Difference in the response to angiotensin II between left and right ventricular endocardial endothelial cells

Previous studies focused on the right ventricular endocardial endothelial cells (EECRs) and showed that angiotensin II (Ang II) induced increase in cytosolic and nuclear calcium via AT1 receptor activation. In the present study, we verified whether the response of left EECs (EECLs) to Ang II is different than that of EECRs. Our results showed that the EC50 of the Ang II-induced increase of cytosolic and nuclear calcium in EECLs was 10× higher (around 2 × 10−13 mol/L) than in EECRs (around 8 × 10−12 mol/L). The densities of both AT1 and AT2 receptors were also higher in EECLs than those previously reported in EECRs. The effect of Ang II was mediated in both cell types via the activation of AT1 receptors. Treatment with Ang II induced a significant increase of cytosolic and nuclear AT1 receptors in EECRs, whereas the opposite was found in EECLs. In both cell types, there was a transient increase of cytosolic and nuclear AT2 receptors following the Ang II treatment. In conclusion, our results showed that both AT1 and AT2 receptors densities are higher in both EECLs compared to what was reported in EECRs. The higher density of AT1 receptors in EECLs compared to REECs may explain, in part, the higher sensitivity of EECLs to Ang II.

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Angiotensin II induces apoptosis of human right and left ventricular endocardial endothelial cells by activating the AT2 receptor

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2018-0592 ◽

2019 ◽

Vol 97 (6) ◽

pp. 581-588 ◽

Cited By ~ 4

Author(s):

Danielle Jacques ◽

Chantale Provost ◽

Alexandre Normand ◽

Nadia Abou Abdallah ◽

Johny Al-Khoury ◽

...

Keyword(s):

Endothelial Cells ◽

Angiotensin Ii ◽

Annexin V ◽

Receptor Activation ◽

Left Ventricular ◽

Dependent Manner ◽

Ang Ii ◽

Concentration Dependent Manner ◽

Endocardial Endothelial Cells ◽

Induced Apoptosis

Endocardial endothelial cells (EECs) form a monolayer lining the ventricular cavities. Studies from our laboratory and the literature have shown differences between EECs isolated from the right and left ventricles (EECRs and EECLs, respectively). Angiotensin II (Ang II) was shown to induce apoptosis of different cell types mainly via AT1 receptor activation. In this study, we verified whether Ang II induces apoptosis of human EECRs and EECLs (hEECRs and hEECLs, respectively) and via which type of receptor. Using the annexin V labeling and in situ TUNEL assays, our results showed that Ang II induced apoptosis of both hEECRs and hEECLs in a concentration-dependent manner. Our results using specific AT1 and AT2 receptor antagonists showed that the Ang-II-induced apoptosis in both hEECRs and hEECLs is mediated mainly via the AT2 receptor. However, AT1 receptor blockade partially prevented Ang-II-induced apoptosis, particularly in hEECRs. Hence, our results suggest that mainly AT2 receptors mediate Ang-II-induced apoptosis of hEECRs and hEECLs. The damage of EECs would affect their function as a physical barrier between the blood and cardiomyocytes, thus affecting cardiomyocyte functions.

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Angiotensin II and its receptors in human endocardial endothelial cells: role in modulating intracellular calcium

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y03-046 ◽

2003 ◽

Vol 81 (3) ◽

pp. 259-266 ◽

Cited By ~ 22

Author(s):

Danielle Jacques ◽

Nelly A. Abdel Malak ◽

Sawsan Sader ◽

Claudine Perreault

Keyword(s):

