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Type-2 diabetes-induced changes in vascular extracellular matrix gene expression: Relation to vessel size
WeiWei Song, Adviye Ergul
Cardiovascular Diabetology , 2006, DOI: 10.1186/1475-2840-5-3
Abstract: Aorta and mesenteric artery samples were isolated from control, Type 2 diabetic Goto-Kakizaki (GK) rats and GK rats treated with ETA antagonist ABT-627. Gene expression profile of MMP-2, MMP-9, MT1-MMP, fibronectin, procollagen type 1, c-fos and c-jun, were determined by quantitative real-time (qRT) PCR. In addition, aortic gene expression profile was evaluated by an ECM & Adhesion Molecules pathway specific microarray approach.Analysis of the qRT-PCR data demonstrated a significant increase in mRNA levels of MMPs and ECM proteins as compared to control animals after 6 weeks of mild diabetes. Futhermore, these changes were comparable in aorta and mesentery samples. In contrast, treatment with ETA antagonist prevented diabetes-induced changes in expression of MMPs and procollagen type 1 in mesenteric arteries but not in aorta. Microaarray analysis provided evidence that 27 extracellular matrix genes were differentially regulated in diabetes. Further qRT-PCR with selected 7 genes confirmed the microarray data.These results suggest that the expression of both matrix scaffold protein and matrix degrading MMP genes are altered in macro and microvascular beds in Type 2 diabetes. ETA antagonism restores the changes in gene expression in the mesenteric bed but not in aorta suggesting that ET-1 differentially regulates microvascular gene expression in Type 2 diabetes.Changes in vascular wall structure occur in diabetes and contribute to both micro- and macrovascular complications. Previous studies in streptozosin (STZ)-induced model of Type 1 diabetes documented increased intimal proliferation and medial thickness as well as extracellular matrix (ECM) deposition in microvessels such as mesenteric arteries as early as 3 weeks of experimental diabetes [1-4]. Vascular remodeling and hypertrophy associated with augmented expression of dedifferentiation markers of vascular smooth muscle cells also occur in larger vessels like aorta [5]. While these studies provided evidence for d
Oxidative stress and the use of antioxidants in diabetes: Linking basic science to clinical practice
Jeanette Johansen, Alex K Harris, David J Rychly, Adviye Ergul
Cardiovascular Diabetology , 2005, DOI: 10.1186/1475-2840-4-5
Abstract: It is a well-established fact that diabetes is a risk factor for cardiovascular disease [1,2]. While microvascular complications of diabetes include nephropathy and retinopathy, macrovascular complications resulting in atherosclerotic cardiovascular disease such as coronary artery disease, cerebrovascular disease and peripheral vascular disease are the leading cause of death in the diabetic population [3,4]. The Diabetes Control and Complications trial (DCCT) demonstrated that tight control of blood glucose is effective in reducing clinical complications significantly, but even optimal control of blood glucose could not prevent complications suggesting that alternative treatment strategies are needed [4]. Since numerous studies demonstrated that oxidative stress, mediated mainly by hyperglycemia-induced generation of free radicals, contributes to the development and progression of diabetes and related contributions, it became clear that ameliorating oxidative stress through treatment with antioxidants might be an effective strategy for reducing diabetic complications. To this end, several clinical trials investigated the effect of the antioxidant vitamin E on the prevention of diabetic complications. However, these trials failed to demonstrate relevant clinical benefits of this antioxidant on cardiovascular disease [5-7]. The negative results of the clinical trials with antioxidants prompted new studies focusing on the mechanisms of oxidative stress in diabetes in order to develop causal antioxidant therapy. In this article, sources of free radicals contributing to oxidative stress and the natural defense mechanisms in diabetes are briefly reviewed. Experimental and clinical evidence with respect to the use of conventional antioxidants in diabetes is summarized and causal therapy approaches with novel antioxidants are discussed.Oxidative stress is defined in general as excess formation and/or insufficient removal of highly reactive molecules such as reactive oxygen
