Molecular Insights and Therapeutic Targets for Diabetic Endothelial Dysfunction

Xu, Jian; Zou, Ming‐Hui

doi:10.1161/circulationaha.108.835223

Cited by 299 publications

(284 citation statements)

References 249 publications

(242 reference statements)

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“…Accordingly, NO production was also increased by palmitate and so was the release of ROS. Notably, a number of studies have demonstrated that NO release is increased under diabetic conditions (Xu & Zou 2009). It was recently shown that palmitate stimulates ROS production in aortic endothelial cells through PKCdependent activation (Inoguchi et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Erdogdu

Eriksson

et al. 2013

Journal of Molecular Endocrinology

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Experimental studies have indicated that endothelial cells play an important role in maintaining vascular homeostasis. We previously reported that human coronary artery endothelial cells (HCAECs) express the glucagon-like peptide 1 (GLP1) receptor and that the stable GLP1 mimetic exendin-4 is able to activate the receptor, leading to increased cell proliferation. Here, we have studied the effect of exendin-4 and native GLP1 (7-36) on lipoapoptosis and its underlying mechanisms in HCAECs. Apoptosis was assessed by DNA fragmentation and caspase-3 activation, after incubating cells with palmitate. Nitric oxide (NO) and reactive oxidative species (ROS) were analyzed. GLP1 receptor activation, PKA-, PI3K/Akt-, eNOS-, p38 MAPK-, and JNK-dependent pathways, and genetic silencing of transfection of eNOS were also studied. Palmitate-induced apoptosis stimulated cells to release NO and ROS, concomitant with upregulation of eNOS, which required activation of p38 MAPK and JNK. Exendin-4 restored the imbalance between NO and ROS production in which ROS production decreased and NO production was further augmented. Incubation with exendin-4 and GLP1 (7-36) protected HCAECs against lipoapoptosis, an effect that was blocked by PKA, PI3K/Akt, eNOS, p38 MAPK, and JNK inhibitors. Genetic silencing of eNOS also abolished the anti-apoptotic effect afforded by exendin-4. Our results support the notion that GLP1 receptor agonists restore eNOS-induced ROS production due to lipotoxicity and that such agonists protect against lipoapoptosis through PKA-PI3K/Akt-eNOS-p38 MAPK-JNK-dependent pathways via a GLP1 receptor-dependent mechanism.

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Section: Discussionmentioning

confidence: 99%

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Erdogdu

Eriksson

et al. 2013

Journal of Molecular Endocrinology

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“…Although many diseases [1][2][3][4][5][6][7][8] involve endothelial damage in pathophysiological features, and new treatments of such diseases are already targeted at the endothelial repair, little is known about how the damaged endothelium is reconstructed at the cellular level. To our knowledge, this is the first study to clearly demonstrate that resident ECs adjacent to the lesion mostly, if not exclusively, restore the endothelium by elongation, migration, and proliferation.…”

Section: Discussionmentioning

confidence: 99%

Resident Endothelial Cells Surrounding Damaged Arterial Endothelium Reendothelialize the Lesion

