Angiotensin II modulates nitric oxide-induced cardiac fibroblast apoptosis by activation of AKT/PKB

2003 ◽  
Vol 285 (3) ◽  
pp. H1105-H1112 ◽  
Author(s):  
Bin Tian ◽  
Jian Liu ◽  
Peter Bitterman ◽  
Robert J. Bache
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Cardiac Fibroblast ◽  
Inos Expression ◽  
No Production ◽  
Ang Ii ◽  
Phosphatidylinositol 3 Kinase ◽  
No Donor ◽  
At1 Antagonist ◽  
Phosphatidylinositol 3

Previously we found that interleukin-1β (IL-1β)-activated inducible nitric oxide (NO) synthase (iNOS) expression and that NO production can trigger cardiac fibroblast (CFb) apoptosis. Here, we provide evidence that angiotensin II (ANG II) significantly attenuated IL-1β-induced iNOS expression and NO production in CFbs while simultaneously decreasing apoptotic frequency. The anti-apoptotic effect of ANG II was abolished when cells were pretreated with the specific ANG II type 1 receptor (AT1) antagonist losartan, but not by the AT2 antagonist DP-123319. Furthermore, ANG II also protected CFbs from apoptosis induced by the NO donor diethylenetriamine NONOate and this effect was associated with phosphorylation of Akt/protein kinase B at Ser473. The effects of ANG II on Akt phosphorylation and NO donor-induced CFb apoptosis were abrogated when cells were preincubated with the specific phosphatidylinositol 3-kinase inhibitors wortmannin or LY-294002. These data demonstrate that ANG II protection of CFbs from IL-1β-induced apoptosis is associated with downregulation of iNOS expression and requires an intact phosphatidylinositol 3-kinase-Akt survival signal pathway. The findings suggest that ANG II and NO may play a role in regulating the cell population size by their countervailing influences on cardiac fibroblast viability.

Tanshinone IIA Inhibits Angiotensin II-Induced Cell Proliferation in Rat Cardiac Fibroblasts

2011 ◽  
Vol 39 (02) ◽  
pp. 381-394 ◽  
Author(s):  
Paul Chan ◽  
Ju-Chi Liu ◽  
Li-Jen Lin ◽  
Po-Yuan Chen ◽  
Tzu-Hurng Cheng ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cell Proliferation ◽  
Angiotensin Ii ◽  
Cardiac Fibroblasts ◽  
Tanshinone Iia ◽  
No Production ◽  
Ang Ii ◽  
Erk Phosphorylation ◽  
Enos Phosphorylation ◽  
Ros Formation

Tanshinone IIA extracted from Danshen, a popular medicinal herb used in traditional Chinese medicine, exhibits cardio-protective effects. However, the mechanism of its cardioprotective effect is not well established. The aims of this study were to examine whether tanshinone IIA may alter angiotensin II (Ang II)-induced cell proliferation and to identify the putative underlying signaling pathways in rat cardiac fibroblasts. Cultured rat cardiac fibroblasts were pre-treated with tanshinone IIA and stimulated with Ang II, cell proliferation and endothelin-1 (ET-1) expression were examined. The effect of tanshinone IIA on Ang II-induced reactive oxygen species (ROS) formation, and extracellular signal-regulated kinase (ERK) phosphorylation were also examined. In addition, the effect of tanshinone IIA on nitric oxide (NO) production, and endothelial nitric oxide synthase (eNOS) phosphorylation were tested to elucidate the intracellular mechanism. The increased cell proliferation and ET-1 expression by Ang II (100 nM) were partially inhibited by tanshinone IIA. Tanshinone IIA also inhibited Ang II-increased ROS formation, and ERK phosphorylation. In addition, tanshinone IIA was found to increase the NO generation, and eNOS phosphorylation. NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS, and the short interfering RNA transfection for eNOS markedly attenuated the inhibitory effect of tanshinone IIA on Ang II-induced cell proliferation. The results suggest that tanshinone IIA prevents cardiac fibroblast proliferation by interfering with the generation of ROS and involves the activation of the eNOS-NO pathway.

