Biomedical subjects

Adviye Ergul

Publications and source records attributed to Adviye Ergul.

27 records · Page 2Linked to original sources

PubMed2003

Neuroprotection by tempol in a model of iron-induced oxidative stress in acute ischemic stroke.

Studies suggest iron exacerbates the damage caused by ischemic stroke. Our aim was to elucidate the effect of iron overload on infarct size after middle cerebral artery occlusion (MCAO) and to evaluate the efficacy of tempol, a superoxide dismutase mimetic, as a neuroprotective agent. Rats were administered iron +/- tempol before MCAO; control rats received saline. The middle cerebral artery was occluded for 24 h, and the size of the resultant infarct was assessed and expressed as the percentage of the hemisphere infracted (%HI). Iron treatment increased infarct size compared with control (51.83 +/- 3.55 vs. 27.56 +/- 3.28%HI iron treated vs. control, P = 0.01); pretreatment with tempol reversed this (51.83 +/- 3.55 vs. 26.09 +/- 9.57%HI iron treated vs. iron + tempol treated, P = 0.02). We hypothesized that reactive oxygen species (ROS) were responsible for the iron-induced damage. We measured ROS generated by exogenous iron in brain and peripheral vasculature from rats that had not undergone MCAO. There was no increase in ROS production in the brain of iron-treated rats or in brain slices incubated with iron citrate. However, ROS generation in carotid arteries incubated with iron citrate was significantly increased. ROS generation from the brain was assessed after MCAO by dihydroethidine staining; there was a dramatic increase in the ROS generation by the brain in the iron-treated rats compared with control 30 min after MCAO. We propose that iron-induced ROS generation in the cerebral vasculature adds to oxidative stress during an ischemic episode after the disruption of the blood-brain barrier.

Animals↗

PubMed2003

Nuclear localization of endothelin-converting enzyme-1: subisoform specificity.

OBJECTIVE: The biosynthesis of endothelin-1 (ET-1), the most potent vasoconstrictor with mitogenic properties, involves the processing of intermediate protein big ET-1 by a unique metalloprotease, endothelin-converting enzyme-1 (ECE-1). ECE-1 has 4 subisoforms that possess the same catalytic properties but different localization patterns on the plasma membrane and cytosol. We investigated the trafficking of ECE-1 subisoforms using green fluorescent protein-tagged recombinant enzymes in target and nontarget cells. METHODS AND RESULTS: ECE-1 localization was studied using confocal microscopy, which provides evidence for the first time that both ET-1 and ECE-1a are also found in the nuclear compartment in transiently transfected cells as well as in native endothelial cells that endogenously possess the ET system. In cells maintained in high-glucose medium, ECE-1a-specific staining shifted from plasma membrane to intracellular compartments. ECE-1b subisoform, however, is mainly in the cytosolic compartment, indicating a subisoform specificity for nuclear localization. CONCLUSIONS: Our findings define a novel localization pattern for the ET system, which may be differentially regulated under pathophysiological conditions.

Animals↗

PubMed2003

Stress upregulates arterial matrix metalloproteinase expression and activity via endothelin A receptor activation.

Degradation of the extracellular matrix proteins by matrix metalloproteinases (MMP) is an important regulatory step in the vascular remodeling process. Recent studies demonstrated that ETA receptors regulate cardiac MMP activity and fibrosis in DOCA-salt hypertension. However, little is known about endothelin (ET)-1 regulation of vascular MMP activity in hypertension. Thus early changes in ET-1-mediated regulation of MMP activity were measured in borderline hypertensive rats that develop impaired vasorelaxation and hypertension with chronic exposure to stress. Experiments were performed after 10 days of exposure to the behavioral stressor, air-jet stress, but before the onset of stress-induced hypertension. Study groups were 1) control (n = 8); 2) air-jet stress for 10 days (n = 8); 3) control plus ETA antagonist ABT-627 (n = 4), and 4) air-jet stress plus ETA antagonist (n = 4). MMP activity in the thoracic aorta was assessed by gelatin zymography. MMP protein and tissue ET-1 levels were evaluated by immunohistochemistry, and ET receptor density was determined by immunoblotting. Exposure to stress caused a twofold increase in plasma ET-1 levels (P < 0.05), and there was increased ET-1 staining at the tissue level. Total MMP activity and expression of MMP-2 and MMP-9 were increased in the stress group. ETA receptor antagonism prevented the increase in MMP expression and activation in the stress group. These results provide evidence that the MMP system is activated before the development of hypertension and ET-1 mediates these early events in vascular remodeling.

