Diacylglycerol kinase zeta inhibits myocardial atrophy and restores cardiac dysfunction in streptozotocin-induced diabetes mellitus.
Diacylglycerol kinase zeta inhibits myocardial atrophy and restores cardiac dysfunction in streptozotocin-induced diabetes mellitus.
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DOI：
10.1186/1475-2840-7-2
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发表时间：
2008-02-04
影响因子：
9.3
通讯作者：
Kubota, Isao
中科院分区：
文献类型：
--
作者：
Bilim, Olga;Takeishi, Yasuchika;Kitahara, Tatsuro;Arimoto, Takanori;Niizeki, Takeshi;Sasaki, Toshiki;Goto, Kaoru;Kubota, Isao
二酰基甘油（DAG）-蛋白激酶C（PKC）通路的激活与许多糖尿病并发症的发病机制有关。二酰基甘油激酶（DGK）将DAG转化为磷脂酸，并作为PKC活性的内源性调节剂。Akt/PKB与下游胰岛素信号通路相关，PKCβ减弱胰岛素刺激的Akt磷酸化。我们研究了转基因小鼠心脏特异性过表达DGK-TG（DGK-TG）相比，野生型（WT）小鼠链脲佐菌素诱导（STZ，150毫克/公斤）糖尿病和非糖尿病条件。8周后，糖尿病WT小鼠的心脏重量和心脏重量/体重比的降低在DGK-TG小鼠中受到抑制。STZ注射后8周的超声心动图显示，在WT小鼠中观察到的左心室舒张末期直径和缩短分数的降低在DGK-TG小鼠中减弱。糖尿病WT心脏的室间隔和后壁变薄在DGK-TG小鼠中被阻断。从糖尿病WT小鼠的左心室分离的心肌细胞的横径的减小在DGK-TG小鼠中减弱。糖尿病DGK-TG小鼠的心脏纤维化比糖尿病WT小鼠少得多。Western印迹显示糖尿病WT小鼠心脏中PKCβ和δ亚型易位到膜组分，Akt/PKB磷酸化降低。而在糖尿病DGK/TG小鼠中，既未观察到PKC易位，也未观察到Akt/PKB磷酸化的变化。DGK β调节细胞内信号传导并改善糖尿病心肌病的病程。这些数据可能表明DGK β是预防或逆转糖尿病心肌病的新治疗靶点。
Activation of the diacylglycerol (DAG)-protein kinase C (PKC) pathway has been implicated in the pathogenesis of a number of diabetic complications. Diacylglycerol kinase (DGK) converts DAG to phosphatidic acid and acts as an endogenous regulator of PKC activity. Akt/PKB is associated with a downstream insulin signaling, and PKCβ attenuates insulin-stimulated Akt phosphorylation. We examined transgenic mice with cardiac-specific overexpression of DGKζ (DGKζ-TG) compared to wild type (WT) mice in streptozotocin-induced (STZ, 150 mg/kg) diabetic and nondiabetic conditions. After 8 weeks, decreases in heart weight and heart weight/body weight ratio in diabetic WT mice were inhibited in DGKζ-TG mice. Echocardiography at 8 weeks after STZ-injection demonstrated that decreases in left ventricular end-diastolic diameter and fractional shortening observed in WT mice were attenuated in DGKζ-TG mice. Thinning of the interventricular septum and the posterior wall in diabetic WT hearts were blocked in DGKζ-TG mice. Reduction of transverse diameter of cardiomyocytes isolated from the left ventricle in diabetic WT mice was attenuated in DGKζ-TG mice. Cardiac fibrosis was much less in diabetic DGKζ-TG than in diabetic WT mice. Western blots showed translocation of PKCβ and δ isoforms to membrane fraction and decreased Akt/PKB phosphorylation in diabetic WT mouse hearts. However in diabetic DGKζ-TG mice, neither translocation of PKC nor changes Akt/PKB phosphorylation was observed. DGKζ modulates intracellular signaling and improves the course of diabetic cardiomyopathy. These data may suggest that DGKζ is a new therapeutic target to prevent or reverse diabetic cardiomyopathy.
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影响因子：
13.7
作者：
Abraham, Prema;Adelman, Ron A.;Zhi, Xin (Eric)
通讯作者：
Zhi, Xin (Eric)
DOI：
10.1152/ajpheart.00927.2006
发表时间：
2007-02-01
影响因子：
4.8
作者：
Niizeki, Takeshi;Takeishi, Yasuchika;Kubota, Isao
通讯作者：
Kubota, Isao
影响因子：
4.3
作者：
Rodrigues, B;Cam, MC;McNeill, JH
通讯作者：
McNeill, JH
影响因子：
7.7
作者：
Arikawa, Emi;Ma, Ronald C. W.;King, George L.
通讯作者：
King, George L.
影响因子：
37.8
作者：
Nozaki, N;Shishido, T;Kubota, I
通讯作者：
Kubota, I