Feed-forward signaling of TNF-α and NF-κB via IKK-β pathway contributes to insulin resistance and coronary arteriolar dysfunction in type 2 diabetic mice

Yang, Ji-Yeon; Park, Young Joo; Zhang, Hanrui; Xu, Xiangbin; Laine, Glen A.; Dellsperger, Kevin C.; Zhang, Cuihua

doi:10.1152/ajpheart.01199.2008

Cited by 107 publications

(96 citation statements)

References 46 publications

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“…The serum insulin and APN levels were measured with commercial kits (Alpco diagnostics and Millipore, respectively) using spectrophotometry according to company protocol. Insulin resistance was determined by using homeostasis assessment model (HOMA-IR) (52). HOMA-IR used the following formula: HOMA-IR ϭ fasting glucose (mmol/l) ϫ fasting insulin (mU/l)/22.5.…”

Section: Methodsmentioning

confidence: 99%

Exercise training improves endothelial function via adiponectin-dependent and independent pathways in type 2 diabetic mice

Lee

Park

Dellsperger

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Lee S, Park Y, Dellsperger KC, Zhang C. Exercise training improves endothelial function via adiponectin-dependent and independent pathways in type 2 diabetic mice. Am J Physiol Heart Circ Physiol 301: H306 -H314, 2011. First published May 20, 2011 doi:10.1152/ajpheart.01306.2010.-Type 2 diabetes (T2D) is a leading risk factor for a variety of cardiovascular diseases including coronary heart disease and atherosclerosis. Exercise training (ET) has a beneficial effect on these disorders, but the basis for this effect is not fully understood. This study was designed to investigate whether the ET abates endothelial dysfunction in the aorta in T2D. Heterozygous controls (m Lepr db ) and type 2 diabetic mice (db/db; Lepr db ) were either exercise entrained by forced treadmill exercise or remained sedentary for 10 wk. Ex vivo functional assessment of aortic rings showed that ET restored acetylcholine-induced endothelial-dependent vasodilation of diabetic mice. Although the protein expression of endothelial nitric oxide synthase did not increase, ET reduced both IFN-␥ and superoxide production by inhibiting gp91 phox protein levels. In addition, ET increased the expression of adiponectin (APN) and the antioxidant enzyme, SOD-1. To investigate whether these beneficial effects of ET are APN dependent, we used adiponectin knockout (APNKO) mice. Indeed, impaired endothelial-dependent vasodilation occurred in APNKO mice, suggesting that APN plays a central role in prevention of endothelial dysfunction. APNKO mice also showed increased protein expression of IFN-␥, gp91 phox , and nitrotyrosine but protein expression of SOD-1 and -3 were comparable between wild-type and APNKO. These findings in the aorta imply that APN suppresses inflammation and oxidative stress in the aorta, but not SOD-1 and -3. Thus ET improves endothelial function in the aorta in T2D via both APN-dependent and independent pathways. This improvement is due to the effects of ET in inhibiting inflammation and oxidative stress (APN-dependent) as well as in improving antioxidant enzyme (APN-independent) performance in T2D. cardiovascular disease; inflammation; superoxide; vascular biology TYPE 2 DIABETES (T2D) is associated with impairment in endothelial function characterized by impaired endothelial-dependent vasodilation, increased inflammatory cell, and platelet adhesion in both rodents and humans (22,32,41,42,54). Accumulating evidence suggests that endothelial dysfunction is an early stage of atherosclerosis (11,41). Thus endothelial dysfunction with inflammatory cell and platelet adhesion may contribute to the development of atherosclerosis in T2D. Even though the mechanisms responsible for endothelial dysfunction are not fully elucidated, previous studies indicate that a decrease in nitric oxide (NO) bioavailability may play a central role in endothelial dysfunction in T2D (32,36,54).In addition, oxidative stress and chronic inflammation are important pathogenic factors in many diseases including T2D and cardiovascular diseases (CVD) such as stroke, cor...

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Section: Methodsmentioning

confidence: 99%

Exercise training improves endothelial function via adiponectin-dependent and independent pathways in type 2 diabetic mice

Lee

Park

Dellsperger

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Thus, telmisartan might inhibit IKKb; however, it is still to be elucidated. 22 Incubation of HUVEC with TNFa significantly induced VCAM-1 gene expression. The induction of TNFa-induced VCAM-1 mRNA expression is known to be markedly suppressed by co-treatment with the NF-kB inhibitor, BAY11-7082, 15 suggesting that induction of VCAM-1 mRNA is NF-kB dependent.…”

Section: Telmisartan Inhibits Induction Of Vcam-1 Mrnamentioning

confidence: 97%

Telmisartan inhibits cytokine-induced nuclear factor-κB activation independently of the peroxisome proliferator-activated receptor-γ

et al. 2009

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Telmisartan is an angiotensin-II type 1 receptor (AT1R) blocker, currently used to treat patients with hypertension. Telmisartan, in addition to its effect on AT1R, is thought to activate the nuclear transcription factor, peroxisome proliferator-activated receptor-c (PPAR c), thereby acting as a partial PPARc agonist. This study was conducted to examine whether telmisartan might suppress cytokine-induced inflammatory signaling in vascular endothelial cells, thereby attenuating cellular inflammation possibly by PPARc activation. Telmisartan caused a dose-dependent suppression of the tumor necrosis factor-a (TNFa)-induced activation of nuclear factor (NF)-jB in vascular endothelial cells in this study. The PPARc antagonist, GW9662, did not influence the inhibitory effect of telmisartan on NF-jB activation. The thiazolidinediones neither influenced TNFa-induced NF-jB activation nor influenced the inhibitory effect of telmisartan in this process. Telmisartan dose dependently diminished the TNFa-induced gene expression of VCAM-1, and GW9662 did not attenuate this effect. Thus, telmisartan inhibits the cytokine-induced expression of the VCAM-1 gene by blocking NF-jB activation independently of PPARc activation. Although the mechanism by which this occurs remains unclear, our findings suggest that telmisartan-induced anti-inflammatory effects might have favorable effects on vasculature in hypertensive patients.

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“…A growing body of preclinical data suggests that glomerular hypertrophy appears within the period of hyperinsulinemia itself, before the onset of overt diabetes (2,9). Profibrotic TGF-␤ damages glomerular function by overproduction of interstitial tissue matrix, thickening of the glomerular basement membrane, and the down-regulation of matrix metalloproteinase (MMP)-2, an enzyme involved in matrix degradation, eventually ending in albumin leakage into the urine (10).…”

mentioning

confidence: 99%

Metformin Improves Metabolic Memory in High Fat Diet (HFD)-induced Renal Dysfunction

Tikoo

Sharma

Amara

et al. 2016

Journal of Biological Chemistry

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Feed-forward signaling of TNF-α and NF-κB via IKK-β pathway contributes to insulin resistance and coronary arteriolar dysfunction in type 2 diabetic mice

Abstract: . Feed-forward signaling of TNF-␣ and NF-B via IKK-␤ pathway contributes to insulin resistance and coronary arteriolar dysfunction in type 2 diabetic mice.

Cited by 107 publications

References 46 publications

Exercise training improves endothelial function via adiponectin-dependent and independent pathways in type 2 diabetic mice

Exercise training improves endothelial function via adiponectin-dependent and independent pathways in type 2 diabetic mice

Telmisartan inhibits cytokine-induced nuclear factor-κB activation independently of the peroxisome proliferator-activated receptor-γ

Metformin Improves Metabolic Memory in High Fat Diet (HFD)-induced Renal Dysfunction

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