EET intervention on Wnt1, NOV, and HO-1 signaling prevents obesity-induced cardiomyopathy in obese mice
EET intervention on Wnt1, NOV, and HO-1 signaling prevents obesity-induced cardiomyopathy in obese mice
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DOI：
10.1152/ajpheart.00093.2017
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发表时间：
2017-08-01
影响因子：
4.8
通讯作者：
Abraham, Nader G.
中科院分区：
文献类型：
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作者：
Cao, Jian;Singh, Shailendra P.;Abraham, Nader G.
我们以前曾报道，epoxyeicosatrienoic acid（EET）对血管功能有多种有益的影响，除了其抗凋亡作用，它增加胰岛素敏感性和抑制炎症。为了揭示EET减少心肌病的信号传导机制，我们假设EET输注可能通过改善心脏组织中血红素加氧酶（HO）-1，Wnt 1，产热基因水平和线粒体完整性以及改善心包脂肪表型来改善肥胖诱导的心肌病。EET降低空腹血糖和促炎脂肪因子水平，包括肾母细胞瘤过度表达（NOV）信号，同时增加超声心动图缩短分数和O-2消耗。有趣的是，我们还注意到线粒体完整性、产热基因以及Wnt 1和HO-1信号传导机制的显著改善。过氧化物酶体增殖物激活受体-γ共激活因子-1 α基因敲除EET处理小鼠中的PGC-1 α导致这些有益作用的逆转，包括心肌Wnt 1和HO-1表达的减少和NOV的增加。为了进一步阐明EET对心包脂肪组织的影响，我们观察到EET处理增加了脂联素、PGC-1 α、磷酸AMP活化蛋白激酶，胰岛素受体磷酸化和产热基因，导致高脂饮食下的“布朗宁”心包脂肪表型。总的来说，这些实验表明，EET激动剂增加Wnt 1和HO-1信号，同时减少NOV途径和心肌病的进展。此外，这份报告提出了一个门户网站到潜在的治疗方法，用于治疗心力衰竭和代谢syndrome.NEW & NOTEWORTHY EET作用于肥胖引起的心肌病的机制是未知的。在这里，我们描述了一种以前未被认识到的EET输注功能，它可以抑制肾母细胞瘤过表达（NOV）水平并激活Wnt 1，从而将NOV抑制和增强Wnt 1表达确定为预防和治疗心肌病和心力衰竭的新药理学靶点。http://ajpheart.physiology.org/content/early/2017/05/31/ajpheart.00093.2017
We have previously reported that epoxyeicosatrienoic acid (EET) has multiple beneficial effects on vascular function; in addition to its antiapoptotic action, it increases insulin sensitivity and inhibits inflammation. To uncover the signaling mechanisms by which EET reduces cardiomyopathy, we hypothesized that EET infusion might ameliorate obesity-induced cardiomyopathy by improving heme oxygenase (HO)-1, Wnt1, thermogenic gene levels, and mitochondrial integrity in cardiac tissues and improved pericardial fat phenotype. EET reduced levels of fasting blood glucose and proinflammatory adipokines, including nephroblastoma overexpressed (NOV) signaling, while increasing echocardiographic fractional shortening and O-2 consumption. Of interest, we also noted a marked improvement in mitochondrial integrity, thermogenic genes, and Wnt 1 and HO-1 signaling mechanisms. Knockout of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) in EET-treated mice resulted in a reversal of these beneficial effects including a decrease in myocardial Wnt1 and HO-1 expression and an increase in NOV. To further elucidate the effects of EET on pericardial adipose tissues, we observed EET treatment increases in adiponectin, PGC-1 alpha, phospho-AMP-activated protein kinase, insulin receptor phosphorylation, and thermogenic genes, resulting in a "browning" pericardial adipose phenotype under high-fat diets. Collectively, these experiments demonstrate that an EET agonist increased Wnt1 and HO-1 signaling while decreasing NOV pathways and the progression of cardiomyopathy. Furthermore, this report presents a portal into potential therapeutic approaches for the treatment of heart failure and metabolic syndrome.NEW & NOTEWORTHY The mechanism by which EET acts on obesity-induced cardiomyopathy is unknown. Here, we describe a previously unrecognized function of EET infusion that inhibits nephroblastoma overexpressed (NOV) levels and activates Wnt1, hence identifying NOV inhibition and enhanced Wnt1 expression as novel pharmacological targets for the prevention and treatment of cardiomyopathy and heart failure.Listen to this article's corresponding podcast at http://ajpheart.physiology.org/content/early/2017/05/31/ajpheart.00093.2017.