scholarly journals Analysis of Genes Related to Angiotensin II-Induced Arterial Injury Using a Time Series Microarray

2018 ◽  
Vol 48 (3) ◽  
pp. 983-992 ◽  
Author(s):  
Yun-Long Zhang ◽  
Lian-Yun Zhi ◽  
Lei-Xin Zou ◽  
Chen Chen ◽  
Jie Bai ◽  
...  
Keyword(s):  
Time Series ◽  
Angiotensin Ii ◽  
Gene Network ◽  
Arterial Injury ◽  
Pathological Examination ◽  
Dependent Manner ◽  
Biological Processes ◽  
Ang Ii ◽  
Network Analyses ◽  
Time Series Microarray

Background/Aims: Angiotensin II (Ang II)-mediated hypertension is a major risk factor for cardiovascular diseases. Ang II induces changes in vessel structure and function through the activation of genes related to signaling pathways. However, the changes in the gene expression profiles of blood vessels in response to Ang II remain unclear. Methods: Wild-type C57BL/6 mice were infused with Ang II (1500 ng/kg/min) using an osmotic pump for 1, 3, and 7 days. Vascular wall inflammation and remodeling were evaluated by pathological examination. Time-series microarray and quantitative PCR analyses were performed. Bioinformatics analyses were conducted to identify key genes, pathways, and biological processes. Results: After Ang II infusion, blood pressure and aortic remodeling were increased over time. Microarray analysis identified a totally of 3631 differentially expressed genes in aortas at days 1, 3, and 7 of Ang II infusion. These genes were involved in multiple biological processes, including cell adhesion, angiogenesis, cell migration, protein phosphorylation, immune system, and cell cycle, which may play important roles in regulating Ang II-induced arterial injury during hypertension. The genes were classified into 50 profiles by hierarchical cluster analysis, and finally, 14 significant profiles were identified. Among these genes, protein kinase cAMP-activated catalytic subunit alpha (Prkaca), a gene that directly regulated 137 neighboring genes, was located at the center of the gene network in Ang II-infused aortas. Further, Prkaca protein expression and cAMP level were downregulated in a time-dependent manner in Ang II-infused aortas. Conclusions: The combined use of DNA microarrays and cluster and gene network analyses identified Prkaca as a key Ang II-responsive gene that may mediate early vascular injury and hypertension.

Modulation of Ca2+ transients in neonatal and adult rat cardiomyocytes by angiotensin II and endothelin-1

1996 ◽  
Vol 270 (3) ◽  
pp. H857-H868 ◽  
Author(s):  
R. M. Touyz ◽  
J. Fareh ◽  
G. Thibault ◽  
B. Tolloczko ◽  
R. Lariviere ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Receptor Agonist ◽  
Dependent Manner ◽  
Induced Responses ◽  
Ang Ii ◽  
Binding Studies ◽  
Vasoactive Peptides ◽  
Adult Cardiomyocytes ◽  
Etb Receptor ◽  
Dose Dependent

Vasoactive peptides may exert inotropic and chronotropic effects in cardiac muscle by modulating intracellular calcium. This study assesses effects of angiotensin II (ANG II) and endothelin-1 (ET-1) on intracellular free calcium concentration ([Ca2+]i) in cultured cardiomyocytes from neonatal and adult rats. [Ca2+]i was measured microphotometrically and by digital imaging using fura 2 methodology. Receptor subtypes through which these agonists induce responses were determined pharmacologically and by radioligand binding studies. ANG II and ET-1 increased neonatal atrial and ventricular cell [Ca2+]i transients in a dose-dependent manner. ANG II (10(-11) to 10(-7) M) failed to elicit [Ca2+]i responses in adult cardiomyocytes, whereas ET-1 increased [Ca2+]i in a dose-dependent manner. The ETA receptor antagonist BQ-123 significantly reduced (P 7< 0.05) ET-1 induced responses, and the ETB receptor agonist IRL-1620 (10(-7) to 10(-5) M) significantly increased (P < 0.05) [Ca2+]i in neonatal and adult cardiomyocytes. ET-1 binding studies demonstrated 85% displacement by BQ-123 and approximately 15% by the ETB receptor agonist sarafotoxin S6c, suggesting a predominance of ETA receptors. Competition binding studies for ANG II failed to demonstrate significant binding on adult ventricular myocytes, indicating the absence or presence of very few ANG II receptors. These data demonstrate that ANG II and ET-1 have stimulatory [Ca2+]i effects on neonatal cardiomyocytes, whereas in adult cardiomyocytes, ANG II-induced effects are insignificant, and only ET-1-induced responses, which are mediated predominantly via ETA receptors, are preserved. Cardiomyocyte responses to vasoactive peptides may thus vary with cardiac development.

