Adiponectin modulates oxidative stress-induced autophagy in cardiomyocytes.
Adiponectin modulates oxidative stress-induced autophagy in cardiomyocytes.
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DOI：
10.1371/journal.pone.0068697
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sam F
中科院分区：
文献类型：
--
作者：
Essick EE;Wilson RM;Pimentel DR;Shimano M;Baid S;Ouchi N;Sam F
舒张性心力衰竭(HF)，即“射血分数保留的HF”(HF保留的EF)占所有HF的50%；然而，治疗方面一直没有进展。这在一定程度上源于对HF保存的EF的不完全理解。高血压是HF保留EF的主要原因，而HF保留EF也与肥胖高度相关。同样，过多的活性氧(ROS)，即氧化应激，发生在高血压和肥胖中，使心脏对肾素-血管紧张素-醛固酮系统敏感，诱导自噬II型程序性细胞死亡，并加速不利的心脏重构、舒张期功能障碍和心衰的倾向。脂联素(APN)是一种脂肪因子，具有心肌保护作用，但APN是否调节心肌细胞自噬尚不清楚。我们测试了APN改善氧化应激诱导的心肌细胞自噬的假设。分离的成年大鼠心室肌细胞用重组APN(30微克/毫升)预处理，然后用1 mM过氧化氢(H_2O_2)处理。给野生型(WT)和APN缺陷型(APN-KO)小鼠灌胃血管紧张素(Ang)-II(3.2 mg/kg/d)14天，建立氧化应激模型。检测自噬相关蛋白、mTOR、AMPK和ERK的表达。H_2O_2诱导的LC_3I向LC_3 II的转化为原来的3.4±1.0倍，而用APN处理后，这一效应被抑制了44.5±10%。然而，过氧化氢和APN均不影响ATG5、ATG7和Beclin-1的表达。H_2O_2使磷酸化AMPK升高49±6.0%，而APN使磷酸化AMPK降低26±4%。H_2O_2使磷酸化mTOR降低36±13%，APN可使之恢复。ERK抑制表明ERK-mTOR通路参与了过氧化氢诱导的自噬。慢性Ang-II输注显著增加APN-KO与WT小鼠心肌LC3II/I蛋白表达比率。这些数据表明，过量的ROS导致心肌细胞自噬，APN通过抑制H_2O_2诱导的AMPK/mTOR/ERK依赖机制而改善这种自噬。这些发现证明了APN在氧化应激相关的心血管疾病中的抗氧化潜力，例如高血压引起的心衰保存的EF。
Diastolic heart failure (HF) i.e., “HF with preserved ejection fraction” (HF-preserved EF) accounts for up to 50% of all HF presentations; however there have been no therapeutic advances. This stems in part from an incomplete understanding about HF-preserved EF. Hypertension is the major cause of HF-preserved EF whilst HF-preserved EF is also highly associated with obesity. Similarly, excessive reactive oxygen species (ROS), i.e., oxidative stress occurs in hypertension and obesity, sensitizing the heart to the renin-angiotensin-aldosterone system, inducing autophagic type-II programmed cell death and accelerating the propensity to adverse cardiac remodeling, diastolic dysfunction and HF. Adiponectin (APN), an adipokine, mediates cardioprotective actions but it is unknown if APN modulates cardiomyocyte autophagy. We tested the hypothesis that APN ameliorates oxidative stress-induced autophagy in cardiomyocytes. Isolated adult rat ventricular myocytes were pretreated with recombinant APN (30µg/mL) followed by 1mM hydrogen peroxide (H2O2) exposure. Wild type (WT) and APN-deficient (APN-KO) mice were infused with angiotensin (Ang)-II (3.2mg/kg/d) for 14 days to induced oxidative stress. Autophagy-related proteins, mTOR, AMPK and ERK expression were measured. H2O2 induced LC3I to LC3II conversion by a factor of 3.4±1.0 which was abrogated by pre-treatment with APN by 44.5±10%. However, neither H2O2 nor APN affected ATG5, ATG7, or Beclin-1 expression. H2O2 increased phospho-AMPK by 49±6.0%, whilst pretreatment with APN decreased phospho-AMPK by 26±4%. H2O2 decreased phospho-mTOR by 36±13%, which was restored by APN. ERK inhibition demonstrated that the ERK-mTOR pathway is involved in H2O2-induced autophagy. Chronic Ang-II infusion significantly increased myocardial LC3II/I protein expression ratio in APN-KO vs. WT mice. These data suggest that excessive ROS caused cardiomyocyte autophagy which was ameliorated by APN by inhibiting an H2O2-induced AMPK/mTOR/ERK-dependent mechanism. These findings demonstrate the anti-oxidant potential of APN in oxidative stress-associated cardiovascular diseases, such as hypertension-induced HF-preserved EF.
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影响因子：
7.8
作者：
Degtyarev, Michael;De Maziere, Ann;Orr, Christine;Lin, Jie;Lee, Brian B.;Tien, Janet Y.;Prior, Wei W.;van Dijk, Suzanne;Wu, Hong;Gray, Daniel C.;Davis, David P.;Stern, Howard M.;Murray, Lesley J.;Hoeflich, Klaus P.;Klumperman, Judith;Friedman, Lori S.;Lin, Kui
通讯作者：
Lin, Kui
DOI：
10.1016/0735-1097(96)00140-4
发表时间：
1996-08-01
影响因子：
24
作者：
Dhalla, AK;Hill, MF;Singal, PK
通讯作者：
Singal, PK
影响因子：
3.6
作者：
Aoki, Hiroshi;Takada, Yasunari;Kondo, Yasuko
通讯作者：
Kondo, Yasuko
影响因子：
8.7
作者：
Hotta, K;Funahashi, T;Matsuzawa, Y
通讯作者：
Matsuzawa, Y
影响因子：
6.6
作者：
Hariharan, Nirmala;Zhai, Peiyong;Sadoshima, Junichi
通讯作者：
Sadoshima, Junichi