• The Korean Journal of Physiology and Pharmacology
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• v.13 no.5
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• pp.385-392
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• 2009

Angiotensin II (Ang II) plays an important role in vascular hypertension. The role of the chemokine CCL5 on Ang II-induced activities in vascular smooth muscle cells (VSMCs) has not been studied. In this study, we elucidated the effect of CCL5 on Ang II-induced 12-lipoxygenase (LO) expression and cell proliferation in spontaneously hypertensive rats (SHR) VSMCs. CCL5 decreased Ang II-induced 12-LO mRNA expression and protein production, and it increased Ang II type 2 ($AT_2$) receptor expression in SHR VSMCs. The inhibitory effect of CCL5 on Ang II-induced 12-LO mRNA expression was mediated through the $AT_2$ receptor. Although treatment of CCL5 alone induced SHR VSMCs proliferation, CCL5 inhibited Ang II-induced VSMCs proliferation and PD123,319, an $AT_2$ receptor antagonist, blocked the inhibitory effect of CCL5 on Ang II-induced VSMCs proliferation. Phosphorylation of p38 was detected in VSMCs treated with Ang II or CCL5 alone. But, decrease of p38 phosphorylation was detected in VSMCs treated with Ang II and CCL5 simultaneously (Ang II/CCL5) and PD123,319 increased p38 phosphorylation in VSMCs treated with Ang II/CCL5. Therefore, these results suggest that the inhibitory effect of CCL5 on Ang II-induced VSMCs proliferation is mediated by the $AT_2$ receptor via p38 inactivation, and CCL5 may play a beneficial role in Ang II-induced vascular hypertension.

• Journal of Pharmacopuncture
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• v.22 no.2
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• pp.95-101
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• 2019

Objectives: Angiotensin II (AngII), a major product of renin-angiotensin system (RAS) has important role in induction of hypertension and antihypertensive effect of several medicinal plant was mediated by effect on this agent. Therefore, this study examined the possible effect of hydroalcoholic extract of Crocus sativus (C. sativus) on hypertension induced by AngII. Methods: Six groups (n = 6) of rats were used as follow: 1) Control, 2) AngII (300 ng/kg), 3) Losartan (Los, 10 mg/kg) + AngII and 4-6) C. sativus extract (10, 20 & 40 mg/kg,) + AngII. The femoral artery and vein were cannulated for recording cardiovascular parameters and drugs administration, respectively. All drugs were injected intravenously (i.v). Los and all doses of C. sativus injected 10 min before AngII. Systolic blood pressure (SBP), mean arterial blood pressure (MAP) and heart rate (HR) were recorded throughout the experiment and those peak changes (${\Delta}$) were calculated and compared to control and AngII. Results: AngII significantly increased ${\Delta}MAP$, ${\Delta}SBP$ and ${\Delta}HR$ than control (P < 0. 01 to P < 0.001) and these increments were significantly attenuated by Los. All doses of C. sativus significantly reduced peak ${\Delta}MAP$, ${\Delta}SBP$, and ${\Delta}HR$ than AngII group (P < 0. 05 to P < 0.001). In addition, peak ${\Delta}MAP$, ${\Delta}SBP$ in doses 10 and 20 were significant than Los + AngII group (P<0.05 to P< 0.01) but in dose 40 only MAP was significant (P<0.05). Peak ${\Delta}HR$ in all doses of C sativus was not significant than Los+ AngII. Conclusion: Regarding the improving effect of the C. sativus extract on AngII induced hypertension, it seems that this ameliorating effect partly mediated through inhibition of RAS.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.6
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• pp.667-674
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• 2017