Angiotensin II decreases inducible nitric oxide synthase expression in rat astroglial cultures

1995 ◽  
Vol 268 (3) ◽  
pp. C700-C707 ◽  
Author(s):  
L. J. Chandler ◽  
K. Kopnisky ◽  
E. Richards ◽  
F. T. Crews ◽  
C. Sumners
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Nitric Oxide Synthase ◽  
Receptor Antagonist ◽  
Maximal Response ◽  
No Production ◽  
Dependent Manner ◽  
Ang Ii ◽  
Subsequent Formation ◽  
Oxide Synthase

Consistent with stimulation of expression of an inducible form of nitric oxide synthase (iNOS), exposure of rat astroglial cultures to lipopolysaccharide (LPS) caused a time-dependent increase in the accumulation of nitrite in the culture media. Addition of the peptide angiotensin II (ANG II) with LPS decreased subsequent formation of nitrite in a concentration-dependent manner (concentration inhibiting 50% of maximal response approximately 1 nM). The ANG II effect could be blocked by the ANG II type 1 (AT1 receptor antagonist losartan but not by the ANG II type 2 (AT2) receptor antagonist PD-123177. ANG II had no effect on nitrite formation stimulated by a combination of inflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha, and interferon-gamma). A brief 10-min exposure to ANG II was sufficient to cause an approximately 30% inhibition of the LPS response, with maximal inhibition of approximately 65% after 3 h, and occurred only when ANG II was added during the iNOS induction phase. Consistent with partial inhibition of LPS-stimulated expression of iNOS, ANG II reduced the levels of both iNOS mRNA and iNOS protein. These results demonstrate that ANG II can decrease LPS-stimulated NO production in astroglia by inhibiting induction of iNOS expression.

Angiotensin II receptor subtypes determine induced NO production in rat glomerular mesangial cells

2000 ◽  
Vol 279 (6) ◽  
pp. F1092-F1100 ◽  
Author(s):  
Jörg Schwöbel ◽  
Tina Fischer ◽  
Bettina Lanz ◽  
Markus Mohaupt
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Mesangial Cells ◽  
Receptor Expression ◽  
Receptor Subtypes ◽  
No Production ◽  
Ang Ii ◽  
Glomerular Mesangial Cells ◽  
Nitrite Production ◽  
The Impact

Angiotensin II (ANG II) and nitric oxide (NO) have contrasting vascular effects, yet both sustain inflammatory responses. We investigated the impact of ANG II on lipopolysaccharide (LPS)/interferon-γ (IFN)-induced NO production in cultured rat mesangial cells (MCs). LPS/IFN-induced nitrite production, the inducible form of nitric oxide synthase (NOS-2) mRNA, and protein expression were dose dependently inhibited by ANG II on coincubation, which was abolished on ANG II type 2 (AT2) receptor blockade by PD-123319. Homology-based RT-PCR verified the presence of AT1A, AT1B, and AT2 receptors. To shift the AT receptor expression toward the type 1 receptor, two sets of experiments were performed: LPS/IFN preincubation for 24 h was followed by 8-h coincubation with ANG II; or during 24-h coincubation of LPS/IFN and ANG II, dexamethasone was added for the last 6-h period. Both led to an amplified overall expression of NOS-2 protein and NO production that was inhibitable by actinomycin D in the first setup. Induced NO production was enhanced via the AT1 receptor; however, it was diminished via the AT2 receptor. In conclusion, induced NO production is negatively controlled by the AT2, whereas AT1 receptor stimulation enhanced NO synthesis in MCs. The overall NO availability depended on the onset of the inflammatory stimuli with respect to ANG II exposure and the available AT receptors.

