Gurusamy Narasimman, Watanabe Kenichi, Ma Meilei, Zhang Shaosong, Muslin Anthony J, Kodama Makoto, Aizawa Yoshifusa
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Japan.
Biol Pharm Bull. 2005 Jun;28(6):957-62. doi: 10.1248/bpb.28.957.
Diabetic cardiomyopathy is associated with cardiac hypertrophy and fibrosis. Activation of protein kinase C (PKC) has been implicated in the diabetes-induced cardiovascular complications. PKCbeta2 isoform is preferentially found to be activated in the diabetic myocardium. However, the role of PKCbeta2 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 PKCbeta2 in the diabetic myocardium. Cardiac myocyte diameter, content of cardiac fibrosis, left ventricular tissue expressions of atrial natriuretic peptide, transforming growth factor beta1, collagen III and PKCbeta2 were significantly elevated 28 and 56 d 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 PKCbeta2 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 PKCbeta2 in the diabetic myocardium.
糖尿病性心肌病与心脏肥大和纤维化相关。蛋白激酶C（PKC）的激活与糖尿病诱导的心血管并发症有关。PKCβ2亚型在糖尿病心肌中被优先发现处于激活状态。然而，PKCβ2在糖尿病性心肌病中的作用尚不清楚。14-3-3家族成员是二聚体磷酸丝氨酸结合蛋白，可调节信号转导、凋亡和检查点控制途径，并已被证明可与PKC同工酶结合并负向调节其酶活性。本研究使用心脏特异性过表达显性负性（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，我们研究了糖尿病心肌中14-3-3蛋白与PKCβ2之间的关系。与非转基因对照相比，转基因DN-14-3-3小鼠在注射STZ后28天和56天，心肌细胞直径、心脏纤维化含量、心房利钠肽、转化生长因子β1、胶原蛋白III和PKCβ2的左心室组织表达均显著升高。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。心脏肥大和纤维化的加剧与DN-14-3-3小鼠中PKCβ2表达的增强显著正相关。我们的结果首次表明，14-3-3蛋白可能通过控制糖尿病心肌中PKCβ2的表达来负向调节心脏肥大和纤维化。