Angiotensin II (Ang II) is metabolized from N-terminal by aminopeptidases and from C-terminal by Ang converting enzyme (ACE) to generate several truncated angiotensin peptides (Angs). The truncated Angs have different biological effects but it remains unknown whether Ang-(4-8) is an active peptide. The present study was to investigate the effects of Ang-(4-8) on hemodynamics and atrial natriuretic peptide (ANP) secretion using isolated beating rat atria. Atrial stretch caused increases in atrial contractility by 60% and in ANP secretion by 70%. Ang-(4-8) (0.01, 0.1, and $1{\mu}M$) suppressed high stretch-induced ANP secretion in a dose-dependent manner. Ang-(4-8) ($0.1{\mu}M$)-induced suppression of ANP secretion was attenuated by the pretreatment with an antagonist of Ang type 1 receptor ($AT_1R$) but not by an antagonist of $AT_2R$ or $AT_4R$. Ang-(4-8)-induced suppression of ANP secretion was attenuated by the pretreatment with inhibitor of phospholipase (PLC), inositol triphosphate ($IP_3$) receptor, or nonspecific protein kinase C (PKC). The potency of Ang-(4-8) to inhibit ANP secretion was similar to Ang II. However, Ang-(4-8) $10{\mu}M$ caused an increased mean arterial pressure which was similar to that by 1 nM Ang II. Therefore, we suggest that Ang-(4-8) suppresses high stretch-induced ANP secretion through the $AT_1R$ and $PLC/IP_3/PKC$ pathway. Ang-(4-8) is a biologically active peptide which functions as an inhibition mechanism of ANP secretion and an increment of blood pressure.

• Journal of Life Science
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• v.25 no.2
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• pp.231-236
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• 2015

Angiotensin II (AngII) is an essential hormone that affects vascular physiology. For example, stimulation of vascular smooth muscle cells (VSMCs) rapidly induces vasoconstriction and results in the up-regulation of blood pressure. Chronic stimulation of VSMCs with AngII also results in hypertrophy. In this study, we confirmed an involvement of phosphatidylinositol 3-kinase (PI3K)-dependent calcium mobilization in AngII-induced generation of reactive oxygen species (ROS). Stimulation of rat aortic smooth muscle cells (RASMCs) with AngII significantly induced the generation of ROS in a dose- and time-dependent manner. AngII-induced generation of ROS was completely abolished by pharmacological inhibition of PI3K (with LY294002), but inhibition of the ERK signaling pathway had no effect. AngII-induced calcium mobilization was completely blocked by inhibition of PI3K, whereas inhibition of the ERK signaling pathway by PD98059 was ineffective. Depletion of extracellular calcium or inhibition of the L-type calcium channel by nifedipine completely blocked AngII-induced calcium mobilization. Depletion of extracellular calcium by EGTA and incubation of RASMCs with calcium-free medium both significantly blocked AngII-induced ROS generation. Inhibition of the L-type calcium channel also significantly blocked AngII-induced ROS generation. These results suggest that AngII-induced ROS generation is regulated by calcium mobilization, which, in turn, is modulated by a PI3K/L-type calcium channel signaling pathway.

• Journal of Community Nutrition
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• v.8 no.2
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• pp.69-75
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• 2006

Adipose tissue has now been recognized as a rich source of metabolically active molecules that include leptin and angiotensinogen (AGT), the precursor of angiotensin II (Ang II). Both of which have been implicated in the pathogenesis of metabolic alteration and hypertension associated with obesity. In this study, we examined the relationship between body mass index (BMI), adipocyte size, leptin, Ang II secretion and mRNA expression in human adipose tissue obtained from female subjects. Leptin and Ang II were analyzed using specific radioimmunoassay kits following a 48hour tissue culture. Leptin and Ang II secretion varied from 1.4 - 72.1ng/g and 0.8 - 57.3pg/g of tissue respectively. These large individual variations limit significant correlation between BMI, leptin and Ang II secretion. Ang II secretion was significantly higher in the obese than the non-obese (p < 0.05) and positively correlated with BMI. However, no difference in leptin secretion between the obese and the non-obese was observed and leptin secretion showed negative correlation with BMI. No difference in leptin and AGT mRNA expression in adipose tissue between the obese and the non-obese was observed. Although several limitations of this study, we found increased Ang II secretion in obese patients compared with non-obese patients, and positive correlation between AGT and BMI. Observed difference in AGT expression between the obese and the non-obese in this study might be of importance in relation with obesity related hypertension. (J Community Nutrition 8(2): 69-75, 2006)

