Barbato Joel E, Zuckerbraun Brian S, Overhaus Marcus, Raman Kathleen G, Tzeng Edith
Dept. of Surgery, Univ. of Pittsburgh, A1010 PUH, 200 Lothrop St., Pittsburgh, PA 15213, USA.
Am J Physiol Heart Circ Physiol. 2005 Jul;289(1):H228-36. doi: 10.1152/ajpheart.00982.2004. Epub 2005 Feb 25.
Type 2 diabetes mellitus (DM) and the metabolic syndrome, both characterized by insulin resistance, are associated with an accelerated form of atherosclerotic vascular disease and poor outcomes following vascular interventions. These vascular effects are thought to stem from a heightened inflammatory environment and reduced bioavailability of nitric oxide (NO). To better understand this process, we characterized the vascular injury response in the obese Zucker rat by examining the expression of adhesion molecules, the recruitment of inflammatory cells, and the development of intimal hyperplasia. We also evaluated the ability of exogenous NO to inhibit the sequela of vascular injury in the metabolic syndrome. Obese and lean Zucker rats underwent carotid artery balloon injury. ICAM-1 and P-selectin expression were increased following injury in the obese animals compared with the lean rats. The obese rats also responded with increased macrophage infiltration of the vascular wall as well as increased neointima formation compared with their lean counterparts (intima/media = 0.91 vs. 0.52, P = 0.001). After adenovirus-mediated inducible NO synthase (iNOS) gene transfer, ICAM-1, P-selectin, inflammatory cell influx, and oxidized low-density lipoprotein (LDL) receptor expression were all markedly reduced versus injury alone. iNOS gene transfer also significantly inhibited proliferative activity (54% and 73%; P < 0.05) and neointima formation (53% and 67%; P < 0.05) in lean and obese animals, respectively. The vascular injury response in the face of obesity and the metabolic syndrome is associated with increased adhesion molecule expression, inflammatory cell infiltration, oxidized LDL receptor expression, and proliferation. iNOS gene transfer is able to effectively inhibit this heightened injury response and reduce neointima formation in this proinflammatory environment.
2型糖尿病（DM）和代谢综合征均以胰岛素抵抗为特征，与动脉粥样硬化性血管疾病的加速发展形式以及血管介入治疗后的不良预后相关。这些血管效应被认为源于炎症环境的加剧和一氧化氮（NO）生物利用度的降低。为了更好地理解这一过程，我们通过检测黏附分子的表达、炎症细胞的募集以及内膜增生的发展，对肥胖 Zucker 大鼠的血管损伤反应进行了表征。我们还评估了外源性 NO 抑制代谢综合征中血管损伤后遗症的能力。肥胖和瘦 Zucker 大鼠接受颈动脉球囊损伤。与瘦大鼠相比，肥胖动物损伤后细胞间黏附分子-1（ICAM-1）和 P-选择素的表达增加。与瘦大鼠相比，肥胖大鼠血管壁巨噬细胞浸润增加，新生内膜形成也增加（内膜/中膜 = 0.91 对 0.52，P = 0.001）。腺病毒介导的诱导型一氧化氮合酶（iNOS）基因转移后，与单纯损伤相比，ICAM-1、P-选择素、炎症细胞流入以及氧化型低密度脂蛋白（LDL）受体表达均显著降低。iNOS 基因转移还分别显著抑制了瘦动物和肥胖动物的增殖活性（分别为 54%和 73%；P < 0.05）以及新生内膜形成（分别为 53%和 67%；P < 0.05）。面对肥胖和代谢综合征时的血管损伤反应与黏附分子表达增加、炎症细胞浸润、氧化型 LDL 受体表达以及增殖相关。iNOS 基因转移能够有效抑制这种增强的损伤反应，并在这种促炎环境中减少新生内膜形成。
