Liver X receptor agonist treatment attenuates cardiac dysfunction in type 2 diabetic db/db mice.
Liver X receptor agonist treatment attenuates cardiac dysfunction in type 2 diabetic db/db mice.
复制标题
肝 X 受体激动剂治疗可减轻 2 型糖尿病 db/db 小鼠的心功能障碍
DOI：
10.1186/s12933-014-0149-0
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发表时间：
2014-11-22
影响因子：
9.3
通讯作者：
He B
中科院分区：
文献类型：
--
作者：
He Q;Pu J;Yuan A;Yao T;Ying X;Zhao Y;Xu L;Tong H;He B
肝脏X受体（LXR）在代谢和炎症中发挥着关键的调节作用，且已证实其参与心血管生理/病理过程。在本研究中，我们探究了强效LXR激动剂GW3965对2型糖尿病db/db小鼠糖尿病心肌病（DCM）的影响。
非糖尿病db/+小鼠和糖尿病db/db小鼠分别接受载体或LXR激动剂GW3965处理12周。通过葡萄糖耐量试验和胰岛素抵抗稳态模型评估来评价全身胰岛素抵抗情况。通过超声心动图和心导管插入术评估终末心脏功能。收集心室组织用于组织学检查以及基因/蛋白质表达分析。未经治疗的db/db糖尿病小鼠表现出舒张功能障碍，并伴有不良的结构重塑（包括心肌纤维化和细胞凋亡增加）。GW3965处理显著减轻了糖尿病db/db小鼠的心肌功能障碍和结构重塑。从机制上看，GW3965恢复了Akt的磷酸化，抑制了丝裂原活化蛋白激酶（MAP激酶）的磷酸化，并减轻了糖尿病心肌中的氧化/硝化应激以及炎症反应。
我们的数据表明，GW3965（至少部分地）通过减轻胰岛素抵抗、调节Akt和MAP激酶信号通路以及减轻氧化/硝化应激和炎症反应，对糖尿病心肌病发挥心脏保护作用。这些研究结果有力地表明，LXR激动剂可能在治疗糖尿病心肌病方面具有治疗潜力。
Background:Liver X receptor (LXR) plays a critical regulatory role in metabolism and inflammation, and has been demonstrated to be involved in cardiovascular physiology/pathology. In the present study, we investigated the effect of GW3965, a potent LXR agonist, on diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice.Methods and results:Non-diabetic db/+ mice and diabetic db/db mice received either vehicle or LXR agonist GW3965 for 12 weeks. Systemic insulin resistance was evaluated by glucose tolerance test and homeostasis model assessment for insulin resistance. Endpoint cardiac function was assessed by echocardiography and catheterization. Ventricular tissue was collected for histology and gene/protein expression analysis. Untreated db/db diabetic mice exhibited diastolic dysfunction with adverse structural remodeling (including myocardial fibrosis and increased apoptosis). Treatment with GW3965 remarkably attenuated myocardial dysfunction and structural remodeling in diabetic db/db mice. Mechanistically, GW3965 restored Akt phosphorylation and inhibited MAP kinases phosphorylation, and reduced oxidative/nitrative stress and inflammation response in the diabetic myocardium.Conclusions:Our data demonstrate that GW3965 exerts a cardioprotective effect against DCM by (at least in part) attenuating insulin resistance, modulating Akt and MAP kinases pathways, and reducing oxidative/nitrative stress and inflammatory response. These findings strongly suggest that LXR agonist may have therapeutic potential in treating DCM.
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影响因子：
3.7
作者：
Lu D;Lian H;Zhang X;Shao H;Huang L;Qin C;Zhang L
通讯作者：
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DOI：
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