Involvement of endogenous nitric oxide in angiotensin II-induced activation of vascular mitogen-activated protein kinases

2007 ◽  
Vol 293 (4) ◽  
pp. H2403-H2408 ◽  
Author(s):  
Guo-Xing Zhang ◽  
Yukiko Nagai ◽  
Toshitaka Nakagawa ◽  
Hiroshi Miyanaka ◽  
Yoshihide Fujisawa ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Map Kinase ◽  
Map Kinases ◽  
No Synthase ◽  
Dependent Manner ◽  
Ang Ii ◽  
No Donor ◽  
Mitogen Activated Protein ◽  
Kinase Phosphorylation

Angiotensin II (ANG II) is a powerful activator of mitogen-activated protein (MAP) kinase cascades in cardiovascular tissues through a redox-sensitive mechanism. Nitric oxide (NO) is considered to antagonize the vasoconstrictive and proarteriosclerotic actions of ANG II. However, the role of endogenous NO in ANG II-induced redox-sensitive signal transduction is not yet clear. In this study using catheterized, conscious rats, we found that acute intravenous administration of NG-nitro-l-arginine methyl ester (l-NAME; 5 mg/kg) enhanced phosphorylation of aortic MAP kinases extracellular signal regulated kinase (ERK) 1/2 and p38, which were suppressed only partially by a superoxide dismutase mimetic (Tempol), whereas ANG II-induced MAP kinase phosphorylation was markedly suppressed by Tempol. FK409, a NO donor, had little effect on vascular MAP kinase phosphorylation. On the other hand, acute exposure to a vasoconstrictor dose of ANG II (200 ng·kg−1·min−1 iv) failed to enhance phosphorylation of aortic MAP kinases in the chronically l-NAME-treated rats, whereas the vasoconstrictor effect of ANG II was not affected by l-NAME treatment. Furthermore, three different inhibitors of NO synthase suppressed, in a dose-dependent manner, ANG II-induced MAP kinase phosphorylation in rat vascular smooth muscle cells, which was closely linked to superoxide generation in cells. These results indicate the involvement of endogenous NO synthase in ANG II-induced signaling pathways, leading to activation of MAP kinase, and that NO may have dual effects on the vascular MAP kinase activation associated with redox sensitivity.

Nitric oxide modulates angiotensin II- and norepinephrine-dependent vasoconstriction in rat kidney

1996 ◽  
Vol 270 (3) ◽  
pp. R630-R635 ◽  
Author(s):  
N. Parekh ◽  
L. Dobrowolski ◽  
A. P. Zou ◽  
M. Steinhausen
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Angiotensin Ii ◽  
Rat Kidney ◽  
Ang Ii ◽  
No Donor ◽  
Renal Vasoconstriction ◽  
Medullary Blood Flow ◽  
Series Of Experiments ◽  
Synthase Inhibitor

This study compared the vasoconstrictor action of angiotensin II (ANG II) and norepinephrine (NE) with different levels of nitric oxide (NO) in the kidney of anesthetized rats. In one series of experiments, the drugs were infused intravenously, and systemic NO content was reduced by a NO synthase inhibitor, nitro-L-arginine methyl ester (L-NAME). L-NAME significantly enhanced the renal blood flow (RBF) reduction produced by ANG II from 26 to 49%, but it had no significant effect on the change in RBF induced by NE. Medullary blood flow was not influenced by either ANG II or NE given alone or given after L-NAME. In the second series of experiments, all drugs were infused into the renal artery to avoid their systemic and, hence, extrarenal effects. In these experiments, renal content of NO was increased by the NO donor sodium nitroprusside (SNP), decreased by L-NAME, or restored by replacing endogenous NO by exogenous NO (L-NAME + SNP). Effects of both ANG II and NE on RBF were similarly and significantly attenuated by SNP (60% of control), enhanced by L-NAME (200% of control), and restored by L-NAME + SNP (90% of control, not significant). Our results indicate that NO attenuates the renal vasoconstriction due to ANG II or NE and that the antagonism between vasoconstrictors and NO is not due to a constrictor-induced production of NO because exogenous and endogenous NO were equally effective.