Endothelial Cells ◽

Angiotensin Ii ◽

Confocal Microscopy ◽

Intracellular Calcium ◽

Fluorescence Signal ◽

Ang Ii ◽

Microscopy Technique ◽

Endocardial Endothelial Cells ◽

Microscopy Techniques ◽

Dose Dependent

he aims of the present study are to investigate the presence and distribution of angiotensin II (Ang II), as well as AT1 and AT2 receptors, in endocardial endothelial cells (EECs) and to determine if the effect of Ang II on intracellular calcium in these cells is mediated via the AT1 or the AT2 receptor. Immunofluorescence and 3D confocal microscopy techniques were used on 20-week-old fetal human EECs. Our results showed that Ang II and its receptors, the AT1 and the AT2 types, are present and exhibit a different distribution in human EECs. Ang II labelling is found throughout the cell with a fluorescence signal higher in the cytosol when compared with the nucleus. Like Ang II, the AT1 receptor fluorescence signal is also homogeneously distributed in human EECs but with a preferential labelling at the level of the nucleus, while the AT2 receptor labelling is solely present in the nucleus. Using fluo-3 and 3D confocal microscopy technique, superfusion of human EECs with increasing concentration of Ang II induced a dose-dependent sustained increase in free cytosolic and nuclear Ca2+ levels. This effect of Ang II on human EEC's intra cellular Ca2+ ([Ca2+]i) was completely prevented by losartan, an AT1 receptor antagonist. Our results suggest that Ang II, as well as AT1 and AT2 receptors, is present but differentially distributed in EECs of 20-week-old fetal human hearts, and that the AT1 receptor mediates the effects of Ang II on [Ca2+]i in these cells.Key words: angiotensin II, nuclear receptors, endocardial endothelial cells, Ang II receptors, intracellular calcium.

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Lipid signal transduction pathways in angiotensin II type 1 receptor-transfected fibroblasts

AJP Cell Physiology ◽

10.1152/ajpcell.1995.269.2.c435 ◽

1995 ◽

Vol 269 (2) ◽

pp. C435-C442 ◽

Cited By ~ 19

Author(s):

Y. Wen ◽

M. C. Cabot ◽

E. Clauser ◽

S. L. Bursten ◽

J. L. Nadler

Keyword(s):

Signal Transduction ◽

Angiotensin Ii ◽

Chinese Hamster ◽

Receptor Activation ◽

Signal Transduction Pathways ◽

Ang Ii ◽

Vascular Type ◽

Lipid Signal ◽

Fibroblast Line

A stable Chinese hamster ovary fibroblast line expressing the rat vascular type 1a angiotensin II (ANG II) receptor was used to study the lipid-derived signal transduction pathways elicited by type 1a ANG II receptor activation. ANG II caused a biphasic and dose-dependent increase in diacylglycerol (DAG) accumulation with an initial peak at 15 s (181 +/- 11% of control, P < 0.02) and a second sustained peak at 5-10 min (214 +/- 10% of control, P < 0.02). The late DAG peak was derived from phosphatidylcholine (PC), and the formation was blocked by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. ANG II also increased phosphatidic acid (PA) production nearly fourfold by 7.5 min. In the presence of ethanol, ANG II markedly increased phosphatidylethanol (PEt) formation, indicating activation of phospholipase D (PLD). ANG II was shown to increase the mass of three separate PA species, one of which apparently originated from DAG kinase action on PC-phospholipase C (PLC)-produced DAG, providing evidence for PC-PLC activity. ANG II also formed a third PA species, which originated neither from PLD nor from DAG kinase. These results demonstrate that multiple lipid signals propagated via collateral stimulation of PLC and PLD are generated by specific activation of the vascular type 1a ANG II receptor.

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Abstract WMP78: The Efficacy of Angiotensin II Peptide Vaccination Against White Matter Lesions of Vascular Dementia in Rats

Stroke ◽

10.1161/str.51.suppl_1.wmp78 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Kouji Wakayama ◽

Munehisa Shimamura ◽

Hironori Nakagami ◽

Ryuichi Morishita

Keyword(s):

