Improvement of Retinal Vascular Injury in Diabetic Rats by Statins Is Associated With the Inhibition of Mitochondrial Reactive Oxygen Species Pathway Mediated by Peroxisome Proliferator–Activated Receptor γ Coactivator 1α

Zheng, Zhi; Chen, Haibing; Wang, Hongjie; Ke, Bilian; Zheng, Bo; Li, Qian; Li, Peiyu; Su, Lili; Gu, Qing; Xu, Xun

doi:10.2337/db10-0638

Cited by 67 publications

(52 citation statements)

References 39 publications

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“…Retinal vascular permeability was assessed with Evans blue using a published protocol [23,24]. Briefly, after anesthesia by intraperitoneal injection of 1% pentobarbital sodium (10 mg/kg body weight), the right jugular vein and right iliac artery were cannulated with 0.28-and 0.58-mm internal diameter polyethylene tubing, respectively, and filled with heparinized saline (400 units heparin/ml saline).…”

Section: Measurement Of Retinal Vascular Permeabilitymentioning

confidence: 99%

Curcumin Attenuates Retinal Vascular Leakage by Inhibiting Calcium/Calmodulin-Dependent Protein Kinase II Activity in Streptozotocin-Induced Diabetes

Li¹,

Wang²,

Jia³

et al. 2016

Cell Physiol Biochem

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Background: Curcumin possesses many pharmacological properties including anti-inflammatory effects. Although prior studies indicate that curcumin has beneficial effects for diabetic retinopathy, the mechanism of action is not known. To address this issue, we investigated the effect of curcumin against diabetes-induced retinal vascular damage and its mechanism of action by using cultured retinal Müller cells stimulated with high glucose. Methods: We studied the effects of curcumin in vivo in the retinas of rats rendered diabetic by streptozotocin and in vitro in Müller cells stimulated with high glucose. We administered curcumin, or KN93, an inhibitor of calcium/calmodulin dependent protein kinase II (CaMKII), or saline vehicle to experimental animals on a daily basis for 12 weeks. Primary cultures of rat Müller cells were incubated with normal glucose or high glucose, with or without curcumin, KN93, or pyrrolidine dithiocarbamate (PDTC), an inhibitor of the transcription protein nuclear factor κB (NF-κB). We examined mRNA and protein levels of vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS) and intercellular adhesion molecule-1 (ICAM-1) by real-time RT-PCR and Western blotting, respectively. Retinal levels of CaMKII and NF-κB were examined by Western blotting. Vascular leakage was evaluated using Evans blue. Results: Curcumin and KN93 significantly inhibited the activation of CaMKII/NF-κB signaling induced by diabetes or elevated glucose, and subsequently decreased the expression of VEGF, iNOS and ICAM-1. These changes were associated with a decrease of diabetes-induced retinal vascular leakage. Conclusion: Curcumin protects the diabetic rat retina against early retinal vascular damage, by inhibition of CaMKII activity. Curcumin is currently used to treat a number of clinical conditions, and may prove beneficial for the management of diabetic retinopathy.

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Section: Measurement Of Retinal Vascular Permeabilitymentioning

confidence: 99%

Curcumin Attenuates Retinal Vascular Leakage by Inhibiting Calcium/Calmodulin-Dependent Protein Kinase II Activity in Streptozotocin-Induced Diabetes

Li¹,

Wang²,

Jia³

et al. 2016

Cell Physiol Biochem

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“…3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, that have been reported to exert impressive beneficial effects, such as anti-inflammation, antioxidation, protecting against cardiovascular events and DR and anticancer efficacy via lipid-independent mechanisms (10)(11)(12) tions and markedly reduce retinal microvascular permeability through mitigation of oxidative stress and inflammatory status by downregulating reactive oxygen species (ROS) generation, VEGF and intercellular adhesion molecule (ICAM-1) expression in diabetic animals (10,11,13). Oxidative stress and elevated ROS generation have been incriminated in many pathological conditions, including diabetes and cancer (14,15).…”

