Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.3.1 (NADPH oxidase)
 11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously determined that augmented EGFR tyrosine kinase (EGFRtk) impairs vascular function in type 2 diabetic mouse (TD2). Here we determined that EGFRtk causes vascular dysfunction through NADPH oxidase activity in TD2. Mesenteric resistance arteries (MRA) from C57/BL6 and db-/db- mice were mounted in a wired myograph and pre-incubated for 1h with either EGFRtk inhibitor (AG1478) or exogenous EGF. The inhibition of EGFRtk did not affect the contractile response to phenylephrine-(PE) and thromboxane-(U46619) or endothelium-dependent relaxation (EDR) to acetylcholine in MRA from control group. However, in TD2 mice, AG1478 reduced the contractile response to U46619, improved vasodilatation and reduced p22phox-NADPH expression, but had no effect on the contractile response to PE. The incubation of MRA with exogenous EGF potentiated the contractile response to PE in MRA from control and diabetic mice. However, EGF impaired the EDR and potentiated the vasoconstriction to U46619 only in the control group. Interestingly, NADPH oxidase inhibition in the presence of EGF restored the normal contraction to PE and improved the EDR but had no effect on the potentiated contraction to U46619. Vascular function improvement was associated with the rescue of eNOS and Akt and reduction in phosphorylated Rho-kinase, NOX4 mRNA levels, and NADPH oxidase activity. MRA from p47phox-/- mice incubated with EGF potentiated the contraction to U46619 but had no effect to PE or ACh responses. The present study provides evidence that augmented EGFRtk impairs vascular function by NADPH oxidase-dependent mechanism. Therefore, EGFRtk and oxidative stress should be potential targets to treat vascular dysfunction in TD2.
 ...
PMID:Augmented EGF receptor tyrosine kinase activity impairs vascular function by NADPH oxidase-dependent mechanism in type 2 diabetic mouse. 2603 45

Endothelial cells covering the luminal surface of all blood vessels have a pivotal role in the control of vascular homeostasis mostly via the activation of protective mechanisms. These mechanisms include the endothelial formation of nitric oxide (NO) in response to the activation of endothelial NO synthase, endothelium-dependent hyperpolarization involving endothelial SKCa and IKCa, which is subsequently transmitted to the underlying vascular smooth muscle via myoendothelial junctions, and in some blood vessels, also prostacyclin. These endothelial protective mechanisms will promote vasodilatation, inhibit platelet activation, and also prevent the expression of pro-atherothrombotic factors. In most types of cardiovascular diseases including type 1 and 2 diabetes (T2D), an endothelial dysfunction as indicated by blunted endothelium-dependent vasorelaxations and often also by the appearance of endothelium-dependent cyclooxygenase-mediated contractile responses is observed early in the development of the pathology and has been suggested to contribute to the development of both macro-vascular and micro-vascular complications in T2D. The impaired endothelium-dependent relaxations in T2D has indicated the involvement of reduced NO and endothelium-dependent hyperpolarization components and is associated with increased oxidative stress in the arterial wall involving superoxide anion and hydrogen peroxide predominantly due to an up-regulation of NADPH oxidase and possibly also uncoupling of endothelial NO synthase. Investigations in experimental animals and humans have also suggested that the angiotensin system contributes to the impaired endothelial function in T2D. Several sources of polyphenols (i.e., cocoa and plant extracts) have been shown to retard the induction of endothelial dysfunction in TD2 in part by preventing oxidative stress in the arterial wall most likely by normalizing the expression of NADPH oxidase, cyclooxygenase-1 and 2, eNOS uncoupling, and the angiotensin system. Both pre-clinical and clinical data will be presented and discussed. In addition, polyphenols may possibly also improve the endothelial function by preventing the induction of endothelial senescence to high glucose and angiotensin II. Thus, polyphenols by improving the endothelial dysfunction might help to retard the development of both macro- and micro-vascular complications in diabetes.
...
PMID:Role of polyphenols in improving endothelial dysfunction in diabetes. 2646 Dec 84