Angiotensin II Regulates Th1 T Cell Differentiation Through Angiotensin II Type 1 Receptor-PKA-Mediated Activation of Proteasome

Background/Aims: Naive CD4+ T cells differentiate into T helper cells (Th1 and Th2) that play an essential role in the cardiovascular diseases. However, the molecular mechanism by which angiotensin II (Ang II) promotes Th1 differentiation remains unclear. The aim of this study was to determine whether the Ang II-induced Th1 differentiation regulated by ubiquitin-proteasome system (UPS). Methods: Jurkat cells were treated with Ang II (100 nM) in the presence or absence of different inhibitors. The gene mRNA levels were detected by real-time quantitative PCR analysis. The protein levels were measured by ELISA assay or Western blot analysis, respectively. Results: Ang II treatment significantly induced a shift from Th0 to Th1 cell differentiation, which was markedly blocked by angiotensin II type 1 receptor (AT1R) inhibitor Losartan (LST). Moreover, Ang II significantly increased the activities and the expression of proteasome catalytic subunits (β1, β1i, β2i and β5i) in a dose- and time-dependent manner. However, Ang II-induced proteasome activities were remarkably abrogated by LST and PKA inhibitor H-89. Mechanistically, Ang II-induced Th1 differentiation was at least in part through proteasome-mediated degradation of IκBα and MKP-1 and activation of STAT1 and NF-κB. Conclusions: This study for the first time demonstrates that Ang II activates AT1R-PKA-proteasome pathway, which promotes degradation of IκBα and MKP-1 and activation of STAT1 and NF-κB thereby leading to Th1 differentiation. Thus, inhibition of proteasome activation might be a potential therapeutic target for Th1-mediated diseases.

Download Full-text

Angiotensin II Suppresses Rev-erbα Expression in THP-1 Macrophages via the Ang II Type 1 Receptor/Liver X Receptor α Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000488431 ◽

2018 ◽

Vol 46 (1) ◽

pp. 303-313 ◽

Cited By ~ 1

Author(s):

Shipeng Wang ◽

Xia Gu ◽

Qi Zhang ◽

Xiling Zhang ◽

Yilan Li ◽

...

Keyword(s):

Angiotensin Ii ◽

Protein Expression ◽

Atherosclerotic Lesion ◽

Liver X Receptor ◽

Time Dependent ◽

Dependent Manner ◽

Ang Ii ◽

Raw264.7 Macrophages ◽

Liver X Receptor Α

Background/Aims: Angiotensin II (Ang II) regulates the expression of some core clock genes; excess Ang II leads to atherosclerosis advancement. Macrophage Rev-erbα mediates clockwork and inflammation, and plays a role in atherosclerotic lesion progression. However, the role of Ang II in regulating Rev-erbα expression in macrophages remains unclarified. Methods: We induced THP-1 macrophages by phorbol 12-myristate 13-acetate and investigated the effect of Ang II on Rev-erbα expression via real-time polymerase chain reaction, western blotting and small interfering RNA (siRNA) techniques. The cytotoxicity of the Rev-erbα agonist SR9009 was analyzed using a (3-[4,5-dimethylthiazol-2-yl])-2,5- diphenyltetrazolium bromide assay. Results: Ang II suppressed Rev-erbα mRNA and protein expression in THP-1 macrophages in a dose and time dependent manner. This effect was mediated via Ang II type 1 receptor (AT1R), and not Ang II type 2 receptor or peroxisome proliferator-activated receptor γ (PPARγ). Consistent with Rev-erbα expression regulated by Ang II, the liver X receptor α (LXRα) protein expression was downregulated in a time-dependent manner after Ang II treatment. The activation or silence of LXRα significantly increased or decreased Rev-erbα expression regulated by Ang II, respectively. This suggests that LXRα is involved in the effect of Ang II on Rev-erbα expression. MMP-9 mRNA expressions were significantly suppressed by SR9009 in THP-1 and RAW264.7 macrophages; moreover, SR9009-treatment significantly reduced Ang II–induced MMP-9 protein expressions in two types of macrophages. Conclusion: Ang II downregulates Rev-erbα expression in THP-1 macrophages via the AT1R/LXRα pathway.

