Inactivation of 14-3-3 protein exacerbates cardiac hypertrophy and fibrosis through enhanced expression of protein kinase C β2 in experimental diabetes
Inactivation of 14-3-3 protein exacerbates cardiac hypertrophy and fibrosis through enhanced expression of protein kinase C β2 in experimental diabetes
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DOI：
10.1248/bpb.28.957
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发表时间：
2005-06-01
影响因子：
2
通讯作者：
Aizawa, Y
中科院分区：
文献类型：
--
作者：
Gurusamy, N;Watanabe, K;Aizawa, Y
糖尿病性心肌病与心脏肥大和纤维化有关。蛋白激酶C（PKC）的激活与糖尿病引起的心血管并发症有关。发现PKC β 2亚型优先在糖尿病心肌中被激活。然而，PKC β 2在糖尿病心肌病中的作用尚不清楚。14-3-3家族成员是调节信号转导、凋亡和检查点控制途径的二聚磷酸丝氨酸结合蛋白，并且已显示与PKC同工酶结合并负调节其酶活性。本研究使用心脏特异性过表达显性阴性（DN）14 - 3 - 3蛋白的转基因小鼠，测试14 - 3 - 3蛋白是否调节链脲佐菌素（STZ）诱导的糖尿病小鼠的心脏肥大和纤维化。此外，我们还研究了糖尿病心肌中14-3-3蛋白与PKC β 2的关系。STZ注射后28和56 d，转基因DN-14-3-3小鼠心肌细胞直径、心肌纤维化程度、左心室组织心钠素、转化生长因子β 1、Ⅲ型胶原和PKC β 2的表达均显著高于非转基因小鼠。这些结果清楚地表明，DN-14-3 -3小鼠中14-3-3蛋白的功能失活加剧了糖尿病诱导的心脏肥大和纤维化。DN-14-3-3小鼠心肌肥厚和纤维化的加重与PKC β 2的表达增强显著正相关。我们的研究结果首次表明，14-3-3蛋白负性调节心肌肥厚和纤维化，可能通过控制糖尿病心肌中PKC β 2的表达。
Diabetic cardiomyopathy is associated with cardiac hypertrophy and fibrosis. Activation of protein kinase C (PKC) has been implicated in the diabetes-induced cardiovascular complications. PKC beta 2 isoform is preferentially found to be activated in the diabetic myocardium. However, the role of PKC,82 in diabetic cardiomyopathy is not clear. 14-3-3 family members are dimeric phosphoserine-binding proteins that regulate signal transduction, apoptotic and checkpoint control pathways, and have been shown to bind with PKC isozymes and negatively regulate their enzymatic activities. The present study tests whether 14-3-3 protein regulates cardiac hypertrophy and fibrosis in streptozotocin (STZ)-induced diabetic mice, using transgenic mice with cardiac specific over-expression of dominant negative (DN) 14-3-3 protein. In addition, we examined the relationship between 14-3-3 protein and PKC beta 2 in the diabetic myocardium. Cardiac myocyte diameter, content of cardiac fibrosis, left ventricular tissue expressions of atrial natriuretic peptide, transforming growth factor beta 1, collagen III and PKC beta 2 were significantly elevated 28 and 56d after STZ injection in transgenic DN-14-3-3 mice, when compared to their non-transgenic counterparts. These results clearly demonstrate that the functional inactivation of 14-3-3 protein in DN-14-3-3 mice exacerbates diabetes-induced cardiac hypertrophy and fibrosis. The exacerbations of cardiac hypertrophy and fibrosis were significantly and positively correlated with the enhanced expression of PKC beta 2 in DN-14-3-3 mice. Our results indicate for the first time that 14-3-3 protein negatively regulates cardiac hypertrophy and fibrosis, possibly through controlling the expression of PKC beta 2 in the diabetic myocardium.