Section: Introductionmentioning

confidence: 99%

Endothelial NO synthase and reactive oxygen species mediated effect of simvastatin on vessel structure and function: Pleiotropic and dose-dependent effect on tumor vascular stabilization

Chen

Zhang

Peng

et al. 2013

International Journal of Oncology

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Abstract.Statins have been confirmed with protective effect to microvessels in diabetic retinopathy, implicated as reducing vascular permeability, maintaining endothelial junction integrity and improving blood perfusion, which are surrogate markers of vascular 'normalization', but no data are currently available on efficacy of statins on tumor endothelial functions. Since statins have been shown to exhibit a biphasic dose-related response on biological behaviour of microvessels, we sought to determine whether statins with bipolar concentrations can ameliorate vessel dysfunction and then increase efficiency of chemotherapeutics in Lewis lung carcinoma and B16F10 melanoma models. Our in vitro study showed that simvastatin reduces hypoxia-induced endothelium leakage in human umbilical vein endothelial cells (HUVEC) in a concentration-dependent manner. In tumor-bearing mice, low-dose simvastatin (0.2 mg/kg) induced upregulation of endothelial NO synthase (eNOS) skewed vessels to a pericyte-coated and stable pattern, while high-dose simvastatin (10 mg/kg) remarkably deceased reactive oxygen species (ROS)-induced hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) expression, attenuating VEGF-drived tumor vessel hyperpermeability. These changes ultimately improved intratumoral perfusion and decreased tumor hypoxia. Administration of cisplatin and cyclophosphamide to the simvastatin-treated mice resulted in slower tumor growth. Collectively, simvastatin may promote tumor vessel normalization and show clinical benefit when used in combination with chemotherapeutics. IntroductionPathological angiogenesis and abnormal vessel structures and functions are common features of solid tumors and several non-malignant diseases, such as schwannomas and diabetic retinopathy (DR) (1,2). Vessels in these lesions are highly disorganized and inefficient, and lack pericytes or normal attachment between pericytes and endothelial cells (ECs) (3-5). Such abnormalities of tumor vessels in turn lead to impairment of endothelial barrier function, decreased blood flow and subsequent aggravation of hypoxia in tumor tissues, which result in a poor delivery of anticancer therapeutics and augmentation of radioresistance in tumors. Similar vessel phenotypes are shown in DR characterized by breakdown of the blood-retinal barrier (BRB) that lead to diabetic macular edema and vision loss (6).By correcting the aberrance in morphological structure and function of vessels, we could normalize the microenvironment of retina in favor of disease control and improve response to other therapies (7,8). The strategies for vascular normalization are likely multifaceted. Substantial evidence indicates that anti-angiogenic treatment could achieve this goal by pharmacological inhibition of vascular endothelial growth factor (VEGF) signaling and it has become a widely accepted treatment for several diseases where neovascularization and permeability plays a pivotal role, including cancer and retinal disorders (8,9). Bevacizumab, a humanized...

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“…9,10 Tyrosine nitration of PGIS and associated thromboxane receptor activation are important contributors to the initiation and progression of vascular complications in diabetes. 11 Although there is evidence that the risk of diabetic retinopathy is associated with the presence of both oxidative stress and toxic eicosanoids, 6,12 the role of ONOO Ϫ and nitration of PGIS in the pathogenesis of diabetic retinopathy remains to be determined. In this study, we investigated the mechanisms by which LDL oxidation and glycation contribute to pericyte loss in diabetes.…”

mentioning

confidence: 99%

“…This proposed relationship is supported by the findings that oxidative stress is increased in the retinas of diabetic animals, and antioxidants inhibit the development of retinopathy in diabetic animals. 6 Many proteins are likely affected by increased oxidative stress. We have found 7,8 that prostacyclin synthase (PGIS), an enzyme that releases vasoprotective prostacyclin (PGI 2 ), is particularly susceptible to tyrosine nitration by RNS, including peroxynitrite (ONOO Ϫ ).…”

mentioning

confidence: 99%

Tyrosine Nitration of Prostacyclin Synthase Is Associated with Enhanced Retinal Cell Apoptosis in Diabetes