Inhibition of angiotensinogen production by angiotensin II analogues in human hepatoma cell line

1989 ◽  
Vol 257 (5) ◽  
pp. C888-C895 ◽  
Author(s):  
E. Coezy ◽  
I. Darby ◽  
J. Mizrahi ◽  
B. Cantau ◽  
M. H. Donnadieu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cell Line ◽  
Binding Sites ◽  
Inhibitory Effect ◽  
Hepatoma Cell Line ◽  
Dependent Manner ◽  
Human Hepatoma ◽  
Ang Ii ◽  
Hep G2 ◽  
Dose Dependent

The aim of this study was to examine in Hep G2, a human hepatoma-derived cell line, the presence of angiotensin II (ANG II) receptors and the effect of ANG II and its analogues on angiotensinogen production. The presence of ANG II receptors was demonstrated using a long-acting ANG II analogue, 125I-labeled [Sar1]ANG II. A single class of specific binding sites was identified in these cells with a dissociation constant (Kd) of 2 nM. The number and affinity of these binding sites were not changed by [Sar1]ANG II treatment over 24 h. ANG II showed an inhibitory effect on angiotensinogen production. [Sar1]ANG II also exhibited a similar inhibitory effect as that of ANG II but to a greater extent and therefore was used throughout these studies. [Sar1]ANG II inhibited angiotensinogen production in a dose-dependent manner, exhibiting a half-maximal inhibitory concentration (IC50) of 2 nM. Other ANG II analogues showed similar effects on angiotensinogen production. In order of decreasing ability, they were [Sar1]ANG II greater than [Sar1-Ala8]ANG II greater than [Sar1-Val8]ANG II greater than [Sar1-Val5-(Br5)-Phe8]ANG II greater than [Sar1-Val5-DPhe8]ANG II. Results of these studies show that the Hep G2 cell possesses specific ANG II receptors and that [Sar1]ANG II induces a dose-dependent inhibition of angiotensinogen production in this system.

scholarly journals Loss of Apelin Augments Angiotensin II-Induced Cardiac Dysfunction and Pathological Remodeling

2019 ◽  
Vol 20 (2) ◽  
pp. 239 ◽  
Author(s):  
Teruki Sato ◽  
Ayumi Kadowaki ◽  
Takashi Suzuki ◽  
Hiroshi Ito ◽  
Hiroyuki Watanabe ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Angiotensin Converting Enzyme ◽  
Knockout Mice ◽  
Cardiac Dysfunction ◽  
Transforming Growth Factor ◽  
Heart Function ◽  
Dependent Manner ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Pathological Remodeling

Apelin is an inotropic and cardioprotective peptide that exhibits beneficial effects through activation of the APJ receptor in the pathology of cardiovascular diseases. Apelin induces the expression of angiotensin-converting enzyme 2 (ACE2) in failing hearts, thereby improving heart function in an angiotensin 1–7-dependent manner. Whether apelin antagonizes the over-activation of the renin–angiotensin system in the heart remains elusive. In this study we show that the detrimental effects of angiotensin II (Ang II) were exacerbated in the hearts of aged apelin-gene-deficient mice. Ang II-mediated cardiac dysfunction and hypertrophy were augmented in apelin knockout mice. The loss of apelin increased the ratio of angiotensin-converting enzyme (ACE) to ACE2 expression in the Ang II-stressed hearts, and Ang II-induced cardiac fibrosis was markedly enhanced in apelin knockout mice. mRNA expression of pro-fibrotic genes, such as transforming growth-factor beta (TGF-β) signaling, were significantly upregulated in apelin knockout hearts. Consistently, treatment with the ACE-inhibitor Captopril decreased cardiac contractility in apelin knockout mice. In vitro, apelin ameliorated Ang II-induced TGF-β expression in primary cardiomyocytes, accompanied with reduced hypertrophy. These results provide direct evidence that endogenous apelin plays a crucial role in suppressing Ang II-induced cardiac dysfunction and pathological remodeling.

