Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
Eur J Pharm Sci. 2012 Oct 9;47(3):604-14. doi: 10.1016/j.ejps.2012.04.018. Epub 2012 Apr 28.
The development of diabetic cardiomyopathy is accompanied with a high membrane-bound protein kinase C (PKC) levels. Curcumin is a naturally occurring compound which is known to inhibit PKC activity. However, the effects of curcumin on ameliorating diabetic cardiomyopathy are still undefined. We evaluated whether curcumin treatment is associated with the modulation of PKC-α and -β₂-mitogen-activated protein kinase (MAPK) pathway in experimental diabetic cardiomyopathy. Diabetes was induced in male Sprague-Dawley rats by streptozotocin (STZ). Curcumin (100mg/kg/day) was started three weeks after STZ injection and was given for 8 weeks. We demonstrate that curcumin significantly prevented diabetes-induced translocation of PKC-α and -β2 to membranous fraction and diabetes-induced increased phosphorylation of p38MAPK and extracellular regulated-signal kinase (ERK)1/2 in left ventricular tissues of diabetic rats. Curcumin treatment also markedly decreased NAD(P)H oxidase subunits (p67phox, p22phox, gp91phox), growth factors (transforming growth factor-β, osteopontin) and myocyte enhancer factor-2 protein expression as well as inhibited NF-κB activity at nuclear level. Furthermore, curcumin decreased the mRNA expression of transcriptional coactivator p300 and atrial natriuretic peptide, decreased accumulation of ECM protein and reversed the increment of superoxide production in left ventricular tissues, as evidenced by dihydroethidium staining. It is also significantly lowered plasma glucose and attenuated oxidative stress, as determined by lipid peroxidation and activity of anti-oxidant enzyme, and as a result attenuated cardiomyocyte hypertrophy, myocardial fibrosis and left ventricular dysfunction. Taken together, it is suggested that curcumin by inhibiting PKC-α and -β₂-MAPK pathway may be useful as an adjuvant therapy for the prevention of diabetic cardiomyopathy.
糖尿病性心肌病的发展伴随着高膜结合蛋白激酶 C（PKC）水平。姜黄素是一种天然存在的化合物，已知可抑制 PKC 活性。然而，姜黄素对改善糖尿病性心肌病的作用仍未确定。我们评估了姜黄素治疗是否与实验性糖尿病性心肌病中 PKC-α 和-β₂-有丝分裂原激活蛋白激酶（MAPK）途径的调节有关。雄性 Sprague-Dawley 大鼠通过链脲佐菌素（STZ）诱导糖尿病。姜黄素（100mg/kg/天）在 STZ 注射后 3 周开始，并持续 8 周。我们证明，姜黄素可显著防止糖尿病诱导的 PKC-α 和-β2向膜部分的易位，以及糖尿病诱导的左心室组织中 p38MAPK 和细胞外调节信号激酶（ERK）1/2 的磷酸化增加。姜黄素治疗还明显降低了 NAD（P）H 氧化酶亚基（p67phox、p22phox、gp91phox）、生长因子（转化生长因子-β、骨桥蛋白）和肌细胞增强因子-2 蛋白的表达，并抑制了核水平的 NF-κB 活性。此外，姜黄素降低了转录共激活因子 p300 和心钠肽的 mRNA 表达，减少了 ECM 蛋白的积累，并逆转了左心室组织中超氧阴离子产生的增加，如二氢乙啶染色所示。它还显著降低了血浆葡萄糖并减轻了氧化应激，如脂质过氧化和抗氧化酶活性所确定的，结果减轻了心肌细胞肥大、心肌纤维化和左心室功能障碍。总之，姜黄素通过抑制 PKC-α 和-β₂-MAPK 途径，可能有助于预防糖尿病性心肌病。