Endothelial Cells ◽

Cognitive Function ◽

Angiotensin Ii ◽

White Matter ◽

Western Blot ◽

Vascular Dementia ◽

White Matter Lesions ◽

Ang Ii ◽

Peptide Vaccination ◽

Brdu Assay

Background & Purposes: There had been no attempt to show the efficacy of therapeutic vaccination in vascular dementia. A rat model of vascular dementia was prepared by bilateral common carotid artery ligation (2VO). The purpose of this study is to investigate whether pre-exposure Angiotensin II (Ang II) peptide vaccination exhibits the protective effects against white matter lesions (WML) in 2VO rats. Methods: After subcutaneous injection of Ang II peptide vaccine (10μg/200μl) or saline (200μl) to Wistar rats (male) at the time point of 6, 8 and 10 week-old, 2VO or sham surgery was performed at 12 week-old. Cognitive function was evaluated after 14 days of 2VO using the novel object recognition (NOR) test. Anti-Ang II antibody (Ab) level was quantified using ELISA. Histological examinations of WML and demyelination in the corpus callosum (CC) were evaluated using immunohistochemistry (IHC), 5-bromodeoxyuridine (BrdU) assay and Klüver-Barrera staining. Western blot analyses of VCAM-1, FGF2, phospho-CREB and CREB using proteins extracted from CC were performed to investigate the mechanism of restoration of WML by Ang II vaccination. Results: Histological examinations presented that exacerbation of WML and demyelination observed in saline treated (S) rats was ameliorated in Ang II vaccinated (V) rats. The results of NOR test indicated that cognitive dysfunction observed in S rats was improved in V rats at 14 days after 2VO. Expression of VCAM-1 in CC of S rats was significantly reduced in V rats at 7 days after 2VO. BrdU assay exhibited that vaccination accelerated the differentiation of oligodendrocyte progenitor cells (OPCs) in WML from 14 days to 28 days of 2VO. Western blot presented that both CREB phosphorylation and FGF2 expression in CC were increased in V rats compared with S rats at 14 days after 2VO. Double IHC showed that FGF2 expressing cells were mostly endothelial cells and astrocytes in WML. Conclusions: Ang II vaccination restored WML as well as cognitive function in 2VO rats. Our findings suggested that Ang II vaccination ameliorated cerebrovascular endothelial dysfunction which could accelerate the OPCs differentiation through increased expression of FGF2 in endothelial cells or astrocytes in 2VO rats.

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Alpha-Asarone Protects Endothelial Cells from Injury by Angiotensin II

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2014/682041 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Hai-Xia Shi ◽

Jiajun Yang ◽

Tao Yang ◽

Yong-Liang Xue ◽

Jun Liu ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Angiotensin Ii ◽

Cell Injury ◽

Fluorescent Dyes ◽

Umbilical Vein ◽

Protective Effects ◽

Ang Ii ◽

Versus Model

α-Asarone is the major therapeutical constituent ofAcorus tatarinowiiSchott. In this study, the potential protective effects ofα-asarone against endothelial cell injury induced by angiotensin II were investigatedin vitro. The EA.hy926 cell line derived from human umbilical vein endothelial cells was pretreated withα-asarone (10, 50, 100 µmol/L) for 1 h, followed by coincubation with Ang II (0.1 µmol/L) for 24 h. Intracellular nitric oxide (NO) and reactive oxygen species (ROS) were detected by fluorescent dyes, and phosphorylation of endothelial nitric oxide synthase (eNOS) atSer1177was determined by Western blotting.α-Asarone dose-dependently mitigated the Ang II-induced intracellular NO reduction (P<0.01versus model) and ROS production (P<0.01versus model). Furthermore, eNOS phosphorylation (Ser1177) by acetylcholine was significantly inhibited by Ang II, while pretreatment for 1 h withα-asarone partially prevented this effect (P<0.05versus model). Additionally, cell viability determined by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay (105~114.5% versus control,P>0.05) was not affected after 24 h of incubation withα-asarone at 1–100 µmol/L. Therefore,α-asarone protects against Ang II-mediated damage of endothelial cells and may be developed to prevent injury to cardiovascular tissues.

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Skeletal muscle-endothelial cell cross talk through angiotensin II

AJP Cell Physiology ◽

10.1152/ajpcell.00306.2010 ◽

2010 ◽

Vol 299 (6) ◽

pp. C1402-C1408 ◽

Cited By ~ 17

Author(s):

Leeann M. Bellamy ◽

Adam P. W. Johnston ◽

Michael De Lisio ◽

Gianni Parise

Keyword(s):