Download Full-text

Angiotensin II type 1 receptor blocker attenuates the activation of ERK and NADPH oxidase by mechanical strain in mesangial cells in the absence of angiotensin II

AJP Renal Physiology ◽

10.1152/ajprenal.00580.2007 ◽

2009 ◽

Vol 296 (5) ◽

pp. F1052-F1060 ◽

Cited By ~ 24

Author(s):

Junichi Yatabe ◽

Hironobu Sanada ◽

Midori Sasaki Yatabe ◽

Shigeatsu Hashimoto ◽

Minoru Yoneda ◽

...

Keyword(s):

Oxidative Stress ◽

Angiotensin Ii ◽

Nadph Oxidase ◽

Mesangial Cells ◽

Mechanical Strain ◽

Dependent Manner ◽

Ang Ii ◽

Erk Phosphorylation ◽

Extracellular Signal

It has been reported that mechanical strain activates extracellular signal-regulated protein kinases (ERK) without the involvement of angiotensin II (Ang II) in cardiomyocytes. We examined the effects of mechanical strain on ERK phosphorylation levels in the absence of Ang II using rat mesangial cells. The ratio of phosphorylated ERK (p-ERK) to total ERK expression was increased by cyclic mechanical strain in a time- and elongation strength-dependent manner. With olmesartan [Ang II type 1 receptor (AT1R) antagonist] pretreatment, p-ERK plateau levels decreased in a dose-dependent manner (EC50 = 1.3 × 10−8 M, maximal inhibition 50.6 ± 11.0% at 10−5 M); a similar effect was observed with RNA interference against Ang II type 1A receptor (AT1AR) and Tempol, a superoxide dismutase mimetic. In addition to the inhibition of p-ERK levels, olmesartan blocked the increase in cell surface and phosphorylated p47phox induced by mechanical strain and also lowered the mRNA expression levels of NADPH oxidase subunits. These results demonstrate that mechanical strain stimulates AT1R to phosphorylate ERK in mesangial cells in the absence of Ang II. This mechanotransduction mechanism is involved in the oxidative stress caused by NADPH oxidase and is blocked by olmesartan. The inverse agonistic activity of this AT1R blocker may be useful for the prevention of mesangial proliferation and renal damage caused by mechanical strain/oxidative stress regardless of circulating or tissue Ang II levels.

Download Full-text

mTORC1 Signaling Contributes to Drinking But Not Blood Pressure Responses to Brain Angiotensin II

Endocrinology ◽

10.1210/en.2016-1243 ◽

2016 ◽

Vol 157 (8) ◽

pp. 3140-3148 ◽

Cited By ~ 4

Author(s):

Kenjiro Muta ◽

Donald A. Morgan ◽

Justin L. Grobe ◽

Curt D. Sigmund ◽

Kamal Rahmouni

Keyword(s):

Angiotensin Ii ◽

Water Intake ◽

Drinking Behavior ◽

Subfornical Organ ◽

Dependent Manner ◽

Ang Ii ◽

Mtorc1 Signaling ◽

Wide Range ◽

The Brain

Mechanistic target of rapamycin complex 1 (mTORC1) is a molecular node that couples extracellular cues to a wide range of cellular events controlling various physiological processes. Here, we identified mTORC1 signaling as a critical mediator of angiotensin II (Ang II) action in the brain. In neuronal GT1–7 cells, we show that Ang II stimulates neuronal mTORC1 signaling in an Ang II type 1 receptor-dependent manner. In mice, a single intracerebroventricular (ICV) injection or chronic sc infusion of Ang II activated mTORC1 signaling in the subfornical organ, a critical brain region in cardiovascular control and fluid balance. Moreover, transgenic sRA mice with brain-specific overproduction of Ang II displayed increased mTORC1 signaling in the subfornical organ. To test the functional role of brain mTORC1 in mediating the action of Ang II, we examined the consequence of mTORC1 inhibition with rapamycin on Ang II-induced increase in water intake and arterial pressure. ICV pretreatment with rapamycin blocked ICV Ang II-mediated increases in the frequency, duration, and amount of water intake but did not interfere with the pressor response evoked by Ang II. In addition, ICV delivery of rapamycin significantly reduced polydipsia, but not hypertension, of sRA mice. These results demonstrate that mTORC1 is a novel downstream pathway of Ang II type 1 receptor signaling in the brain and selectively mediates the effect of Ang II on drinking behavior.

