title: Effects of cyclooxygenase-2 gene inactivation on cardiac autonomic and left ventricular function in experimental diabetes.
abstract: 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.
authors.affiliation: University of Michigan, Department of Internal Medicine, Ann Arbor, MI, USA.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Kellogg
authors.forename: Kimber
authors.initials: K
authors.lastname: Converso
authors.forename: Tim
authors.initials: T
authors.lastname: Wiggin
authors.forename: Martin
authors.initials: M
authors.lastname: Stevens
authors.forename: Rodica
authors.initials: R
authors.lastname: Pop-Busui
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003094:Collagen / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000172:deficiency* / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D015150:Echocardiography, Doppler; D020868:Gene Silencing; D005978:Glutathione / Q000378:metabolism; D006321:Heart / Q000294:innervation*; D006339:Heart Rate; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress; D011453:Prostaglandins / Q000378:metabolism; D013318:Stroke Volume; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left
chemical_list: D001786:Blood Glucose; D018836:Inflammation Mediators; D011453:Prostaglandins; D014409:Tumor Necrosis Factor-alpha; D008315:Malondialdehyde; D003094:Collagen; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D005978:Glutathione