Elevated Epidermal Growth Factor Receptor Phosphorylation Induces Resistance Artery Dysfunction in Diabetic <i>db/db</i> Mice

Belmadani, Souâd; Palen, Desiree I; González-Villalobos, Romer A.; Boulares, Hamid; Matrougui, Khalid

doi:10.2337/db07-0739

Cited by 98 publications

(107 citation statements)

References 36 publications

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“…In a recent study, using telemetry, we have shown that db/db mice are normotensive. 38 Blood pressure was normal and similar in all groups indicating that type 2 diabetic mice are not hypertensive. Our data are not in agreement with the Bagi et al study showing an increase of systolic blood pressure in diabetic mice.…”

Section: Discussionmentioning

confidence: 89%

Role of Advanced Glycation End Products With Oxidative Stress in Resistance Artery Dysfunction in Type 2 Diabetic Mice

Lucchesi

González-Villalobos

et al. 2008

ATVB

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Objective-Type 2 diabetes is associated with increased advanced glycation end product (AGE) formation and vasculopathy.We hypothesized that AGEs contribute to resistance artery dysfunction. Methods and Results-Type 2 diabetic dbϪ /db Ϫ (diabetic) and nondiabetic db Ϫ /db ϩ (control) mice were treated with the AGE inhibitor (aminoguanidine: 50 mg/Kg/d) for 3 months. Isolated mesenteric resistance arteries (MRAs) were mounted in an arteriograph. Pressure-induced myogenic tone (MT) was increased in diabetic mice but was unaffected by aminoguanidine treatment. Phenylephrine-induced contraction and nitric oxide donor-induced endotheliumindependent relaxation were similar in all groups. In diabetic mice, endothelium-dependent relaxation in response to shear-stress or acetylcholine was altered and was associated with reduced eNOS protein and mRNA expression. Aminoguanidine treatment improved endothelial function and restored eNOS expression. AGE formation and hypoxia markers (plasminogen activator inhibitor 1 and Bnip3) were increased in MRA from diabetic mice and normalized with Aminoguanidine. Primary cultured endothelial cells (ECs) isolated from resistance arteries subjected to high glucose for 48 hours showed decreased eNOS expression and phosphorylation in response to calcium ionophore. High glucose decreased antioxidant protein (MnSOD) and increased prooxidant proteins (gp91phox) expression leading to increased oxidative stress generation, as assessed by DHE staining and endothelial NADH/NADPH oxidase activity. The preincubation of ECs with aminoguanidine restored eNOS-phosphorylation and expression as well as the balance between pro-and antioxidant factors induced by high glucose. Conclusions-We provide evidence of a link between AGEs, oxidative stress, and resistance artery EC dysfunction in type 2 diabetic mice. Thus, AGEs and oxidative stress may be a potential target for overcoming diabetic microvessels complications. (Arterioscler Thromb Vasc Biol. 2008;28:1432-1438) Key Words: resistance artery Ⅲ oxidative stress Ⅲ AGEs Ⅲ type 2 diabetic mice R esistance arteries are exposed to hemodynamic forces, including pressure and shear stress. Endothelial cells (ECs) have been proposed to be the primary sensors of wall shear stress for the transduction of mechanical stimuli into biological responses. 1 Resistance arteries play a crucial role in blood pressure control, tissue perfusion, and metabolism because they are prime determinants of local blood flow to subsequent tissue perfusion. Resistance artery tone is mainly regulated by mechanical factors (pressure and flow; mechanotransduction) and vasoactive agents. 2 The control of resistance artery tone is dependent on a complex interplay between ECs and vascular smooth muscle cells (VSMCs). In general, flow induces endothelium-dependent vasodilation via release of nitric oxide (NO), prostacylin I2, and endothelium-derived hyperpolarizing factor from ECs. 3 On the other hand, pressure-induced contraction (myogenic tone [MT]) is endothelium-independent and is media...