Cerebral Neovascularization and Remodeling Patterns in Two Different Models of Type 2 Diabetes
Roshini Prakash, Maribeth Johnson, Susan C. Fagan, Adviye Ergul
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0056264
Abstract: We previously reported intense pial cerebral collateralization and arteriogenesis in a mild and lean model of type 2 diabetes (T2D), Goto-Kakizaki (GK) rats. Increased cerebral neovascularization differed regionally and was associated with poor vessel wall maturity. Building upon these findings, the goals of this study were to determine whether a) glycemic control prevents this erratic cerebral neovascularization in the GK model, and b) this pathological neovascularization pattern occurs in Leprdb/db model, which is the most commonly used model of T2D for studies involving cerebral complications of diabetes. Vascular volume, surface area and structural parameters including microvessel/macrovessel ratio, non-FITC (fluorescein) perfusing vessel abundance, vessel tortuosity, and branch density were measured by 3D reconstruction of FITC stained vasculature in GK rats or Leprdb/db mice. GK rats exhibited an increase in all of these parameters, which were prevented by glycemic control with metformin. In Leprdb/db mice, microvascular density was increased but there was no change in nonFITC-perfusing vessels. Increased PA branch density was associated with reduced branch diameter. These results suggest that T2D leads to cerebral neovascularization and remodeling but some structural characteristics of newly formed vessels differ between these models of T2D. The prevention of dysfunctional cerebral neovascularization by early glucose control suggests that hyperglycemia is a mediator of this response.
Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke
Livia S Machado, Anna Kozak, Adviye Ergul, David C Hess, Cesario V Borlongan, Susan C Fagan
BMC Neuroscience , 2006, DOI: 10.1186/1471-2202-7-56
Abstract: Both MMP-2 and MMP-9 were elevated in the ischemic tissue as compared to the contra-lateral hemisphere after 3 hours occlusion and 21 hours survival (p < 0.0001 for MMP-9). Intraperitoneal minocycline at 45 mg/kg concentration twice a day (first dose immediately after the onset of reperfusion) significantly reduced gelatinolytic activity of ischemia-elevated MMP-2 and MMP-9 (p < 0.0003). Treatment also reduced protein concentration of both enzymes (p < 0.038 for MMP-9 and p < 0.018 for MMP-2). In vitro incubation of minocycline in concentrations as low as 0.1 μg/ml with recombinant MMP-2 and MMP-9 impaired enzymatic activity and MMP-9 was more sensitive at lower minocycline concentrations (p < 0.05).Minocycline inhibits enzymatic activity of gelatin proteases activated by ischemia after experimental stroke and is likely to be selective for MMP-9 at low doses. Minocycline is a potential new therapeutic agent to acute treatment of ischemic stroke.Matrix metalloproteases (MMPs) are a family of zinc dependent proteases responsible for the extracellular matrix turnover and degradation of bioactive proteins. In cerebral ischemia, MMPs 2 and 9, also designated as gelatinases A (72 kDa) and B (92 kDa) have been identified to mediate the degradation of the basal lamina [1,2] and hemorrhagic transformation [3]. MMPs 2 and 9 have been shown to be elevated a few hours after ischemia [4] and to maintain increased activity for days after the onset [2,5]. The inhibition of these enzymes by specific class inhibitors reverts breakdown of laminin [6] and prevents increased barrier permeability, edema, and hemorrhage after ischemic stroke [7-9]. The development of MMP inhibitors as therapeutic agents has been limited by their poor solubility.Minocycline is a commonly used semi-synthetic tetracycline with anti-inflammatory and anti-apoptotic properties [10,11]. Minocycline interferes with MMP activity [12,13] and has been shown to be neuroprotective in cerebral ischemia [14] and in oth