Animals↗

PubMed2002

Saphenous vein endothelin system expression and activity in African American patients.

OBJECTIVE: Plasma endothelin (ET)-1 levels are significantly higher in African American hypertensive patients than in white hypertensive patients. However, whether the molecular components of vascular ET-1 biosynthesis and function are altered in this population remains to be established. Accordingly, the overall goal of this study was to investigate the effects of race on vascular mRNA and protein levels of ET-converting enzyme (ECE)-1 subisoforms, ET-1, and ET receptor profiles in hypertension. METHODS AND RESULTS: Saphenous vein samples were obtained from African American (n=13) and white (n=15) patients undergoing coronary artery grafting surgery. The expression of preproET-1 and of ECE-1a was upregulated approximately 2- and 3-fold, respectively, in African Americans. In endothelium-intact vessels, the ET(A) expression was higher in whites. In endothelium-denuded vessels, the ET(B) mRNA was 3-fold higher in African Americans, suggesting that vasoconstriction-promoting ET(B) receptors are upregulated in this population. Vascular tissue ET-1 levels and ECE-1 activity were also augmented in African American patients. CONCLUSIONS: This study demonstrated that the biosynthetic pathway of ET-1 is activated to a higher degree and that the ET(B) receptor subtype expression is altered in the peripheral vasculature of African American hypertensive patients. The augmented synthesis and altered expression of ET(B) receptors may both contribute to the increased incidence of hypertension and related complications in this patient population.

Aged↗

PubMed2002

Endothelin-1 and endothelin receptor antagonists as potential cardiovascular therapeutic agents.

Endothelin (ET)-1 is an endothelium-derived peptide with potent vasoconstrictor and proliferative properties. The ET system is activated in several cardiovascular disease states associated with functional and structural vascular changes, including hypertension and heart failure. The two ET receptor subtypes are known as ET(A)R and ET(B)R. The former is located mainly on vascular smooth muscle cells and is responsible for mediating vasoconstriction and proliferation. The latter is present predominantly on endothelial cells and mediates vasorelaxation as well as ET-1 clearance. Activation of smooth muscle ET(B)R causes vasoconstriction. Selective ET(A)R antagonists as well as nonselective ET(A)R-ET(B)R antagonists have been developed. Studies with animal models and early-phase clinical trials provided strong evidence that these agents are effective in the treatment of heart failure, essential hypertension, pulmonary hypertension, and atherosclerosis. However, the complexity of biologic effects mediated by two different receptor subtypes complicates therapy with selective versus nonselective ET receptor antagonists. In addition to subtype selectivity and potency, changes in receptor subtype distribution under different pathologic conditions and different patient populations will play a crucial role in the evaluation of these potentially therapeutic drugs.

Animals↗

PubMed2002

Evidence for a matrix metalloproteinase induction/activation system in arterial vasculature and decreased synthesis and activity in diabetes.

Pathological remodeling characterized by extracellular matrix (ECM) deposition contributes to the diabetic vascular complications. Matrix metalloproteinases (MMPs) regulate ECM turnover. However, the expression profile of the MMP system in diabetic human tissue remains unknown. The objectives of this study were 1) to identify a local MMP induction/activation system that exists in arterial vasculature and 2) to determine how the MMP system may be altered in diabetes. Internal mammary artery specimens were obtained from patients who did (n = 14) and did not (n = 14) have diabetes and were undergoing coronary artery bypass grafting surgery. ECM inducer protein (EMMPRIN); membrane-type MMP (MT-MMP); and MMP-1, -2, and -9 were quantified by immunoblotting and densitometric scanning (pixels). Pro-MMP-1 and MMP-2 levels were decreased from 952 +/- 120 and 1,081 +/- 508 pixels, respectively, in nondiabetic tissue to 398 +/- 62 and 249 +/- 42 pixels in the diabetic tissue (P < 0.05). Both EMMPRIN and MT-MMP expression and total MMP activity were decreased by twofold in diabetic patients (P < 0.05). These results demonstrated for the first time that an MMP induction and activation system exists in human arterial vasculature and that it is downregulated in diabetes. Decreased MMP activity may contribute to increased collagen deposition and pathological remodeling in diabetes.

Collagen Type I↗

PubMed2002

Selective downregulation of endothelin-B receptors in diabetic African-American patients.