Skeletal Muscle ◽

Endothelial Cells ◽

Cell Migration ◽

Endothelial Cell ◽

Angiotensin Ii ◽

Branch Point ◽

Endothelial Cell Migration ◽

Tube Length ◽

Ang Ii

The role of angiotensin II (ANG II) in postnatal vasculogenesis and angiogenesis during skeletal muscle (SKM) regeneration is unknown. We examined the capacity of ANG II to stimulate capillary formation and growth during cardiotoxin-induced muscle regeneration in ACE inhibitor-treated ANG II type 1a receptor knockout (AT1a−/−) and C57Bl/6 control mice. Analysis of tibialis anterior (TA) cross-sections revealed 17% and 23% reductions in capillarization in AT1a−/− and captopril treated mice, respectively, when compared with controls, 21 days postinjury. Conversely, no differences in capillarization were detected at early time points (7 and 10 days). These results identify ANG II as a regulator of angiogenesis but not vasculogenesis in vivo. In vitro angiogenesis assays of human umbilical vein endothelial cells (HUVECs) further confirmed ANG II as proangiogeneic as 71% and 124% increases in tube length and branch point number were observed following ANG II treatment. Importantly, treatment of HUVECs with conditioned media from differentiated muscle cells resulted in an 84% and 203% increase in tube length and branch point number compared with controls, which was abolished following pretreatment of the cells with an angiotensin-converting enzyme inhibitor. The pro-angiogenic effect of ANG II can be attributed to an enhanced endothelial cell migration because both transwell and under agarose migration assays revealed a 37% and 101% increase in cell motility, respectively. Collectively, these data highlight ANG II as a proangiogenic regulator during SKM regeneration in vivo and more importantly demonstrates that ANG II released from SKM can signal endothelial cells and regulate angiogenesis through the induction of endothelial cell migration.

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Abstract 476: Renal AT2 Receptor Activation Prevents Sodium Retention And Lowers Blood Pressure In Angiotensin II-Dependent Hypertension

Hypertension ◽

10.1161/hyp.64.suppl_1.476 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Shetal H Padia ◽

Nancy L Howell ◽

Brandon A Kemp ◽

John J Gildea ◽

Susanna R Keller ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Receptor Activation ◽

Pressure Probe ◽

Ang Ii ◽

Induced Hypertension ◽

Group 5 ◽

Group 2 ◽

Angiotensin Type

A major proposed mechanism for the initiation of hypertension involves a primary increase in renal tubular sodium (Na+) reabsorption. Activation of intrarenal angiotensin type-2 receptors (AT2R) increases Na+ excretion; however, the role of intrarenal angiotensin type-2 receptors (AT2R) in the development of hypertension is unknown. Sprague-Dawley rats (N=36) underwent uninephrectomy and telemetric blood pressure probe implantation. Following a 72h recovery, two osmotic minipumps were inserted in each rat, one for chronic systemic delivery of 5% dextrose in water (D5W) or angiotensin II (Ang II, 200 ng/kg/min), and one for chronic intrarenal delivery of D5W (0.25 μL/h x 7d), highly selective AT2R agonist Compound 21 (C-21; 60 ng/kg/min x 7d), or specific AT2R antagonist PD-1223319 (PD; 10 ng/kg/min x 7d). Five groups of rats were studied: Group 1 (Control; N=10): systemic D5W + intrarenal D5W; Group 2 (Ang II-induced hypertension; N=8): systemic Ang II + intrarenal D5W; Group 3 (N=6): systemic Ang II + intrarenal C-21; Group 4 (N=6): systemic Ang II + 48h lead-in intrarenal C-21; Group 5 (N=6): systemic Ang II + intrarenal PD. Systemic Ang II infusion increased mean systolic blood pressure from 126±5 to 190±3 mm Hg over a 7d period in Group 2 (ANOVA F=73; P<1 X 10-6). Intrarenal administration of AT2R agonist C-21 (Groups 3 and 4) markedly inhibited the pressor effect of systemic Ang II (P<0.0001). Intrarenal AT2R antagonist PD (Group 5) augmented the pressor action of Ang II (P<0.0001). Consecutive 24h urinary Na+ excretion (UNaV) was reduced from 0.95±0.04 to 0.34±0.07 μmol/min (P<0.0001) on day 1 of Ang II infusion; Ang II-induced antinatriuresis was inhibited by intrarenal C-21 (P<0.0001) and augmented by intrarenal PD (P<0.0001) during the entire 7d infusion, demonstrating that one of the mechanisms to prevent Ang II-induced hypertension during intrarenal AT2R activation is the abolition of the initial increase in Na+ reabsorption that triggers the hypertensive cascade in this model. Thus, renal AT2Rs represent a novel therapeutic target for the prevention of hypertension.