Effect of neutrophil depletion on gelatinase expression, edema formation and hemorrhagic transformation after focal ischemic stroke
Alex K Harris, Adviye Ergul, Anna Kozak, Livia S Machado, Maribeth H Johnson, Susan C Fagan
BMC Neuroscience , 2005, DOI: 10.1186/1471-2202-6-49
Abstract: Anti-PMN treatment caused successful depletion of neutrophils in treated animals. There was no difference in either infarct volume or hemorrhage between control and PMN depleted animals. While there were significant increases in gelatinase (MMP-2 and MMP-9) expression and activity and edema formation associated with ischemia, neutrophil depletion failed to cause any change.The main finding of this study is that, in the absence of circulating neutrophils, MMP-2 and MMP-9 expression and activity are still up-regulated following focal cerebral ischemia. Additionally, neutrophil depletion had no influence on indicators of ischemic brain damage including edema, hemorrhage, and infarct size. These findings indicate that, at least acutely, neutrophils are not a significant contributor of gelatinase activity associated with acute neurovascular damage after stroke.The matrix metalloproteinases (MMPs) are a family of some 23 zinc dependent proteases that, collectively, possess the ability to degrade nearly every component of the extra-cellular matrix [1-3]. The activity of the MMPs is tightly controlled through proteolytic activation of the zymogen forms and stoichiometric binding of tissue inhibitors of metalloproteinases (TIMPs). The MMPs play an important role in many physiological processes due to their inherent ability to remodel tissues [2,3]. However, in disease states such as vascular disease and stroke, the MMPs may become deleterious due to dysregulation and can result in tissue injury and inflammation. Specifically, the MMPs may be involved in the degradation of the basal lamina in reperfusion injury resulting in disruption of the blood brain barrier and hemorrhagic transformation [4].Recently, several lines of evidence have demonstrated the involvement of the MMPs in cerebral ischemia. Studies in rat, mouse, and baboon models have shown that MMP-9 is up-regulated following transient focal ischemia [5-8]. Additionally, Asahi et al. have shown that MMP-9 knockout as
Vascular Protection by Angiotensin Receptor Antagonism Involves Differential VEGF Expression in Both Hemispheres after Experimental Stroke
Weihua Guan, Payaningal R. Somanath, Anna Kozak, Anna Goc, Azza B. El-Remessy, Adviye Ergul, Maribeth H. Johnson, Ahmed Alhusban, Sahar Soliman, Susan C. Fagan
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024551
Abstract: We identified that the angiotensin receptor antagonist, candesartan, has profound neurovascular protective properties when administered after ischemic stroke and was associated with a proangiogenic state at least partly explained by vascular endothelial growth factor A (VEGFA). However, the spatial distribution of vascular endothelial growth factor (VEGF) isoforms and their receptors remained unknown. Protein analysis identified a significant increase in vascular endothelial grow factor B (VEGFB) in the cerebrospinal fluid (CSF) and the ischemic hemispheres (with increased VEGF receptor 1 activation) of treated animals (p<0.05) which was co-occurring with an increase in protein kinase B (Akt) phosphorylation (p<0.05). An increase in VEGFA protein in the contralesional hemisphere corresponded to a significant increase in vascular density at seven days (p<0.01) after stroke onset. Vascular restoration by candesartan after stroke maybe related to differential regional upregulation of VEGFB and VEGFA, promoting a “prosurvival state” in the ischemic hemisphere and angiogenesis in the contralesional side, respectively. These vascular changes in both hemispheres after effective treatment are likely to contribute to enhanced recovery after stroke.
