Nacci Carmela, Tarquinio Mariela, De Benedictis Leonarda, Mauro Annamaria, Zigrino Addolorata, Carratù Maria Rosaria, Quon Michael J, Montagnani Monica
Department of Pharmacology and Human Physiology, University of Bari Medical School, Bari, Italy.
Endocrinology. 2009 Feb;150(2):849-61. doi: 10.1210/en.2008-1069. Epub 2008 Oct 9.
Cardiovascular complications of diabetes result from endothelial dysfunction secondary to persistent hyperglycemia. We investigated potential compensatory mechanisms in the vasculature that oppose endothelial dysfunction in diabetes. BALB/c mice were treated with streptozotocin (STZ) to induce type 1 diabetes (T1D). In mesenteric vascular beds (MVBs), isolated ex vivo from mice treated with STZ for 1 wk, dose-dependent vasorelaxation to acetylcholine (ACh) or sodium nitroprusside was comparable with that in age-matched control mice (CTRL). By contrast, MVBs from mice treated with STZ for 8 wk had severely impaired vasodilator responses to ACh consistent with endothelial dysfunction. Pretreatment of MVBs from CTRL mice with nitric oxide synthase inhibitor nearly abolished vasodilation to ACh. In MVB from 1-wk STZ-treated mice, vasodilation to ACh was only partially impaired by L-N(omega)-arginine methyl ester. Thus, vasculature of mice with T1D may have compensatory nitric oxide-independent mechanisms to augment vasodilation to ACh and oppose endothelial dysfunction. Indeed, pretreatment of MVBs isolated from 1-wk STZ-treated mice with NS-398 [selective cyclooxygenase (COX)-2 inhibitor] unmasked endothelial dysfunction not evident in CTRL mice pretreated without or with NS-398. Expression of COX-2 in MVBs, aortic endothelial cells, and aortic vascular smooth muscle cells from STZ-treated mice was significantly increased (vs. CTRL). Moreover, concentrations of the COX-2-dependent vasodilator 6-keto-prostaglandin F-1alpha was elevated in conditioned media from aorta of STZ-treated mice. We conclude that endothelial dysfunction in a mouse model of T1D is opposed by compensatory up-regulation of COX-2 expression and activity in the vasculature that may be relevant to developing novel therapeutic strategies for diabetes and its cardiovascular complications.
糖尿病的心血管并发症源于持续性高血糖继发的内皮功能障碍。我们研究了血管系统中对抗糖尿病内皮功能障碍的潜在代偿机制。用链脲佐菌素（STZ）处理BALB/c小鼠以诱导1型糖尿病（T1D）。在从用STZ处理1周的小鼠离体分离的肠系膜血管床（MVB）中，对乙酰胆碱（ACh）或硝普钠的剂量依赖性血管舒张与年龄匹配的对照小鼠（CTRL）相当。相比之下，用STZ处理8周的小鼠的MVB对ACh的血管舒张反应严重受损，与内皮功能障碍一致。用一氧化氮合酶抑制剂预处理CTRL小鼠的MVB几乎消除了对ACh的血管舒张。在来自用STZ处理1周的小鼠的MVB中，L-N（ω）-精氨酸甲酯仅部分损害了对ACh的血管舒张。因此，T1D小鼠的血管系统可能具有代偿性一氧化氮非依赖性机制，以增强对ACh的血管舒张并对抗内皮功能障碍。事实上，用NS-398 [选择性环氧化酶（COX）-2抑制剂]预处理从用STZ处理1周的小鼠分离的MVB，揭示了在未用或用NS-398预处理的CTRL小鼠中不明显的内皮功能障碍。来自用STZ处理的小鼠的MVB、主动脉内皮细胞和主动脉血管平滑肌细胞中COX-2的表达显著增加（与CTRL相比）。此外，在用STZ处理的小鼠的主动脉条件培养基中，COX-2依赖性血管舒张剂6-酮-前列腺素F-1α的浓度升高。我们得出结论，T1D小鼠模型中的内皮功能障碍被血管系统中COX-2表达和活性的代偿性上调所对抗，这可能与开发针对糖尿病及其心血管并发症的新型治疗策略有关。