Download Full-text

Angiotensin II plays a critical role in diabetic pulmonary fibrosis most likely via activation of NADPH oxidase-mediated nitrosative damage

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00629.2010 ◽

2011 ◽

Vol 301 (1) ◽

pp. E132-E144 ◽

Cited By ~ 34

Author(s):

Junling Yang ◽

Yi Tan ◽

Fenglian Zhao ◽

Zhongsen Ma ◽

Yuehui Wang ◽

...

Keyword(s):

Angiotensin Ii ◽

Nadph Oxidase ◽

Lung Fibrosis ◽

Critical Role ◽

Receptor Expression ◽

Lung Fibroblasts ◽

Dependent Manner ◽

Ang Ii ◽

Diabetic Mice

Diabetic patients have a high risk of pulmonary disorders that are usually associated with restrictive impairment of lung function, suggesting a fibrotic process (van den Borst B, Gosker HR, Zeegers MP, Schols AM. Chest 138: 393–406, 2010; Ehrlich SF, Quesenberry CP Jr, Van Den Eeden SK, Shan J, Ferrara A. Diabetes Care 33: 55–60, 2010). The present study was undertaken to define whether and how diabetes causes lung fibrosis. Lung samples from streptozotocin-induced type 1 diabetic mice, spontaneously developed type 1 diabetic OVE26 mice, and their age-matched controls were investigated with histopathological and biochemical analysis. Signaling mechanism was investigated with cultured normal human lung fibroblasts in vitro. In both diabetes models, histological examination with Sirius red and hemotoxylin and eosin stains showed fibrosis along with massive inflammatory cell infiltration. The fibrotic and inflammatory processes were confirmed by real-time PCR and Western blotting assays for the increased fibronectin, CTGF, PAI-1, and TNFα mRNA and protein expressions. Diabetes also significantly increased NADPH oxidase (NOX) expression and protein nitration along with upregulation of angiotensin II (Ang II) and its receptor expression. In cell culture, exposure of lung fibroblasts to Ang II increased CTGF expression in a dose- and time-dependent manner, which could be abolished by inhibition of superoxide, NO, and peroxynitrite accumulation. Furthermore, chronic infusion of Ang II to normal mice at a subpressor dose induced diabetes-like lung fibrosis, and Ang II receptor AT1 blocker (losartan) abolished the lung fibrotic and inflammatory responses in diabetic mice. These results suggest that Ang II plays a critical role in diabetic lung fibrosis, which is most likely caused by NOX activation-mediated nitrosative damage.

Download Full-text

Angiotensin II type 1 receptor: role in renal growth and gene expression during normal development

AJP Renal Physiology ◽

10.1152/ajprenal.1994.266.6.f911 ◽

1994 ◽

Vol 266 (6) ◽

pp. F911-F918 ◽

Cited By ~ 12

Author(s):

A. Tufro-McReddie ◽

D. W. Johns ◽

K. M. Geary ◽

H. Dagli ◽

A. D. Everett ◽

...