Sex-independent neuroprotection with minocycline after experimental thromboembolic stroke
Md Nasrul Hoda, Weiguo Li, Ajmal Ahmad, Safia Ogbi, Marina A Zemskova, Maribeth H Johnson, Adviye Ergul, William D Hill, David C Hess, Irina Y Sazonova
Experimental & Translational Stroke Medicine , 2011, DOI: 10.1186/2040-7378-3-16
Abstract: Five groups of mice were subjected to thromboembolic stroke: adult males, aged males, adult females, aged females, and adult ovariectomized females. They were treated with phosphate saline (vehicle) or minocycline (6 mg/kg) immediately after stroke onset. Behavioral outcomes, infarct volumes and cerebral blood flow were assessed. The effect of minocycline on expression and activity of MMP-9 was analyzed.The model resulted in reproducible infarct in the experimental groups. As expected, adult females were significantly more resistant to cerebral ischemic injury than males. This advantage was abolished by aging and ovariectomy. Minocycline significantly reduced the infarct volume (P < 0.0001) and also improved neurologic score (P < 0.0001) in all groups. Moreover, minocycline treatment significantly reduced mortality at 24 hours post stroke (P = 0.037) for aged mice (25% versus 54%). Stroke up-regulated MMP-9 level in the brain, and acute minocycline treatment reduced its expression in both genders (P < 0.0001).In a thromboembolic stroke model minocycline is neuroprotective irrespective of mouse sex and age.Interest in sex differences during acute stroke is an area of growing interest. A consistent finding in rodent models of cerebral ischemia is that young females have smaller infarct sizes and better outcomes than young male rodents [1]. This female protection is lost after ovariectomy. However, the sex difference in stroke is only present when the brain is reperfused; in permanent occlusion the sex difference vanishes [2]. Moreover, in older rodents, the sex difference seen in younger animals is lost [3]. Reproductively senescent older female and male mice have similar infarct sizes after 2 hours of ischemia and 22 hours of reperfusion [4].The effect of sex on stroke outcome may also be hormone independent [3]. Recent studies suggest the existence of sex-divergent cell death pathways operating during cerebral ischemia [5]. The neuronal nitric oxide (NO)/Poly ADP ri
Increased hemorrhagic transformation and altered infarct size and localization after experimental stroke in a rat model type 2 diabetes
Adviye Ergul, Mostafa M Elgebaly, Mary-Louise Middlemore, Weiguo Li, Hazem Elewa, Jeffrey A Switzer, Christiana Hall, Anna Kozak, Susan C Fagan
BMC Neurology , 2007, DOI: 10.1186/1471-2377-7-33
Abstract: Diabetic Goto-Kakizaki (GK) or control rats underwent 3 hours of middle cerebral artery occlusion and 21 h reperfusion followed by evaluation of infarct size, hemorrhage and neurological outcome.Infarct size was significantly smaller in GK rats (10 ± 2 vs 30 ± 4%, p < 0.001). There was significantly more frequent hematoma formation in the ischemic hemisphere in GK rats as opposed to controls. Cerebrovascular tortuosity index was increased in the GK model (1.13 ± 0.01 vs 1.34 ± 0.06, P < 0.001) indicative of changes in vessel architecture.These findings provide evidence that there is cerebrovascular remodeling in diabetes. While diabetes-induced remodeling appears to prevent infarct expansion, these changes in blood vessels increase the risk for HT possibly exacerbating neurovascular damage due to cerebral ischemia/reperfusion in diabetes.Ischemic stroke is a leading cause of death and disability in the United States and diabetes is the most rapidly increasing risk factor for stroke. Among patients with recent stroke, 70% have overt diabetes or prediabetes characterized by impaired fasting glucose or impaired glucose tolerance [1]. Type 2 diabetes, a disease that affects more than 17 million Americans with an alarming number of new cases, holds a 2–6 fold increased risk for stroke. Not only is the incidence of stroke increased among diabetics, but stroke patients with diabetes have a worse outcome. Mortality is increased in diabetics at one week, one month and three months after stroke, and diabetic stroke survivors have more profound neurologic deficits and disability [2]. In addition, diabetes and hyperglycemia predict early neurologic deterioration following ischemic stroke [3]. A recent study reported that persistent post-stroke hyperglycemia causes infarct expansion and worse clinical outcome [4]. Vascular complications of diabetes characterized by vascular dysfunction and pathological remodeling contribute to increased cardiovascular mortality and morbidity in
Reduced Endothelium-Dependent Relaxation to Anandamide in Mesenteric Arteries from Young Obese Zucker Rats
Nubia S. Lobato, Fernando P. Filgueira, Roshini Prakash, Fernanda R. Giachini, Adviye Ergul, Maria Helena C. Carvalho, R. Clinton Webb, Rita C. Tostes, Zuleica B. Fortes