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Abstract 095: Human (Pro)renin Receptor Activation Induces an Angiotensin II-Independent Pressor Response Mediated by NADPH Oxidase 4 Activity

Hypertension ◽

10.1161/hyp.66.suppl_1.095 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Michelle N Sullivan ◽

Wencheng Li ◽

Curt D Sigmund ◽

Yumei Feng

Keyword(s):

Angiotensin Ii ◽

Nadph Oxidase ◽

Signaling Pathways ◽

Pressor Response ◽

Receptor Activation ◽

Fold Change ◽

Mrna Levels ◽

Ang Ii ◽

Proteolytic Activation ◽

Nadph Oxidase 4

The binding of prorenin to the (pro)renin receptor (PRR) induces non-proteolytic activation of prorenin and generation of angiotensin II (Ang II). PRR activation can also induce Ang II-independent signaling pathways. However, whether Ang II-independent signaling pathways are critical for blood pressure (BP) regulation is not known. To address this question, we created transgenic mice that overexpress the human PRR (hPRR) selectively in neurons (Syn-hPRR). Activated human prorenin (hPRO) cannot cleave endogenous mouse angiotensinogen to generate Ang II. Therefore, administration of hPRO to Syn-hPRR mice can be used to examine Ang II-independent PRR signaling in BP regulation. Intracerebroventricular (ICV) infusion of hPRO increases BP in Syn-hPRR mice (ΔMAP 23 ± 4.6, n = 4) but has no effect on wildtype (WT) mice (ΔMAP 2 ± 0.8, n = 6). The hPRO-induced pressor response in Syn-hPRR mice is unaffected by co-infusion with the Ang II type 1 receptor blocker losartan (ΔMAP 19 ± 5.2, n = 8), suggesting that the response is independent of Ang II. Interestingly, co-infusion with an inhibitor of the reactive oxygen species-generating enzyme NADPH oxidase (NOX), diphenyleneiodonium, nearly abolishes the hPRO-induced pressor response in Syn-hPRR mice (ΔMAP 4.7 ± 1.0, n = 4), indicating that NOX activity is required. Additionally, we find that basal NOX activity is enhanced in the Syn-hPRR hypothalamus relative to WT mice (1.4 fold change). We next examined which NOX isoform is responsible for the hPRO-induced pressor response and enhanced activity. NOX4 mRNA levels are greater (2.7 ± 0.6 fold change), but NOX1 (1.2 ± 0.3 fold change) and NOX2 (1.2 ± 0.3 fold change) mRNA levels are not different, in the hypothalamus of Syn-hPRR compared to WT mice (n = 3). Adenovirus-mediated delivery of NOX2, NOX4, or a scrambled sequence shRNA was ICV injected in Syn-hPRR mice. After 7 days, we found that treatment with NOX2 (ΔMAP 20 ± 5.2) or scrambled (ΔMAP 23 ± 3.2) shRNA had no effect on the hPRO-induced pressor response (n = 5). However, the hPRO-induced increase in BP is attenuated in Syn-hPRR mice injected with NOX4 shRNA (ΔMAP 5.9 ± 2.8). Together, these data indicate that NOX4 mediates the Ang II-independent pressor response to activation of the human (pro)renin receptor in Syn-hPRR mice.