Keyword(s):

Gene Expression ◽

Body Weight ◽

Angiotensin Ii ◽

Mrna Levels ◽

Ang Ii ◽

Kidney Weight ◽

Renal Growth ◽

Renin Mrna

To determine whether angiotensin II (ANG II) modulates renal growth and renin and angiotensin type 1 (AT1) gene expression via AT1 during development, weanling rats were given ANG II antagonist losartan (DuP 753) for 3 wk. Body weight (g), kidney weight (g), and kidney weight-to-body weight ratio were lower in losartan-treated rats (162 +/- 7, 1.6 +/- 0.06, and 9.5 +/- 0.1 x 10(-3)) than in control rats (184 +/- 5, 1.8 +/- 0.07, and 10.1 +/- 0.1 x 10(-3); P < 0.05). Renal DNA content (mg/kidney) was lower in losartan-treated (2.4 +/- 0.17) than in control rats (3.3 +/- 0.31; P < 0.05), whereas protein-to-DNA and RNA-to-DNA ratios were similar in losartan-treated and control rats. Renin mRNA levels were sevenfold higher in losartan-treated than in control rats, as determined by quantitative standardized dot blot analysis. In addition, blockade of AT1 with losartan induced recruitment of renin-synthesizing and renin-containing cells in the renal vasculature, as determined by immunocytochemistry and in situ hybridization. To establish whether AT1 blockade has a direct effect on renin gene expression, freshly isolated renin-producing cells were exposed in vitro to losartan (10(-6) M) or culture media (control). Losartan induced a twofold increase in steady-state renin mRNA levels above control (P < 0.05). Intrarenal AT1 mRNA levels were not altered by losartan given either in vivo or in vitro to freshly dispersed cells. To define whether immature renin-secreting cells are responsive to ANG II, renin release was determined by reverse hemolytic plaque assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Download Full-text

Angiotensin II type 1 receptor-mediated stimulation of c-fos gene expression in astroglial cultures

AJP Cell Physiology ◽

10.1152/ajpcell.1993.265.4.c1046 ◽

1993 ◽

Vol 265 (4) ◽

pp. C1046-C1049 ◽

Cited By ~ 23

Author(s):

M. K. Raizada ◽

B. Rydzewski ◽

D. Lu ◽

C. Sumners

Keyword(s):

Gene Expression ◽

Angiotensin Ii ◽

Receptor Activation ◽

At1 Receptor ◽

Mrna Levels ◽

Ang Ii ◽

Astroglial Cells ◽

Pai 1 ◽

Stimulation Of

Angiotensin II (ANG II) stimulates plasminogen activator inhibitor 1 (PAI-1) gene expression in astroglial cells prepared from rat brains. In this study, we investigated whether c-fos gene expression may be involved in this cellular action of ANG II. Incubation of astroglial cultures with ANG II caused a time- and dose-dependent transient stimulation of the steady-state levels of c-fos mRNA, with a maximal stimulation of 50-fold observed with 100 nM ANG II within 30-45 min. This stimulation was completely abolished by the presence of the type 1 ANG II (AT1) receptor antagonist losartan but not by the type 2 ANG II receptor blocker PD-123177. Depolarization of brain cell cultures with 50 mM K+ also caused a 100-fold increase in c-fos mRNA levels, an effect partially blocked by losartan. These observations show that AT1 receptor activation stimulates expression of the c-fos gene, which may act as a third messenger in the regulation of cellular actions of ANG II, including PAI-1 gene expression in astroglial cells.

Download Full-text

Angiotensin II increases the permeability and PV-1 expression of endothelial cells

AJP Cell Physiology ◽

10.1152/ajpcell.00138.2011 ◽

2012 ◽

Vol 302 (1) ◽

pp. C267-C276 ◽

Cited By ~ 30

Author(s):

Csaba Bodor ◽

János Péter Nagy ◽

Borbála Végh ◽

Adrienn Németh ◽

Attila Jenei ◽

...

