Diabetes enhances mRNA levels of proapoptotic genes and caspase activity, which contribute to impaired healing
Diabetes enhances mRNA levels of proapoptotic genes and caspase activity, which contribute to impaired healing
复制标题
DOI：
10.2337/diabetes.55.02.06.db05-1201
复制
发表时间：
2006-02-01
期刊：
影响因子：
7.7
通讯作者：
Graves, DT
中科院分区：
文献类型：
--
作者：
Al-Mashat, HA;Kandru, S;Graves, DT
我们以前报道过，在头皮细菌诱导的伤口后，2型糖尿病（db/db）小鼠与血糖正常的对照组相比，成纤维细胞和骨衬细胞的凋亡水平更高，这对愈合至关重要。为了研究可能发生这种情况的机制，在接种牙龈卟啉单胞菌后测量RNA谱和半胱天冬酶活性。糖尿病导致71个直接或间接调节细胞凋亡的基因的两倍以上的诱导，并显着增强caspase-8，-9和-3活性。通过用pancasepase抑制剂z-VAD-favorite（N-苄氧羰基-Val-Ala-Asp-fluoromethylketone）处理糖尿病小鼠来研究糖尿病诱导的细胞凋亡的功能意义。抑制细胞凋亡显着改善愈合的几个参数，包括成纤维细胞密度，增强胶原蛋白I和III的mRNA水平，并增加基质形成。在骨中也观察到改善，骨衬里细胞和新骨形成的数量增加。因此，糖尿病增强的细胞凋亡代表了愈合受损的重要机制，这可以部分地通过糖尿病增加的促凋亡基因和半胱天冬酶活性的表达来解释。
We previously reported that after a bacteria-induced wound in the scalp, type 2 diabetic (db/db) mice had higher levels of apoptosis of fibroblasts and bone-lining cells that are critical for healing compared with normoglycemic controls. To investigate mechanisms by which this might occur, RNA profiling and caspase activity was measured after inoculation of Porphyromonas gingivalis. Diabetes caused a more than twofold induction of 71 genes that directly or indirectly regulate apoptosis and significantly enhanced caspase-8, -9, and -3 activity. The functional significance of diabetes-induced apoptosis was studied by treating diabetic mice with a pancaspase inhibitor, z-VAD-fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone). Inhibiting apoptosis significantly improved several parameters of healing, including fibroblast density, enhanced mRNA levels of collagen I and III, and increased matrix formation. Improvements were also noted in bone, with an increase in the number of bone-lining cells and new bone formation. Thus, diabetes-enhanced apoptosis represents an important mechanism through which healing is impaired, and this can be explained, in part, by diabetes-increased expression of proapoptotic genes and caspase activity.