阐明了二甲双胍的抗肥大作用，特别是AMPK/eNOS/p53通路的作用。在存在或不存在二甲双胍（AMPK激动剂）、氯沙坦[血管紧张素II 1型受体（AT 1 R）阻断剂]、Nω-硝基-L-精氨酸甲酯（L-NAME，pan-NOS抑制剂）、斯普利特霉素（SIRT 1抑制剂）或匹非林-α（p53抑制剂）的情况下，用血管紧张素II（AngII）处理H9 c2大鼠心肌细胞24小时。结果显示，二甲双胍治疗显著减弱AngII诱导的细胞肥大和死亡。二甲双胍减弱AngII诱导的caspase 3激活（裂解）、Bcl-2下调和p53上调。Ang Ⅱ诱导的AT 1 R表达上调减少30%（P < 0.05），AMPK磷酸化水平增加99%（P < 0.01），P-eNOS水平增加3.3倍（P < 0.01）。氯沙坦组AT 1 R表达上调减少，AMPK磷酸化水平增加54%（P < 0.05）。AMPK抑制剂化合物C阻止AT 1 R下调，表明二甲双胍通过AMPK激活介导其作用。二甲双胍和氯沙坦的有益作用集中在线粒体上，表现出高膜电位（Δ Km）和低渗透性转换孔开放。因此，本研究表明二甲双胍的抗肥大作用与AMPK诱导的AT 1 R下调和通过SIRT 1/eNOS/p53途径预防线粒体功能障碍相关。
AMP-kinase (AMPK) activation reduces cardiac hypertrophy, although underlying molecular mechanisms remain unclear. In this study, we elucidated the anti-hypertrophic action of metformin, specifically, the role of the AMPK/eNOS/p53 pathway. H9c2 rat cardiomyocytes were treated with angiotensin II (AngII) for 24 hrs in the presence or absence of metformin (AMPK agonist), losartan [AngII type 1 receptor (AT1R) blocker], Nω-nitro-L-arginine methyl ester (L-NAME, pan-NOS inhibitor), splitomicin (SIRT1 inhibitor) or pifithrin-α (p53 inhibitor). Results showed that treatment with metformin significantly attenuated AngII-induced cell hypertrophy and death. Metformin attenuated AngII-induced activation (cleavage) of caspase 3, Bcl-2 down-regulation and p53 up-regulation. It also reduced AngII-induced AT1R up-regulation by 30% (P < 0.05) and enhanced AMPK phosphorylation by 99% (P < 0.01) and P-eNOS levels by 3.3-fold (P < 0.01). Likewise, losartan reduced AT1R up-regulation and enhanced AMPK phosphorylation by 54% (P < 0.05). The AMPK inhibitor, compound C, prevented AT1R down-regulation, indicating that metformin mediated its effects via AMPK activation. Beneficial effects of metformin and losartan converged on mitochondria that demonstrated high membrane potential (Δψm) and low permeability transition pore opening. Thus, this study demonstrates that the anti-hypertrophic effects of metformin are associated with AMPK-induced AT1R down-regulation and prevention of mitochondrial dysfunction through the SIRT1/eNOS/p53 pathway.
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影响因子：
4.8
作者：
El-Mir, MY;Nogueira, V;Leverve, X
通讯作者：
Leverve, X
DOI：
10.1152/ajpheart.01269.2005
发表时间：
2006-07-01
影响因子：
4.8
作者：
Bertrand, L;Ginion, A;Vanoverschelde, JL
通讯作者：
Vanoverschelde, JL
影响因子：
37.8
作者：
Nagata, D;Takeda, R;Hirata, Y
通讯作者：
Hirata, Y
影响因子：
4.6
作者：
Jugdutt, Bodh I
通讯作者：
Jugdutt, Bodh I
DOI：
10.3109/10253890.2011.648673
发表时间：
2012-09-01
影响因子：
2.3
作者：
Marques, Mirna B.;Ribeiro-Oliveira, Antonio, Jr.;Korbonits, Marta
通讯作者：
Korbonits, Marta