Keyword(s):

Endothelial Cells ◽

Angiotensin Ii ◽

Cell Surface ◽

Map Kinase ◽

Endothelial Permeability ◽

Mrna Levels ◽

Dependent Manner ◽

Ang Ii ◽

Permeability Changes ◽

Sb 203580

Angiotensin II (ANG II), the major effector molecule of the renin-angiotensin system (RAS), is a powerful vasoactive mediator associated with hypertension and renal failure. In this study the permeability changes and its morphological attributes in endothelial cells of human umbilical vein (HUVECs) were studied considering the potential regulatory role of ANG II. The effects of ANG II were compared with those of vascular endothelial growth factor (VEGF). Permeability was determined by 40 kDa FITC-Dextran and electrical impedance measurements. Plasmalemmal vesicle-1 (PV-1) mRNA levels were measured by PCR. Endothelial cell surface was studied by atomic force microscopy (AFM), and caveolae were visualized by transmission electron microscopy (TEM) in HUVEC monolayers. ANG II (10−7 M), similarly to VEGF (100 ng/ml), increased the endothelial permeability parallel with an increase in the number of cell surface openings and caveolae. AT1 and VEGF-R2 receptor blockers (candesartan and ZM-323881, respectively) blunted these effects. ANG II and VEGF increased the expression of PV-1, which could be blocked by candesartan or ZM-323881 pretreatments and by the p38 mitogem-activated protein (MAP) kinase inhibitor SB-203580. Additionally, SB-203580 blocked the increase in endothelial permeability and the number of surface openings and caveolae. In conclusion, we have demonstrated that ANG II plays a role in regulation of permeability and formation of cell surface openings through AT1 receptor and PV-1 protein synthesis in a p38 MAP kinase-dependent manner in endothelial cells. The surface openings that increase in parallel with permeability may represent transcellular channels, caveolae, or both. These morphological and permeability changes may be involved in (patho-) physiological effects of ANG II.

Download Full-text

Regulation of Angiotensin II–induced Neuromodulation by MARCKS in Brain Neurons

The Journal of Cell Biology ◽

10.1083/jcb.142.1.217 ◽

1998 ◽

Vol 142 (1) ◽

pp. 217-227 ◽

Cited By ~ 37

Author(s):

Di Lu ◽

Hong Yang ◽

Robert H. Lenox ◽

Mohan K. Raizada

Keyword(s):

Angiotensin Ii ◽

Map Kinase ◽

Receptor Subtype ◽

Mrna Levels ◽

Ang Ii ◽

Kinase Substrate ◽

Kinase C ◽

Uptake Activity ◽

Stimulation Of

Angiotensin II (Ang II) exerts chronic stimulatory actions on tyrosine hydroxylase (TH), dopamine β-hydroxylase (DβH), and the norepinephrine transporter (NET), in part, by influencing the transcription of their genes. These neuromodulatory actions of Ang II involve Ras-Raf-MAP kinase signal transduction pathways (Lu, D., H. Yang, and M.K. Raizada. 1997. J. Cell Biol. 135:1609–1617). In this study, we present evidence to demonstrate participation of another signaling pathway in these neuronal actions of Ang II. It involves activation of protein kinase C (PKC)β subtype and phosphorylation and redistribution of myristoylated alanine-rich C kinase substrate (MARCKS) in neurites. Ang II caused a dramatic redistribution of MARCKS from neuronal varicosities to neurites. This was accompanied by a time-dependent stimulation of its phosphorylation, that was mediated by the angiotensin type 1 receptor subtype (AT1). Incubation of neurons with PKCβ subtype specific antisense oligonucleotide (AON) significantly attenuated both redistribution and phosphorylation of MARCKS. Furthermore, depletion of MARCKS by MARCKS-AON treatment of neurons resulted in a significant decrease in Ang II–stimulated accumulation of TH and DβH immunoreactivities and [3H]NE uptake activity in synaptosomes. In contrast, mRNA levels of TH, DβH, and NET were not influenced by MARKS-AON treatment. MARCKS pep148–165, which contains PKC phosphorylation sites, inhibited Ang II stimulation of MARCKS phosphorylation and reduced the amount of TH, DβH, and [3H]NE uptake in neuronal synaptosomes. These observations demonstrate that phosphorylation of MARCKS by PKCβ and its redistribution from varicosities to neurites is important in Ang II–induced synaptic accumulation of TH, DβH, and NE. They suggest that a coordinated stimulation of transcription of TH, DβH, and NET, mediated by Ras-Raf-MAP kinase followed by their transport mediated by PKCβ-MARCKS pathway are key in persistent stimulation of Ang II's neuromodulatory actions.