The purpose of this study was to investigate whether there are differences in the expression of the endothelin (ET) system in the peripheral vasculature of diabetic African-American (AA) and Caucasian (CA) patients. Tibial artery specimens were obtained from diabetic (MD = 8 and CAD = 5) and non-diabetic (AAND = 6 and CAND = 5) patients undergoing lower limb amputation. The gene expression of ET-1 precursor (PPET-1), ET(A)R and ET(B)R was determined by a reverse transcriptase polymerase chain reaction technique. PPET-1 and ET(A)R expression was up-regulated 4- and 3-fold, respectively, in both AA and CA diabetics (P<.05 vs non-diabetics). ET(B)R mRNA was significantly lower in AA diabetic patients. Function of ET-1 and ET receptors was assessed by vascular contractility assays. Vascular relaxation in response to sodium nitroprusside in arteries precontracted with ET-1 was significantly lower in AA (58% +/- 9) as compared to CA diabetics (74% +/- 5) (P<.05). In conclusion, this study demonstrated that the ET system is altered in favor of the contractile phenotype in AA diabetics and may contribute to the increased incidence of vascular complications in this population.

Aged↗

PubMed2002

Vascular endothelin converting enzyme-1 expression and activity is upregulated in clinical diabetes.

Circulating and vascular endothelin-1 (ET-1) levels are elevated in diabetes, but the molecular components of the enzymatic activation of ET-1 in the vasculature remains unknown. Furthermore, the distribution of ET receptors favors a contractile phenotype in African Americans with diabetes. Whether there is any difference in local ET-1 activation in this population is unknown. This study examined the expression and activity of ET converting enzyme-1 subisoforms (ECE-1) in the internal mammary artery specimens obtained from patients undergoing coronary artery bypass grafting. The study groups included African-American (AA) and Caucasian (CA), nondiabetic (ND) and diabetic (D) patients: AAND N = 10, CAND N = 9, AAD N = 9, and CAD N = 11. The expression of ECE-1 a, ECE-1 b and ECE-1c subisoforms was studied by RT-PCR. ECE-1 a was upregulated 2- and 4-fold in the CAD and MD groups, respectively (P < .05). In African-American patient groups, ECE-1 activity (fmol/ mg protein.h) was augmented from 2,804 +/- 185 in nondiabetic tissue samples to 6,857 +/- 393 in the diabetic tissue (P < .05). There was a similar increase in the CAD group, which did not significantly differ from AA diabetics. ECE-1 inhibitors, phosphoramidon and FR-901533, inhibited vascular ECE-1 activity by more than 80%. While neutral endopeptidase (NEP) and matrix metalloproteinase-2 (MMP-2) are able to process big ET-1, inhibitors of NEP (thiorphan) and MMP (batimistat) did not affect ECE-1 activity. In conclusion, the enzymatic pathway essential for generating vascular ET-1 is activated in the vasculature of both AA and CA diabetic patients and this activation is highly specific for ECE-1.

Black or African American↗

PubMed2002

Decreased vascular matrix metalloproteinase abundance in diabetic patients with symptomatic macroangiopathy.

The incidence of diabetic amputations is 2- to 3-fold higher in African-American patients compared to Caucasians. Vascular remodeling characterized by extracellular matrix (ECM) deposition occurs in diabetes and contributes to vascular complications. The matrix metalloproteinases (MMP) play important roles in the regulation of collagen turnover and vascular remodeling. However, the temporal expression profile of MMPs in diabetic vascular tissue during the disease process remained unknown. The objective of this study was to compare the vascular MMP system in African-American diabetic patients without symptoms to patients undergoing lower limb amputation due to severe vascular complications. Internal mammary artery (IMA, N = 8) and anterior/posterior tibial artery (AT/PT, N = 8) specimens were obtained from patients undergoing coronary artery bypass grafting and lower limb amputation, respectively. ECM inducer protein (EMMPRIN) and MMP activator membrane-type MMP (MT1-MMP), as well as MMP-1, -2, and -9, were quantified by immunoblotting and densitometry (pixels). MMP-1 and -9 levels were decreased from 398 +/- 61 and 175 +/- 54 pixels, respectively, in IMA tissue to 287 +/- 31 and 51 +/- 36 pixels in the AT/PT tissue (P < .05). Both EMMPRIN and MT1-MMP expression was increased by 3-fold in AT/PT preparations (P < .05). These results provided evidence that the molecular components required for the induction and activation of the MMP system exist in arterial vasculature and, MMP expression is downregulated in diabetic patients with severe complications despite elevated MMP inducer and activator proteins. Decreased MMP activity may contribute to pathological remodeling leading to increased incidence of amputations in African-American patients.

Black or African American↗