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063449
Abstract: Impaired vascular function, manifested by an altered ability of the endothelium to release endothelium-derived relaxing factors and endothelium-derived contracting factors, is consistently reported in obesity. Considering that the endothelium plays a major role in the relaxant response to the cannabinoid agonist anandamide, the present study tested the hypothesis that vascular relaxation to anandamide is decreased in obese rats. Mechanisms contributing to decreased anandamide-induced vasodilation were determined. Resistance mesenteric arteries from young obese Zucker rats (OZRs) and their lean counterparts (LZRs) were used. Vascular reactivity was evaluated in a myograph for isometric tension recording. Protein expression and localization were analyzed by Western blotting and immunofluorescence, respectively. Vasorelaxation to anandamide, acetylcholine, and sodium nitroprusside, as well as to CB1, CB2, and TRPV1 agonists was decreased in endothelium-intact mesenteric arteries from OZRs. Incubation with an AMP-dependent protein kinase (AMPK) activator or a fatty acid amide hydrolase inhibitor restored anandamide-induced vascular relaxation in OZRs. CB1 and CB2 receptors protein expression was decreased in arteries from OZRs. Incubation of mesenteric arteries with anandamide evoked endothelial nitric oxide synthase (eNOS), AMPK and acetyl CoA carboxylase phosphorylation in LZRs, whereas it decreased phosphorylation of these proteins in OZRs. In conclusion, obesity decreases anandamide-induced relaxation in resistance arteries. Decreased cannabinoid receptors expression, increased anandamide degradation, decreased AMPK/eNOS activity as well as impairment of the response mediated by TRPV1 activation seem to contribute to reduce responses to cannabinoid agonists in obesity.
Role of Matrix Metalloproteinase Activity in the Neurovascular Protective Effects of Angiotensin Antagonism
Tauheed Ishrat,Anna Kozak,Ahmed Alhusban,Bindu Pillai,Maribeth H. Johnson,Azza B. El-Remessy,Adviye Ergul,Susan C. Fagan
Stroke Research and Treatment , 2014, DOI: 10.1155/2014/560491
Abstract: Background and Purpose. Oxidative stress and matrix metalloproteinase (MMP) activity have been identified as key mediators of early vascular damage after ischemic stroke. Somewhat surprisingly, the angiotensin II type 1 receptor (AT1) blocker, candesartan, has been shown to acutely increase MMP activity while providing neurovascular protection. We aimed to determine the contribution of MMP and nitrative stress to the effects of angiotensin blockade in experimental stroke. Methods. Wistar rats (n?=?9–14/group; a total of 99) were treated in a factorial design with candesartan 1?mg/kg IV, alone or in combination with either a peroxynitrite decomposition catalyst, FeTPPs, 30?mg/kg IP or GM6001 50?mg/kg IP (MMP inhibitor). Neurological deficit, infarct, size and hemorrhagic transformation (HT) were measured after 3?h of middle cerebral artery occlusion (MCAO) and 21?h of reperfusion. MMP activity and nitrotyrosine expression were also measured. Results. Candesartan reduced infarct size and HT when administered alone ( ) and in combination with FeTPPs ( ). GM6001 did not significantly affect HT when administered alone, but the combination with candesartan caused increased HT ( ) and worsened neurologic score ( ). Conclusions. Acute administration of candesartan reduces injury after stroke despite increasing MMP activity, likely by an antioxidant mechanism. 1. Introduction Ischemic stroke, an obstruction of blood flow in a major cerebral vessel, remains a leading cause of adult disability and death in the United States [1]. Because of its complex pathology, a major research and clinical priority is to develop therapeutic interventions in the ischemic brain through the understanding of underlying mechanisms. Ischemia reperfusion leads to a cascade of pathophysiological processes, resulting in further brain damage. Accumulations of free radicals, oxygen/nitrogen species (ROS/RNS), not only increase the susceptibility of brain tissue to reperfusion-induced damage but also trigger numerous molecular cascades, leading to increased blood-brain barrier (BBB) permeability, brain edema, hemorrhage and inflammation, and brain death [2, 3]. As an important component of free radicals, RNS, including peroxynitrite (ONOO–), play important roles in the process of cerebral ischemia-reperfusion injury. Ischemia reperfusion results in the production of peroxynitrite in ischemic brain, which triggers numerous molecular cascades and leads to vascular damage. In vitro, peroxynitrite strongly activates matrix metalloproteinases (MMPs) [4, 5]. Peroxynitrite formation on
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