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Influence of angiotensin II on pressure natriuresis and renal hemodynamics in volume-expanded rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1991.260.6.r1200 ◽

1991 ◽

Vol 260 (6) ◽

pp. R1200-R1209 ◽

Cited By ~ 14

Author(s):

D. L. Mattson ◽

H. Raff ◽

R. J. Roman

Keyword(s):

Angiotensin Ii ◽

Capillary Pressure ◽

Plasma Levels ◽

Renin Angiotensin System ◽

Plasma Renin ◽

Renal Perfusion ◽

Renal Hemodynamics ◽

Tubular Reabsorption ◽

Ang Ii ◽

The Right

This study examined whether angiotensin II (ANG II) influences the pressure-natriuretic (PN) response by altering renal cortical or medullary hemodynamics. Studies were performed in Inactin-anesthetized rats that were acutely volume expanded to maintain plasma renin activity and ANG II levels in the physiological range. Neural influences on the kidney were eliminated by renal denervation, and plasma levels of norepinephrine, vasopressin, cortisol, and aldosterone were fixed by intravenous infusion. In control rats (n = 8), sodium excretion increased from 3 to 17 microeq.min-1.g kidney wt-1 as renal perfusion pressure (RPP) was elevated from 96 to 141 mmHg (n = 8). Captopril (2 mg/kg, n = 9) reduced plasma levels of ANG II from 48 +/- 5 to 18 +/- 2 pg/ml, but it did not alter the PN relationship. Infusion of ANG II (20 ng.kg-1.min-1, n = 9) increased plasma levels of ANG II to 232 +/- 42 pg/ml and shifted the PN relationship to the right by 14 mmHg. Captopril increased renal blood flow, and infusion of ANG II returned it to control. Captopril had no effect on glomerular filtration rate (GFR) or glomerular capillary pressure (Pglom); however, subsequent ANG II infusion decreased Pglom from 56 +/- 2 to 48 +/- 2 mmHg and reduced GFR by 30%. Neither captopril nor ANG II altered papillary bloodflow or vasa recta capillary pressure at normal levels of RPP. These results indicate that the shift of the PN relationship during infusion of ANG II is due to a decrease in filtered load and enhanced tubular reabsorption of sodium. Acute blockade of the renin-angiotensin system had little effect on the PN response in volume-expanded rats despite affecting renal hemodynamics, because either the plasma and/or intrarenal levels of ANG II were already suppressed below those needed to influence tubular function or volume expansion inhibits tubular reabsorption in the nephron segments normally influenced by ANG II.

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Human glomerular endothelium: interplay among glucose, free fatty acids, angiotensin II, and oxidative stress

AJP Renal Physiology ◽

10.1152/ajprenal.00248.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. F125-F132 ◽

Cited By ~ 46

Author(s):

Edgar A. Jaimes ◽

Ping Hua ◽

Run-Xia Tian ◽

Leopoldo Raij

Keyword(s):

Fatty Acids ◽

Endothelial Cells ◽

Angiotensin Ii ◽

Nadph Oxidase ◽

Free Fatty Acids ◽

High Glucose ◽

Renin Angiotensin System ◽

Macrovascular Disease ◽

Ang Ii ◽

Cox 2

Glomerular endothelial cells (GEC) are strategically situated within the capillary loop and adjacent to the glomerular mesangium. GEC serve as targets of metabolic, biochemical, and hemodynamic signals that regulate the glomerular microcirculation. Unequivocally, hyperglycemia, hypertension, and the local renin-angiotensin system partake in the initiation and progression of diabetic nephropathy (DN). Whether free fatty acids (FFA) and reactive oxygen species (ROS) that have been associated with the endothelial dysfunction of diabetic macrovascular disease also contribute to DN is not known. Since endothelial cells from different organs and from different species may display different phenotypes, we employed human GEC to investigate the effect of high glucose (22.5 mmol/l), FFA (800 μmol/l), and angiotensin II (ANG II; 10−7 mol/l) on the genesis of ROS and their effects on endothelial nitric oxide synthase (eNOS), cyclooxygenase-2 (COX-2), and the synthesis of prostaglandins (PGs). We demonstrated that high glucose but not high FFA increased the expression of a dysfunctional eNOS as well as increased ROS from NADPH oxidase (100%) and likely from uncoupled eNOS. ANG II also induced ROS from NADPH oxidase. High glucose and ANG II upregulated (100%) COX-2 via ROS and significantly increased the synthesis of prostacyclin (PGI2) by 300%. In contrast, FFA did not upregulate COX-2 but increased PGI2 (500%). These novel studies are the first in human GEC that characterize the differential role of FFA, hyperglycemia, and ANG II on the genesis of ROS, COX-2, and PGs and their interplay in the early stages of hyperglcyemia.

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