Download Full-text

Pan-Histone Deacetylase (HDAC) Inhibitor LBH589 Depletes CXCR4 Levels and Signaling, Exerting Synergistic Anti-Leukemia Activity in Combination with CXCR4 Antagonists.

Blood ◽

10.1182/blood.v110.11.537.537 ◽

2007 ◽

Vol 110 (11) ◽

pp. 537-537

Author(s):

Aditya Mandawat ◽

Warren Fiskus ◽

Andrea Jakubowski ◽

Rekha Rao ◽

Zixuan Wang ◽

...

Keyword(s):

Acute Leukemia ◽

Hdac Inhibitor ◽

Jurkat Cells ◽

Pcr Analysis ◽

Mrna Levels ◽

Dependent Manner ◽

Cxcr4 Antagonist ◽

Acute Leukemias

Abstract The trafficking and mobilization of normal hematopoietic progenitors and their leukemic counterparts is programmed in part by chemotactic gradients of CXCL12, which are transduced by CXCR4. This mechanism also results in decreased sensitivity to pro-apoptotic and anti-leukemic agents, mediated through CXCR4 activation of Akt and Raf phosphorylation and/or harboring in a microenvironmental niche. Both CXCL12 and CXCR4 are overexpressed in AML and expression of CXCR4 has been associated with a poor prognosis. Moreover, inhibition of CXCR4 with AMD3100 enhanced the sensitivity of leukemic myeloblasts to anti-leukemic agents. We therefore explored therapeutic mechanisms to decrease CXCR4 expression and tested them in combination with AMD3100 as well as a new generation CXCR4 inverse agonist, FC131. Exposure to 10 to 50 nM of the pan-HDAC inhibitor LBH589 (Novartis) depleted mRNA and protein levels of CXCR4 in the cultured human acute leukemia OCI-AML3, HL-60 and Jurkat cells, as well as in primary AML cells in a dose and time-dependent manner. LBH589 depleted CXCR4 levels in the presence or absence of 10 nM of CXCL12 in the culture medium. LBH589 mediated depletion of CXCR4 levels was partly due to decreased CXCR4 mRNA levels (by RT-PCR analysis). LBH589 induced acetylation of heat shock protein (hsp) 90 and attenuated the binding of CXCR4 to hsp90 with subsequent degradation of CXCR4 by the proteasome. LBH589 treatment also increased hsp70 levels and acetylation, as well as its binding to CXCR4, which also resulted in increased extra-cellular, cell surface co-localization of CXCR4 and hsp70. This was markedly inhibited by siRNA-mediated knockdown of hsp70 in HL-60 cells. While exposure of cultured and primary AML cells to CXCL12 markedly increased cytosolic levels of p-AKT and p-ERK1/2, co-treatment with LBH589 markedly attenuated the phosphorylation of AKT and ERK1/2 induced by CXCL12, resulting in apoptosis of up to 50% of cultured and primary AML cells. Treatment with AMD3100 (10 uM for 24 hours) alone decreased levels of CXCR4, p-AKT and p-ERK1/2, without significantly increasing apoptosis of AML cells. Notably, co-treatment with LBH589 and AMD3100 caused greater depletion of CXCR4, p-AKT and p-ERK1/2 levels, and exerted synergistic apoptotic effects against AML cells with combination indices of < 1.0 utilizing isobologram and median effect analyses. Co-treatment with LBH589 and FC131 (10 nM for 24 hours), which is a more potent CXCR4 antagonist than AMD3100, also induced synergistic apoptosis of cultured and primary AML cells. Taken together, these findings provide direct evidence that CXCR4 is a novel target depleted by LBH589 in AML cells. Furthermore, our in vitro findings highlight the novel combination of LBH589 and a CXCR4 antagonist, AMD3100 or FC131, exerts a synergistic effect on acute leukemia cells. These findings strongly support the in vivo testing of this synergistic combination in the therapy of human acute leukemias that express CXCR4.

Download Full-text

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.

Download Full-text