• Journal of Yeungnam Medical Science
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• v.34 no.1
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• pp.43-54
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• 2017

Background: Extracellular sulfatases (Sulfs), sulfatase 1 (Sulf1) and sulfatase 2 (Sulf2), play a pivotal role in cell signaling by remodeling the 6-O-sulfation of heparan sulfate proteoglycans on the cell surface. The present study examined the effects of Sulfs on angiotensin II (Ang II)-induced hypertensive mediator expression and vascular smooth muscle cells (VSMCs) proliferation in spontaneously hypertensive rats (SHR). Methods: Ang II receptors, 12-lipoxygenase (12-LO), and endothelin-1 (ET-1) messenger RNA (mRNA) expressions in SHR VSMCs were analyzed by real-time polymerase chain reaction and Western blotting. VSMCs proliferation was determined by [$^3H$]-thymidine incorporation. Results: Basal Sulfs mRNAs expression and enzyme activity were elevated in SHR VSMCs. However, Sulfs had no effect on the basal or Ang II-induced 12-LO and ET-1 mRNA expression in SHR VSMCs. The inhibition of Ang II-induced 12-LO and ET-1 expression by blockade of the Ang II type 2 receptor ($AT_2\;R$) pathway was not observed in Sulf1 siRNA-transfected SHR VSMCs. However, Sulf2 did not affect the action of $AT_2\;R$ inhibitor on Ang II-induced 12-LO and ET-1 expression in SHR VSMCs. The down-regulation of Sulf1 induced a reduction of $AT_2\;R$ mRNA expression in SHR VSMCs. In addition, the inhibition of Ang II-induced VSMCs proliferation by blockade of the $AT_2\;R$ pathway was mediated by Sulf1 in SHR VSMCs. Conclusion: These findings suggest that extracellular sulfatase Sulf1 plays a modulatory role in the $AT_2\;R$ pathway that leads to an Ang II-induced hypertensive effects in SHR VSMCs.

• Food Science of Animal Resources
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• v.40 no.1
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• pp.106-117
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• 2020

Cellular senescence is associated with age-related vascular disorders and has been implicated in vascular dysfunctions. Here, we show that duck oil-loaded nanoemulsion (DO-NE) attenuates premature senescence of vascular smooth muscle cells (VSMCs) triggered by angiotensin II (Ang II). Compared with control nanoemulsion (NE), DO-NE significantly inhibited the activity of senescence-associated β-galactosidase, which is a biomarker of cellular senescence, in Ang II-treated VSMCs. SIRT1 protein expression was dose- and time-dependently induced in VSMCs exposed to DO-NE, but not in those exposed to NE, and SIRT1 promoter activity was also elevated. Consistently, DO-NE also dose-dependently rescued Ang II-induced repression of SIRT1 expression, indicating that SIRT1 is linked to the anti-senescence action of DO-NE in VSMCs treated with Ang II. Furthermore, the SIRT1 agonist resveratrol potentiated the effects of DO-NE on VSMCs exposed to Ang II, whereas the SIRT1 inhibitor sirtinol elicited the opposite effect. These findings indicate that DO-NE inhibits senescence by upregulating SIRT1 and thereby impedes vascular aging triggered by Ang II.

