Vascular Pathology Laboratory, Fundación Jiménez Díaz Hospital, Autónoma University, Av. Reyes Católicos 2, Madrid 28040, Spain.
Am J Physiol Heart Circ Physiol. 2009 Dec;297(6):H2109-19. doi: 10.1152/ajpheart.00157.2009. Epub 2009 Oct 9.
The aim of this paper is to study the myocardial damage secondary to long-term streptozotocin-induced type 1 diabetes mellitus (DM1). Normotensive and spontaneously hypertensive rats (SHR) received either streptozotocin injections or vehicle. After 22 or 6 wk, DM1, SHR, DM1/SHR, and control rats were killed, and the left ventricles studied by histology, quantitative PCR, Western blot, ELISA, and electromobility shift assay. Cardiomyocyte cultures were also performed. The expression of profibrotic factors, transforming growth factor-beta (TGF-beta1), connective tissue growth factor, and matrix proteins was increased, and the TGF-beta1-linked transcription factors phospho-Smad3/4 and activator protein-1 were activated in the DM1 myocardium. Proapoptotic molecules FasL, Fas, Bax, and cleaved caspase-3 were also augmented. Myocardial injury in long-term hypertension shared these features. In addition, hypertension was associated with activation of NF-kappaB, increased inflammatory cell infiltrate, and expression of the mediators [interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, monocyte chemoattractant protein 1, vascular cell adhesion molecule 1, angiotensinogen, and oxidants], which were absent in long-term DM1. At this stage, the combination of DM1 and hypertension resulted in nonsignificant additive effects. Moreover, the coexistence of DM1 blunted the inflammatory response to hypertension. Anti-inflammatory IL-10 and antioxidants were induced in long-term DM1 and DM1/SHR hearts. Myocardial inflammation was, however, observed in the short-term model. In cultured cardiomyocytes, IL-10, TGF-beta1, and catalase blocked the glucose-stimulated expression of proinflammatory genes. Fibrosis and apoptosis are features of long-term myocardial damage in experimental DM1. Associated hypertension does not induce additional changes. Myocardial inflammation is present in hypertension and short-term DM1, but is not a key feature in long-term DM1. Local reduction of proinflammatory factors and expression of anti-inflammatory and antioxidant molecules may underlie this effect.
本文旨在研究长期链脲佐菌素诱导的 1 型糖尿病（DM1）继发的心肌损伤。正常血压和自发性高血压大鼠（SHR）接受链脲佐菌素注射或载体注射。22 或 6 周后，处死 DM1、SHR、DM1/SHR 和对照大鼠，通过组织学、定量 PCR、Western blot、ELISA 和电泳迁移率变动分析研究左心室。还进行了心肌细胞培养。DM1 心肌中纤维化因子转化生长因子-β（TGF-β1）、结缔组织生长因子和基质蛋白的表达增加，TGF-β1 相关转录因子磷酸化 Smad3/4 和激活蛋白-1 被激活。促凋亡分子 FasL、Fas、Bax 和 cleaved caspase-3 也增加。长期高血压引起的心肌损伤具有这些特征。此外，高血压与 NF-κB 激活、炎症细胞浸润增加以及介质[白细胞介素-1β（IL-1β）、肿瘤坏死因子-α、单核细胞趋化蛋白 1、血管细胞黏附分子 1、血管紧张素原和氧化剂]的表达有关，这些在长期 DM1 中不存在。在这个阶段，DM1 和高血压的联合作用没有产生显著的附加效应。此外，DM1 的共存削弱了对高血压的炎症反应。长期 DM1 和 DM1/SHR 心脏中诱导了抗炎性的白细胞介素 10 和抗氧化剂。然而，在短期模型中观察到心肌炎症。在培养的心肌细胞中，白细胞介素 10、TGF-β1 和过氧化氢酶阻断了葡萄糖刺激的促炎基因表达。纤维化和细胞凋亡是实验性 DM1 长期心肌损伤的特征。相关的高血压不会引起额外的变化。高血压和短期 DM1 存在心肌炎症，但不是长期 DM1 的关键特征。局部减少促炎因子和抗炎及抗氧化分子的表达可能是这种作用的基础。