Zou

et al. 2011

The American Journal of Pathology

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The risk of diabetic retinopathy is associated with the presence of both oxidative stress and toxic eicosanoids. Whether oxidative stress actually causes diabetic retinopathy via the generation of toxic eicosanoids, however, remains unknown. The aim of the present study was to determine whether tyrosine nitration of prostacyclin synthase (PGIS) contributes to retinal cell death in vitro and in vivo. Exposure of human retinal pericytes to heavily oxidized and glycated LDL (HOG-LDL), but not native forms of LDL (N-LDL), for 24 hours significantly increased pericyte apoptosis, accompanied by increased tyrosine nitration of PGIS and decreased PGIS activity. Inhibition of the thromboxane receptor or cyclooxygenase-2 dramatically attenuated HOG-LDL-induced apoptosis without restoring PGIS activity. Administration of superoxide dismutase (to scavenge superoxide anions) or L-N G -nitroarginine methyl ester (L-NAME, a nonselective nitric oxide synthase inhibitor) restored PGIS activity and attenuated pericyte apoptosis. In Akita mouse retinas, diabetes increased intraretinal levels of oxidized LDL and glycated LDL, induced PGIS nitration, enhanced apoptotic cell death, and impaired blood-retinal barrier function. Chronic administration of tempol, a superoxide scavenger, reduced intraretinal oxidized LDL and glycated LDL levels, PGIS nitration, and retina cell apoptosis, thereby preserving the integrity of blood-retinal barriers. In conclusion, oxidized LDL-mediated PGIS nitration and associated thromboxane receptor stimulation might be important in the initiation and progression of dia- Loss of pericytes from retinal microvessels is an important event in the early stage of diabetic retinopathy, which is associated with increased pericyte apoptosis. Although the mechanisms responsible for pericyte apoptosis remain unclear, several studies have shown associations between dyslipidemia and the severity of diabetic retinopathy.1,2 Specifically, elevated levels of triglycerides, low density lipoprotein (LDL), and apolipoprotein B, a principal lipoprotein component of LDL, have been associated with diabetic retinopathy.1 However, these associations are relatively weak, leading us to hypothesize that the key contribution of lipoproteins to the propagation of diabetic retinopathy is not through changes in their plasma levels but, rather, through extravasation via a disrupted blood-retinal barrier and subsequent modification by glycation and oxidation. In support of this model, we have demonstrated that oxidized LDL is present in the retina in diabetic humans in proportion to the severity of diabetic retinopathy, 3 and in cell culture studies we have shown that oxidized LDL has injurious effects on retinal pericytes. 4,5

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Improvement of Retinal Vascular Injury in Diabetic Rats by Statins Is Associated With the Inhibition of Mitochondrial Reactive Oxygen Species Pathway Mediated by Peroxisome Proliferator–Activated Receptor γ Coactivator 1α

Cited by 67 publications

References 39 publications

Curcumin Attenuates Retinal Vascular Leakage by Inhibiting Calcium/Calmodulin-Dependent Protein Kinase II Activity in Streptozotocin-Induced Diabetes

Curcumin Attenuates Retinal Vascular Leakage by Inhibiting Calcium/Calmodulin-Dependent Protein Kinase II Activity in Streptozotocin-Induced Diabetes

Endothelial NO synthase and reactive oxygen species mediated effect of simvastatin on vessel structure and function: Pleiotropic and dose-dependent effect on tumor vascular stabilization

Tyrosine Nitration of Prostacyclin Synthase Is Associated with Enhanced Retinal Cell Apoptosis in Diabetes

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