Effects of cyclooxygenase-2 gene inactivation on cardiac autonomic and left ventricular function in experimental diabetes
Effects of cyclooxygenase-2 gene inactivation on cardiac autonomic and left ventricular function in experimental diabetes
复制标题
DOI：
10.1152/ajpheart.00678.2008
复制
发表时间：
2009-02-01
影响因子：
4.8
通讯作者：
Pop-Busui, Rodica
中科院分区：
文献类型：
--
作者：
Kellogg, Aaron P.;Converso, Kimber;Pop-Busui, Rodica
凯洛格AP，Converso K，Wiggin T，Stevens M，Pop-Busui R.环氧合酶-2基因失活对实验性糖尿病心脏自主神经和左室功能的影响。Am J Physiol Heart Circ Physiol 296：H453-H461，2009。首次发表于2008年12月5日; doi：10.1152/ajpheart.00678.2008。葡萄糖介导的氧化应激和环氧合酶（考克斯）-2途径活性的上调与包括糖尿病神经病变在内的多种糖尿病血管并发症的发病机制有关。然而，在非糖尿病受试者中，选择性考克斯-2抑制剂的心血管安全性存在争议。本研究旨在探讨高血糖、氧化应激、考克斯-2通路激活、心脏交感神经完整性与实验性糖尿病左室功能障碍之间的关系。6个月后，在对照组和糖尿病考克斯-2缺陷（考克斯-2（-/-））和同窝野生型（考克斯-2（+/+））小鼠中评估R波至R波间期（R-R间期）和使用1%异氟烷通过超声心动图测量的LV功能参数、LV交感神经纤维密度、LV胶原含量和心肌氧化应激、炎症和PG含量的标志物。在基线和之后，非糖尿病（ND）考克斯-2（+/+）和考克斯-2（-/-）小鼠之间的血糖、LV超声心动图测量、胶原含量、交感神经纤维密度以及氧化应激和炎症标志物没有差异。6个月后，糖尿病考克斯-2（+/+）小鼠出现R-R间期显著恶化和LV功能障碍体征。与ND小鼠相比，这些与LV交感神经纤维密度损失、LV胶原含量增加以及心肌氧化应激和炎症显著增加相关。糖尿病考克斯-2（-/-）小鼠对所有这些生化，结构和功能缺陷的保护。这些数据表明，在实验性糖尿病中，选择性考克斯-2失活通过减少心肌内氧化应激、炎症和心肌纤维化来保护交感神经去神经支配和LV功能障碍。
Kellogg AP, Converso K, Wiggin T, Stevens M, Pop-Busui R. Effects of cyclooxygenase-2 gene inactivation on cardiac autonomic and left ventricular function in experimental diabetes. Am J Physiol Heart Circ Physiol 296: H453-H461, 2009. First published December 5, 2008; doi: 10.1152/ajpheart.00678.2008.-Glucose-mediated oxidative stress and the upregulation of cyclooxygenase ( COX)-2 pathway activity have been implicated in the pathogenesis of several vascular complications of diabetes including diabetic neuropathy. However, in nondiabetic subjects, the cardiovascular safety of selective COX-2 inhibition is controversial. The aim of this study was to explore the links between hyperglycemia, oxidative stress, activation of the COX-2 pathway, cardiac sympathetic integrity, and the development of left ventricular (LV) dysfunction in experimental diabetes. R wave-to-R wave interval (R-R interval) and parameters of LV function measured by echocardiography using 1% isoflurane, LV sympathetic nerve fiber density, LV collagen content, and markers of myocardial oxidative stress, inflammation, and PG content were assessed after 6 mo in control and diabetic COX-2-deficient (COX-2(-/-) ) and littermate, wild-type (COX-2(+/+)) mice. There were no differences in blood glucose, LV echocardiographic measures, collagen content, sympathetic nerve fiber density, and markers of oxidative stress and inflammation between nondiabetic (ND) COX-2(+/+) and COX-2(-/-) mice at baseline and thereafter. After 6 mo, diabetic COX-2 (+/+) mice developed significant deteriorations in the R-R interval and signs of LV dysfunction. These were associated with a loss of LV sympathetic nerve fiber density, increased LV collagen content, and a significant increase in myocardial oxidative stress and inflammation compared with those of ND mice. Diabetic COX-2 (-/-) mice were protected against all these biochemical, structural, and functional deficits. These data suggest that in experimental diabetes, selective COX-2 inactivation confers protection against sympathetic denervation and LV dysfunction by reducing intramyocardial oxidative stress, inflammation, and myocardial fibrosis.