scholarly journals Carvedilol Inhibits Angiotensin II-Induced Proliferation and Contraction in Hepatic Stellate Cells through the RhoA/Rho-Kinase Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Ying Wu ◽  
Zhen Li ◽  
Sining Wang ◽  
Aiyuan Xiu ◽  
Chunqing Zhang
Keyword(s):  
Cell Cycle ◽  
Angiotensin Ii ◽  
Liver Fibrosis ◽  
Cell Cycle Progression ◽  
Rho Kinase ◽  
Cell Counting ◽  
Type I ◽  
Dependent Manner ◽  
Ang Ii ◽  
Cycle Progression

Aim. Carvedilol is a nonselective beta-blocker used to reduce portal hypertension. This study investigated the effects and potential mechanisms of carvedilol in angiotensin II- (Ang II-) induced hepatic stellate cell (HSC) proliferation and contraction. Methods. The effect of carvedilol on HSC proliferation was measured by Cell Counting Kit-8 (CCK-8). Cell cycle progression and apoptosis in HSCs were determined by flow cytometry. A collagen gel assay was used to confirm HSC contraction. The extent of liver fibrosis in mice was evaluated by hematoxylin-eosin (H&E) and Sirius Red staining. Western blot analyses were performed to detect the expression of collagen I, collagen III, α-smooth muscle actin (α-SMA), Ang II type I receptor (AT1R), RhoA, Rho-kinase 2 (ROCK2), and others. Results. The results showed that carvedilol inhibited HSC proliferation and arrested the cell cycle at the G0/G1 phase in a dose-dependent manner. Carvedilol also modulated Bcl-2 family proteins and increased apoptosis in Ang II-treated HSCs. Furthermore, carvedilol inhibited HSC contraction induced by Ang II, an effect that was associated with AT1R-mediated RhoA/ROCK2 pathway interference. In addition, carvedilol reduced α-SMA expression and collagen deposition and attenuated liver fibrosis in carbon tetrachloride (CCl4)-treated mice. The in vivo data further confirmed that carvedilol inhibited the expression of angiotensin-converting enzyme (ACE), AT1R, RhoA, and ROCK2. Conclusions. The results indicated that carvedilol dose-dependently inhibited Ang II-induced HSC proliferation by impeding cell cycle progression, thus alleviating hepatic fibrosis. Furthermore, carvedilol could inhibit Ang II-induced HSC contraction by interfering with the AT1R-mediated RhoA/ROCK2 pathway.

scholarly journals Interleukin-9 Deletion Relieves Vascular Dysfunction and Decreases Blood Pressure via the STAT3 Pathway in Angiotensin II-Treated Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Yunzhao Yang ◽  
Shaoqun Tang ◽  
Chunchun Zhai ◽  
Xin Zeng ◽  
Qingjian Liu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Inflammatory Response ◽  
Vascular Dysfunction ◽  
Control Group ◽  
Dependent Manner ◽  
Ang Ii ◽  
Stat3 Pathway

Background. Multiple interleukin (IL) family members were reported to be closely related to hypertension. We aimed to investigate whether IL-9 affects angiotensin II- (Ang II-) induced hypertension in mice. Methods. Mice were treated with Ang II, and IL-9 expression was determined. In addition, effects of IL-9 knockout (KO) on blood pressure were observed in Ang II-infused mice. To determine whether the effects of IL-9 on blood pressure was mediated by the signal transducer and activator of the transcription 3 (STAT3) pathway, Ang II-treated mice were given S31-201. Furthermore, circulating IL-9 levels in patients with hypertension were measured. Results. Ang II treatment increased serum and aortic IL-9 expression in a dose-dependent manner; IL-9 levels were the highest in the second week and continued to remain high into the fourth week after the treatment. IL-9 KO downregulated proinflammatory cytokine expression, whereas it upregulated anti-inflammatory cytokine levels, relieved vascular dysfunction, and decreased blood pressure in Ang II-infused mice. IL-9 also reduced smooth muscle 22α (SM22α) expression and increased osteopontin (OPN) levels both in mice and in vitro. The effects of IL-9 KO on blood pressure and inflammatory response were significantly reduced by S31-201 treatment. Circulating IL-9 levels were significantly increased in patients with the hypertension group than in the control group, and elevated IL-9 levels positively correlated with both systolic blood pressure and diastolic blood pressure in patients with hypertension. Conclusions. IL-9 KO alleviates inflammatory response, prevents phenotypic transformation of smooth muscle, reduces vascular dysfunction, and lowers blood pressure via the STAT3 pathway in Ang II-infused mice. IL-9 might be a novel target for the treatment and prevention of clinical hypertension.