scholarly journals Angiotensin II-mediated hypertension impairs nitric oxide-induced NKCC2 inhibition in thick ascending limbs

2016 ◽  
Vol 310 (8) ◽  
pp. F748-F754 ◽  
Author(s):  
Vanesa D. Ramseyer ◽  
Pablo A. Ortiz ◽  
Oscar A. Carretero ◽  
Jeffrey L. Garvin
Keyword(s):  
Nitric Oxide ◽  
Pde5 Inhibitor ◽  
Cell Types ◽  
No Production ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
No Donor ◽  
Induced Hypertension ◽  
Stimulation Of

In thick ascending limbs (THALs), nitric oxide (NO) decreases NaCl reabsorption via cGMP-mediated inhibition of Na-K-2Cl cotransporter (NKCC2). In angiotensin (ANG II)-induced hypertension, endothelin-1 (ET-1)-induced NO production by THALs is impaired. However, whether this alters NO's natriuretic effects and the mechanisms involved are unknown. In other cell types, ANG II augments phosphodiesterase 5 (PDE5)-mediated cGMP degradation. We hypothesized that NO-mediated inhibition of NKCC2 activity and stimulation of cGMP synthesis are blunted via PDE5 in ANG II-induced hypertension. Sprague-Dawley rats were infused with vehicle or ANG II (200 ng·kg−1·min−1) for 5 days. ET-1 reduced NKCC2 activity by 38 ± 13% ( P < 0.05) in THALs from vehicle-treated rats but not from ANG II-hypertensive rats (Δ: −9 ± 13%). A NO donor yielded similar results as ET-1. In contrast, dibutyryl-cGMP significantly decreased NKCC2 activity in both vehicle-treated and ANG II-hypertensive rats (control: Δ−44 ± 15% vs. ANG II: Δ−41 ± 10%). NO increased cGMP by 2.08 ± 0.36 fmol/μg protein in THALs from vehicle-treated rats but only 1.06 ± 0.25 fmol/μg protein in ANG II-hypertensive rats ( P < 0.04). Vardenafil (25 nM), a PDE5 inhibitor, restored NO's ability to inhibit NKCC2 activity in THALs from ANG II-hypertensive rats (Δ: −60 ± 9%, P < 0.003). Similarly, NO's stimulation of cGMP was also restored by vardenafil (vehicle-treated: 1.89 ± 0.71 vs. ANG II-hypertensive: 2.02 ± 0.32 fmol/μg protein). PDE5 expression did not differ between vehicle-treated and ANG II-hypertensive rats. We conclude that NO-induced inhibition of NKCC2 and increases in cGMP are blunted in ANG II-hypertensive rats due to PDE5 activation. Defects in the response of THALs to NO may enhance NaCl retention in ANG II-induced hypertension.

scholarly journals Signal Regulatory Protein α Ligation Induces Macrophage Nitric Oxide Production through JAK/STAT- and Phosphatidylinositol 3-Kinase/Rac1/NAPDH Oxidase/H2O2-Dependent Pathways

2005 ◽  
Vol 25 (16) ◽  
pp. 7181-7192 ◽  
Author(s):  
Jacqueline Alblas ◽  
Henk Honing ◽  
Chantal Renardel de Lavalette ◽  
Marion H. Brown ◽  
Christine D. Dijkstra ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Regulatory Protein ◽  
Host Cells ◽  
No Production ◽  
Phosphatidylinositol 3 Kinase ◽  
Necrosis Factor Alpha ◽  
Cooperative Action ◽  
Factor Alpha ◽  
Oxide Synthase ◽  
Phosphatidylinositol 3