Itoh

Toriumi

Yamada

et al. 2010

ATVB

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Objective-To evaluate endothelial repair processes in denuded pial vessels to clarify mechanisms for reconstructing endothelium (because endothelial repair of the cerebral artery after its damage is critical for the prevention of thrombosis, the maintenance of vascular tone, and the protection of the brain by the blood-brain barrier). Methods and Results-Endothelial cells (ECs) in a 350-m-long segment of the middle cerebral artery were damaged through a photochemical reaction. Tie2-green fluorescent protein transgenic mice were used for the identification of ECs. Six hours after the endothelial damage, ECs were detached from the luminal surface of the damaged artery, which was then covered with a platelet carpet. Within 24 hours, recovery of the denuded artery started at both edges, with EC elongation and migration. The repair rate was faster at the proximal edge than at the distal edge. Reendothelialization with EC proliferation peaked at 2 to 3 days and ended at 5 days, together with normalization of EC length, with no apparent involvement of foreign progenitor cells. Conclusion-Our in vivo study demonstrated a stepwise reendothelialization process by resident ECs of the pial artery.The prevention of thrombosis, vasospasm, and treatment for blood-brain barrier dysfunction should be considered during the reendothelialization period. Key Words: Tie2 Ⅲ reendothelialization Ⅲ pial artery Ⅲ confocal laser microscopy Ⅲ photochemical reaction B ecause endothelial damage and subsequent exposure of subendothelial tissue in the cerebral artery quickly induces a luminal thrombus and disturbs cerebral blood flow, urgent endothelial repair is critical to minimize ischemic damage, especially after rupture of an atherosclerotic plaque, commonly observed at the carotid artery and the intracranial cerebral arteries. Reendothelialization is also essential to recover normal vascular tone controlled by vasodilatory mediators, such as nitric oxide released from the endothelium. Furthermore, loss of the endothelial tight junction results in breakdown of the blood-brain barrier, causing vasogenic edema. Therefore, restoration of endothelial function in the cerebral vessel is an urgent process for the brain.Endothelial damage of the cerebral artery is a key mechanism involved in the pathophysiology of various brain diseases, including stroke, atherosclerosis, 1 diabetes mellitus, 2 dyslipidemia, 3 hypertension, 4 vasculitis, 5 multiple sclerosis, 6 radiation necrosis, 7 and drug adverse effects. 8 Some markers of endothelial damage are good indicators for the future incidence of cardiovascular events, including stroke. 9 Carotid endarterectomy, a treatment for carotid stenosis, removes atheroma and endothelial cells (ECs), exposing subendothelial tissue. 10 In these conditions, endothelial repair is one of the major targets of treatment.Histological evaluation of reendothelialization and neointima formation after mechanical carotid denudation was previously reported. 11-13 However, the dynamic and minute process of endothelial repair...

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“…There is compelling evidence that endothelial dysfunction serves as a key event in the development and progression of diabetic vascular complications, including nephropathy [4][5][6]. Endothelial cells maintain vascular function and homeostasis by generating paracrine factors that regulate vascular tone, preventing coagulation and platelet aggregation, inhibiting adhesion of leukocytes, and limiting proliferation of vascular smooth muscle cells as well as by constituting a selective barrier to the diffusion of macromolecules into the interstitial space.…”

Section: An Epidemic Of Diabetic Nephropathymentioning

confidence: 99%

“…fibrinolytic properties [10]. Endothelium is a multifunctional organ and it control the release of endothelium derived relaxing factors (EDRF), endothelium derived contracting factors (EDCF), endothelium derived hyperpolarizing factors (EDHF) [11,12] inflammatory mediators such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), nuclear factor kappa-B (NF-kB) and various growth factors like vascular endothelial growth factors (VEGF) and transforming growth factor-β (TGF-β) [4,11]. …”

Section: The Endotheliummentioning

confidence: 99%

Association of HLA Class I and II Antigens with Vitiligo in Egyptian Population

Elgendy¹,

Alshawadfy²,

Ali³

et al. 2016

Mol Enzyme Drug Targ

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Endothelial dysfunction is regarded as an important factor in the pathogenesis of diabetes. Endothelial dysfunction has been posited to play an important role in the pathogenesis of diabetic nephropathy (DN).The vascular complications of diabetes impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Both hyperglycemia, as well as the metabolic consequences of glucose dysregulation, are thought to lead to endothelial cell dysfunction. In this regard, endothelial nitric oxide synthase (eNOS) plays a central role in dysfunction. This review will focus on the mechanisms and therapeutics that specifically target endothelial dysfunction in the context of a diabetic setting.

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Molecular Insights and Therapeutic Targets for Diabetic Endothelial Dysfunction

Cited by 299 publications

References 249 publications

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Resident Endothelial Cells Surrounding Damaged Arterial Endothelium Reendothelialize the Lesion

Association of HLA Class I and II Antigens with Vitiligo in Egyptian Population

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