Potentiation of angiotensin II-stimulated vascular contraction by lithium

1995 ◽  
Vol 268 (5) ◽  
pp. H2009-H2016
Author(s):  
M. E. Ullian ◽  
L. G. Walsh ◽  
K. C. Wong ◽  
C. J. Allan
Keyword(s):  
Angiotensin Ii ◽  
Inositol Phosphate ◽  
Cytosolic Calcium ◽  
Rat Aorta ◽  
Dependent Manner ◽  
Ang Ii ◽  
Concentration Dependent Manner ◽  
Adrenergic Agents ◽  
Phosphoinositide Signaling ◽  
Protein Kinase C Inhibitor

Previous studies have suggested that lithium prolongs or enhances vascular contractions stimulated by alpha-adrenergic agents. The present study was performed to determine whether a similar phenomenon occurs with angiotensin II (ANG II)-stimulated contractions and whether this phenomenon results from interactions with the phosphoinositide signaling system. Contractions of rat aortic rings with 100 nM ANG II were 38% greater in the presence of 20 mM LiCl than in its absence (0.47 +/- 0.07 vs. 0.34 +/- 0.05 g tension/mg dry tissue wt, P < 0.01). The effects of lithium on inositol phosphate responses, diacylglycerol responses, and intracellular calcium concentration on single or repeated stimulations with ANG II were then examined in vascular smooth muscle cells cultured from rat aorta. Cells exposed twice to 100 nM ANG II contained 50% lower inositol trisphosphate levels (InsP3) and 10% lower diacylglycerol levels than cells exposed to ANG II only once. LiCl or lithium acetate abolished these desensitizations in a concentration-dependent manner. Similarly, InsP3 and diacylglycerol responses to a single exposure of ANG II were heightened by lithium (by 75 and 25%, respectively), and the duration of the responses was prolonged by lithium (5- and 2-fold, respectively). In contrast, ANG II-stimulated calcium transients were not enhanced or prolonged by lithium, nor was desensitization of ANG II-stimulated cytosolic calcium mobilization upon serial exposures abolished by lithium. When ring contraction studies were repeated in the presence of the protein kinase C inhibitor staurosporine (150 nM), lithium no longer potentiated ANG II contractions [0.38 +/- 0.03 (control) vs. 0.35 +/- 0.06 g tension/mg dry tissue wt (lithium)].(ABSTRACT TRUNCATED AT 250 WORDS)

Molecular mechanism of ADP-ribosyl cyclase activation in angiotensin II signaling in murine mesangial cells

2008 ◽  
Vol 294 (4) ◽  
pp. F982-F989 ◽  
Author(s):  
Seon-Young Kim ◽  
Rukhsana Gul ◽  
So-Young Rah ◽  
Suhn Hee Kim ◽  
Sung Kwang Park ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Tyrosine Kinase ◽  
Nuclear Translocation ◽  
Mesangial Cells ◽  
Dependent Manner ◽  
Ang Ii ◽  
Akt Phosphorylation ◽  
Cyclase Activation ◽  
Adp Ribosyl Cyclase ◽  
Phosphoinositide 3 Kinase

ADP-ribosyl cyclase (ADPR-cyclase) produces a Ca2+-mobilizing second messenger cyclic ADP-ribose (cADPR) from NAD+. In this study, we investigated the molecular basis of ADPR-cyclase activation and the following cellular events in angiotensin II (ANG II) signaling in mouse mesangial cells (MMCs). Treatment of MMCs with ANG II induced an increase in intracellular Ca2+ concentrations through a transient Ca2+ release via an inositol 1,4,5-trisphosphate receptor and a sustained Ca2+ influx via L-type Ca2+ channels. The sustained Ca2+ signal, but not the transient Ca2+ signal, was blocked by a cADPR antagonistic analog, 8-bromo-cADPR (8-Br-cADPR), and an ADPR-cyclase inhibitor, 4,4′-dihydroxyazobenzene (DHAB). In support of the results, ANG II stimulated cADPR production in a time-dependent manner, and DHAB inhibited ANG II-induced cADPR production. Application of pharmacological inhibitors revealed that activation of ADPR-cyclase by ANG II involved ANG II type 1 receptor, phosphoinositide 3-kinase, protein tyrosine kinase, and phospolipase C-γ1. Moreover, DHAB as well as 8-Br-cADPR abrogated ANG II-mediated Akt phosphorylation, nuclear translocation of nuclear factor of activated T cell, and uptake of [3H]thymidine and [3H]leucine in MMCs. These results demonstrate that ADPR-cyclase in MMCs plays a pivotal role in ANG II signaling for cell proliferation and protein synthesis.