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Section: Discussionmentioning

confidence: 89%

Role of Advanced Glycation End Products With Oxidative Stress in Resistance Artery Dysfunction in Type 2 Diabetic Mice

Lucchesi

González-Villalobos

et al. 2008

ATVB

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“…Administration of AG1478 increased the rate of nerve damage from 40% to 80% at 10.5 mo. Although AG1478 is an effective EGFR inhibitor in vivo (78,79), as with many kinase inhibitors, off-target and systemic effects are possible. AG1478 is less effective in inhibiting other inflammation-related kinases (80).…”

Section: Discussionmentioning

confidence: 99%

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Harder

Braine

Williams

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

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Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wld s allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wld s mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J.Wld s mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/ 2J.Wld s mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.G laucoma is a common disorder characterized by the loss of retinal ganglion cells (RGCs) and degeneration of the optic nerve (1-3). Intraocular pressure (IOP) elevation is a major risk factor for developing glaucoma (4). Harmful IOP leads to changes in immune response pathways in nonneuronal cells, such as astrocytes and microglia/monocytes (5-9). Similar changes occur in many neurodegenerative diseases, including Parkinson's disease (10), Alzheimer's disease (11), and Huntington's disease (12). In glaucoma, immune responses are known to occur at predegenerative stages (5, 8), but key questions remain unanswered (2, 13-15). It is not known whether the earliest immune responses are protective or damaging, or which events irreversibly damage the optic nerve. Moreover, it is not known whether the immune responses are secondary to RGC dysfunction or occur independently, possibly as a more direct result of IOP elevation.In glaucoma, an early insult to RGC axons occurs where they exit the eye in the optic nerve head (ONH) (16)(17)(18)(19)(20). Modeling shows that an increase in IOP inside the eye leads to increased strain in this critical region (21,22). To understand the molecular responses occurring during glaucoma, gene expression profiles of human lamina astrocytes and ONH tissue from animal models hav...

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“…The vessels were pressurized to 50 mmHg using pressureservo control perfusion system (Living Systems Instruments, St. Albans, VT) for a 40-min equilibration period. The vessel diameter was monitored by a video image analyzer as previously described (9,12).…”

Section: General Protocol In Micementioning

confidence: 99%

Enhanced p22^phoxexpression impairs vascular function through p38 and ERK1/2 MAP kinase-dependent mechanisms in type 2 diabetic mice

Kassan

Choi

Galán

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Type 2 diabetes is associated with vascular complication. We hypothesized that increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p22 phox expression impairs vascular endothelium-dependent relaxation (EDR) in type 2 diabetes. Type 2 diabetic (db Ϫ /db Ϫ ) and control (db Ϫ /db ϩ ) mice were treated with reactive oxygen species (ROS) scavenger, polyethylene glycol superoxide dismutase (1,000 U/kg daily ip), or small interfering RNA p22 phox (p22 phox -lentivirus-small interfering RNA, 100 g iv, 2 times/ wk) for 1 mo. EDR was impaired in microvascular bed (coronary arteriole and femoral and mesenteric resistance arteries) from diabetic mice compared with control. Interestingly, ROS scavenger and p22 phox downregulation did not affect blood glucose level or body weight but significantly improved EDR. Mitogen-activated protein kinases (ERK1/2 and p38) phosphorylation and NADPH oxidase activity were increased in arteries from diabetic mice and were reduced after ROS scavenger or p22 phox downregulation in db Ϫ /db Ϫ

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Elevated Epidermal Growth Factor Receptor Phosphorylation Induces Resistance Artery Dysfunction in Diabetic db/db Mice

Cited by 98 publications

References 36 publications

Role of Advanced Glycation End Products With Oxidative Stress in Resistance Artery Dysfunction in Type 2 Diabetic Mice

Role of Advanced Glycation End Products With Oxidative Stress in Resistance Artery Dysfunction in Type 2 Diabetic Mice

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Enhanced p22^phoxexpression impairs vascular function through p38 and ERK1/2 MAP kinase-dependent mechanisms in type 2 diabetic mice

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Elevated Epidermal Growth Factor Receptor Phosphorylation Induces Resistance Artery Dysfunction in Diabetic db/db Mice

Cited by 98 publications

References 36 publications

Role of Advanced Glycation End Products With Oxidative Stress in Resistance Artery Dysfunction in Type 2 Diabetic Mice

Role of Advanced Glycation End Products With Oxidative Stress in Resistance Artery Dysfunction in Type 2 Diabetic Mice

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Enhanced p22phoxexpression impairs vascular function through p38 and ERK1/2 MAP kinase-dependent mechanisms in type 2 diabetic mice

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Enhanced p22^phoxexpression impairs vascular function through p38 and ERK1/2 MAP kinase-dependent mechanisms in type 2 diabetic mice