ABSTRACT Signal regulatory protein α (SIRPα) is a glycoprotein receptor that recruits and signals via the tyrosine phosphatases SHP-1 and SHP-2. In macrophages SIRPα can negatively regulate the phagocytosis of host cells and the production of tumor necrosis factor alpha. Here we provide evidence that SIRPα can also stimulate macrophage activities, in particular the production of nitric oxide (NO) and reactive oxygen species. Ligation of SIRPα by antibodies or soluble CD47 triggers inducible nitric oxide synthase expression and production of NO. This was not caused by blocking negative-regulatory SIRPα-CD47 interactions. SIRPα-induced NO production was prevented by inhibition of the tyrosine kinase JAK2. JAK2 was found to associate with SIRPα in macrophages, particularly after SIRPα ligation, and SIRPα stimulation resulted in JAK2 and STAT1 tyrosine phosphorylation. Furthermore, SIRPα-induced NO production required the generation of hydrogen peroxide (H2O2) by a NADPH oxidase (NOX) and the phosphatidylinositol 3-kinase (PI3-K)-dependent activation of Rac1, an intrinsic NOX component. Finally, SIRPα ligation promoted SHP-1 and SHP-2 recruitment, which was both JAK2 and PI3-K dependent. These findings demonstrate that SIRPα ligation induces macrophage NO production through the cooperative action of JAK/STAT and PI3-K/Rac1/NOX/H2O2 signaling pathways. Therefore, we propose that SIRPα is able to function as an activating receptor.

scholarly journals Activation of Endothelial Nitric Oxide Synthase by the Angiotensin II Type 1 Receptor

Endocrinology ◽  
2006 ◽  
Vol 147 (12) ◽  
pp. 5914-5920 ◽  
Author(s):  
Hiroyuki Suzuki ◽  
Kunie Eguchi ◽  
Haruhiko Ohtsu ◽  
Sadaharu Higuchi ◽  
Sudhir Dhobale ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Enos Gene ◽  
No Production ◽  
Hypertrophic Response ◽  
Cgmp Production ◽  
At1 Antagonist

Enhanced angiotensin II (AngII) action has been implicated in endothelial dysfunction that is characterized as decreased nitric oxide availability. Although endothelial cells have been reported to express AngII type 1 (AT1) receptors, the exact role of AT1 in regulating endothelial NO synthase (eNOS) activity remains unclear. We investigated the possible regulation of eNOS through AT1 in bovine aortic endothelial cells (BAECs) and its functional significance in rat aortic vascular smooth muscle cells (VSMCs). In BAECs infected with adenovirus encoding AT1 and in VSMCs infected with adenovirus encoding eNOS, AngII rapidly stimulated phosphorylation of eNOS at Ser1179. This was accompanied with increased cGMP production. These effects were blocked by an AT1 antagonist. The cGMP production was abolished by a NOS inhibitor as well. To explore the importance of eNOS phosphorylation, VSMCs were also infected with adenovirus encoding S1179A-eNOS. AngII did not stimulate cGMP production in VSMCs expressing S1179A. However, S1179A was able to enhance basal NO production as confirmed with cGMP production and enhanced vasodilator-stimulated phosphoprotein phosphorylation. Interestingly, S1179A prevented the hypertrophic response similar to wild type in VSMCs. From these data, we conclude that the AngII/AT1 system positively couples to eNOS via Ser1179 phosphorylation in ECs and VSMCs if eNOS and AT1 coexist. However, basal level NO production may be sufficient for prevention of AngII-induced hypertrophy by eNOS expression. These data demonstrate a novel molecular mechanism of eNOS regulation and function and thus provide useful information for eNOS gene therapy under endothelial dysfunction.

scholarly journals Nuclear angiotensin II type 2 (AT2) receptors are functionally linked to nitric oxide production

2009 ◽  
Vol 296 (6) ◽  
pp. F1484-F1493 ◽  
Author(s):  
TanYa M. Gwathmey ◽  
Hossam A. Shaltout ◽  
Karl D. Pendergrass ◽  
Nancy T. Pirro ◽  
Jorge P. Figueroa ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Molecular Form ◽  
Rat Kidney ◽  
Renin Angiotensin System ◽  
Receptor Subtypes ◽  
No Production ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin

Expression of nuclear angiotensin II type 1 (AT1) receptors in rat kidney provides further support for the concept of an intracellular renin-angiotensin system. Thus we examined the cellular distribution of renal ANG II receptors in sheep to determine the existence and functional roles of intracellular ANG receptors in higher order species. Receptor binding was performed using the nonselective ANG II antagonist 125I-[Sar1,Thr8]-ANG II (125I-sarthran) with the AT1 antagonist losartan (LOS) or the AT2 antagonist PD123319 (PD) in isolated nuclei (NUC) and plasma membrane (PM) fractions obtained by differential centrifugation or density gradient separation. In both fetal and adult sheep kidney, PD competed for the majority of cortical NUC (≥70%) and PM (≥80%) sites while LOS competition predominated in medullary NUC (≥75%) and PM (≥70%). Immunodetection with an AT2 antibody revealed a single ∼42-kDa band in both NUC and PM extracts, suggesting a mature molecular form of the NUC receptor. Autoradiography for receptor subtypes localized AT2 in the tubulointerstitium, AT1 in the medulla and vasa recta, and both AT1 and AT2 in glomeruli. Loading of NUC with the fluorescent nitric oxide (NO) detector DAF showed increased NO production with ANG II (1 nM), which was abolished by PD and N-nitro-l-arginine methyl ester, but not LOS. Our studies demonstrate ANG II receptor subtypes are differentially expressed in ovine kidney, while nuclear AT2 receptors are functionally linked to NO production. These findings provide further evidence of a functional intracellular renin-angiotensin system within the kidney, which may represent a therapeutic target for the regulation of blood pressure.

scholarly journals Nitric oxide reduces Cl− absorption in the mouse cortical collecting duct through an ENaC-dependent mechanism

2013 ◽  
Vol 304 (11) ◽  
pp. F1390-F1397 ◽  
Author(s):  
Vladimir Pech ◽  
Monika Thumova ◽  
Sergey I. Dikalov ◽  
Edith Hummler ◽  
Bernard C. Rossier ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Collecting Duct ◽  
No Synthase ◽  
Apical Plasma Membrane ◽  
No Production ◽  
Cortical Collecting Duct ◽  
No Donor ◽  
Genetic Ablation

Since nitric oxide (NO) participates in the renal regulation of blood pressure, in part, by modulating transport of Na+ and Cl− in the kidney, we asked whether NO regulates net Cl− flux ( JCl) in the cortical collecting duct (CCD) and determined the transporter(s) that mediate NO-sensitive Cl− absorption. Cl− absorption was measured in CCDs perfused in vitro that were taken from aldosterone-treated mice. Administration of an NO donor (10 μM MAHMA NONOate) reduced JCl and transepithelial voltage ( VT) both in the presence or absence of angiotensin II. However, reducing endogenous NO production by inhibiting NO synthase (100 μM NG-nitro-l-arginine methyl ester) increased JCl only in the presence of angiotensin II, suggesting that angiotensin II stimulates NO synthase activity. To determine the transport process that mediates NO-sensitive changes in JCl, we examined the effect of NO on JCl following either genetic ablation or chemical inhibition of transporters in the CCD. Since the application of hydrochlorothiazide (100 μM) or bafilomycin (5 nM) to the perfusate or ablation of the gene encoding pendrin did not alter NO-sensitive JCl, NO modulates JCl independent of the Na+-dependent Cl−/HCO3− exchanger (NDCBE, Slc4a8), the A cell apical plasma membrane H+-ATPase and pendrin. In contrast, both total and NO-sensitive JCl and VT were abolished with application of an epithelial Na+ channel (ENaC) inhibitor (3 μM benzamil) to the perfusate. We conclude that NO reduces Cl− absorption in the CCD through a mechanism that is ENaC-dependent.

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