Mechanism of angiotensin II-induced arachidonic acid metabolite release in aortic smooth muscle cells: involvement of phospholipase D

1997 ◽  
Vol 136 (2) ◽  
pp. 207-212 ◽  
Author(s):  
Junji Shinoda ◽  
Osamu Kozawa ◽  
Atsushi Suzuki ◽  
Yasuko Watanabe-Tomita ◽  
Yutaka Oiso ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Smooth Muscle Cells ◽  
Phospholipase D ◽  
Muscle Cells ◽  
Dependent Manner ◽  
Ang Ii ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle

Abstract In a previous study, we have shown that angiotensin II (Ang II) activates phosphatidylcholinehydrolyzing phospholipase D due to Ang II-induced Ca2+ influx from extracellular space in subcultured rat aortic smooth muscle cells. In the present study, we have investigated the role of phospholipase D in Ang II-induced arachidonic acid (AA) metabolite release and prostacyclin synthesis in subcultured rat aortic smooth muscle cells. Ang II significantly stimulated AA metabolite release in a concentration-dependent manner in the range between 1 nmol/l and 0·1 μmol/l. d,l-Propranolol hydrochloride (propranolol), an inhibitor of phosphatidic acid phosphohydrolase, significantly inhibited the Ang II-induced release of AA metabolites. The Ang II-induced AA metabolite release was reduced by chelating extracellular Ca2+ with EGTA. Genistein, an inhibitor of protein tyrosine kinases, significantly suppressed the Ang II-induced AA metabolite release. 1,6-Bis-(cyclohexyloximinocarbonylamino)-hexane (RHC-80267), a potent and selective inhibitor of diacylglycerol lipase, significantly inhibited the Ang II-induced AA metabolite release. Both propranolol and RHC-80267 inhibited the Ang II-induced synthesis of 6-keto-prostaglandin F1α, a stable metabolite of prostacyclin. The synthesis was suppressed by genistein. These results strongly suggest that the AA metabolite release induced by Ang II is mediated, at least in part, through phosphatidylcholine hydrolysis by phospholipase D activation in aortic smooth muscle cells. European Journal of Endocrinology 136 207–212

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.

scholarly journals Mechanisms of angiotensin II stimulation of NCC are time-dependent in mDCT15 cells

2015 ◽  
Vol 308 (7) ◽  
pp. F720-F727 ◽  
Author(s):  
Benjamin Ko ◽  
Abinash Mistry ◽  
Lauren Hanson ◽  
Rickta Mallick ◽  
Robert S. Hoover
Keyword(s):  
Angiotensin Ii ◽  
Cell Model ◽  
Surface Protein ◽  
Early Time ◽  
Dependent Manner ◽  
Ang Ii ◽  
Biphasic Effect ◽  
Surface Protein Expression ◽  
Stimulation Of

Angiotensin II (ANG II) increases thiazide-sensitive sodium-chloride cotransporter (NCC) activity both acutely and chronically. ANG II has been implicated as a switch that turns WNK4 from an inhibitor of NCC into an activator of NCC, and ANG II's effect on NCC appears to require WNK4. Chronically, ANG II stimulation of NCC results in an increase in total and phosphorylated NCC, but the role of NCC phosphorylation in acute ANG II actions is unclear. Here, using a mammalian cell model with robust native NCC activity, we corroborate the role that ANG II plays in WNK4 regulation and clarify the role of Ste20-related proline alanine-rich kinase (SPAK)-induced NCC phosphorylation in ANG II action. ANG II was noted to have a biphasic effect on NCC, with a peak increase in NCC activity in the physiologic range of 10−11 M ANG II. This effect was apparent as early as 15 min and remained sustained through 120 min. These changes correlated with significant increases in NCC surface protein expression. Knockdown of WNK4 expression sharply attenuated the effect of ANG II. SPAK knockdown did not affect ANG II action at early time points (15 and 30 min), but it did attenuate the response at 60 min. Correspondingly, NCC phosphorylation did not increase at 15 or 30 min, but increased significantly at 60 min. We therefore conclude that within minutes of an increase in ANG II, NCC is rapidly trafficked to the cell surface in a phosphorylation-independent but WNK4-dependent manner. Then, after 60 min, ANG II induces SPAK-dependent phosphorylation of NCC.

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