Wakasaki H, Koya D, Schoen F J, Jirousek M R, Ways D K, Hoit B D, Walsh R A, King G L
Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9320-5. doi: 10.1073/pnas.94.17.9320.
Increased cardiovascular mortality occurs in diabetic patients with or without coronary artery disease and is attributed to the presence of diabetic cardiomyopathy. One potential mechanism is hyperglycemia that has been reported to activate protein kinase C (PKC), preferentially the beta isoform, which has been associated with the development of micro- and macrovascular pathologies in diabetes mellitus. To establish that the activation of the PKCbeta isoform can cause cardiac dysfunctions, we have established lines of transgenic mice with the specific overexpression of PKCbeta2 isoform in the myocardium. These mice overexpressed the PKCbeta2 isoform transgene by 2- to 10-fold as measured by mRNA, and proteins exhibited left ventricular hypertrophy, cardiac myocyte necrosis, multifocal fibrosis, and decreased left ventricular performance without vascular lesions. The severity of the phenotypes exhibited gene dose-dependence. Up-regulation of mRNAs for fetal type myosin heavy chain, atrial natriuretic factor, c-fos, transforming growth factor, and collagens was also observed. Moreover, treatment with a PKCbeta-specific inhibitor resulted in functional and histological improvement. These findings have firmly established that the activation of the PKCbeta2 isoform can cause specific cardiac cellular and functional changes leading to cardiomyopathy of diabetic or nondiabetic etiology.
糖尿病患者无论有无冠状动脉疾病，心血管死亡率都会升高，这归因于糖尿病性心肌病的存在。一种潜在机制是高血糖，据报道它可激活蛋白激酶C（PKC），尤其是β亚型，这与糖尿病微血管和大血管病变的发展有关。为了证实PKCβ亚型的激活可导致心脏功能障碍，我们构建了心肌中特异性过表达PKCβ2亚型的转基因小鼠品系。通过mRNA检测，这些小鼠中PKCβ2亚型转基因的过表达水平为2至10倍，并且蛋白质表现出左心室肥厚、心肌细胞坏死、多灶性纤维化以及左心室功能下降，但无血管病变。表型的严重程度呈现基因剂量依赖性。还观察到胎儿型肌球蛋白重链、心钠素、c-fos、转化生长因子和胶原蛋白的mRNA上调。此外，用PKCβ特异性抑制剂治疗可导致功能和组织学改善。这些发现已确凿地证实，PKCβ2亚型的激活可引起特定的心脏细胞和功能变化，导致糖尿病或非糖尿病病因的心肌病。