• Reproductive and Developmental Biology
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• v.28 no.1
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• pp.59-63
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• 2004

1. The concentrations of Ang. II were 7.20.91 ${\times}$ $10^3$ , 3.80.34 ${\times}$ $10^3$, 3.50.30 ${\times}$ $10^3$, 2.80.22 ${\times}$ $10^3$ pg/ml in bovine follicular fluids from 1∼3 mm, 3∼5 mm, 5∼7 mm and 8∼10 m follicles, respectively. The concentrations of Ang. II decreased in follicular fluids from large follicles. 2. When oocytes were cultured in media containing various concentrations of Ang. II, a higher proportion of oocytes developed to MII stage in medium with 100 ng/ml (79.5%) Ang II compare to that without Ang. II (58.8%). When oocytes from different sizes of follicles were separately cultured in media containing 100 ng/ml Ang. II, maturation rates were higher in oocytes from small and medium follicles those from controls. 3. GSH content in oocytes cultured for 24 hrs in TCM-199 medium containing 10 and 100 ng/ml of Ang. II was also higher than that of oocytes cultured in medium containing 0 or 10 ng/ml Ang. II. When oocytes were cultured in media containing 0, 10, 100, 1,000 ng/ml of Ang. II, the concentrations of GSH were 5.1M, 5.5M, 7.2M, 8.7M, respectively. 4. When oocytes were cultured in media containing various concentrations of 10, 100, 1,000 ng/ml Ang. II, in vitro maturation and developmental rates were 84.0%, 90.0%, 78.0% and 28.0%, 36.0%, 20.0%, respectively. When oocytes were cultured with an addition of Ang. II in media, in vitro maturation rates higher than that of their controls (76.0%).

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.6
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• pp.499-506
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• 2015

Angiotensin II (Ang II), a key mediator of hypertensive, causes structural changes in the arteries (vascular remodeling), which involve alterations in cell growth, vascular smooth muscle cell (VSMC) hypertrophy. Ang II promotes fibrotic factor like IGFBP5, which mediates the profibrotic effects of Ang II in the heart and kidneys, lung and so on. The purpose of this study was to identify the signaling pathway of IGFBP5 on cell proliferation and migration of Ang II-stimulated VSMC. We have been interested in Ang II-induced IGFBP5 and were curious to determine whether a Pitavastatin would ameliorate the effects. Herein, we investigated the question of whether Ang II induced the levels of IGFBP5 protein followed by proliferation and migration in VSMC. Pretreatment with the specific Angiotensin receptor type 1 (AT1) inhibitor (Losartan), Angiotensin receptor type 2 (AT2) inhibitor (PD123319), MAPK inhibitor (U0126), ERK1/2 inhibitor (PD98059), P38 inhibitor (SB600125) and PI3K inhibitor (LY294002) resulted in significantly inhibited IGFBP5 production, proliferation, and migration in Ang II-stimulated VSMC. In addition, IGFBP5 knockdown resulted in modulation of Ang II induced proliferation and migration via IGFBP5 induction. In addition, Pitavastatin modulated Ang II induced proliferation and migration in VSMC. Taken together, our results indicated that Ang II induces IGFBP5 through AT1, ERK1/2, P38, and PI3K signaling pathways, which were inhibited by Pitavastatin. These findings may suggest that Pitavastatin has an effect on vascular disease including hypertension.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.1
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• pp.99-106
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• 2017

Obesity is a critical risk factor for the hypertension. Although angiotensin II (Ang II) in obese individuals is known to be upregulated in obesity-induced hypertension, direct evidence that explains the underlying mechanism for increased vascular tone and consequent increase in blood pressure (BP) is largely unknown. The purpose of this study is to investigate the novel mechanism underlying Ang II-induced hyper-contractility and hypertension in obese rats. Eight-week old male Sprague-Dawley rats were fed with 60% fat diet or normal diet for 4 months. Body weight, plasma lipid profile, plasma Ang II level, BP, Ang II-induced vascular contraction, and expression of regulatory proteins modulating vascular contraction with/without Ang II stimulation were measured. As a result, high fat diet (HFD) accelerated age-dependent body weight gaining along with increased plasma Ang II concentration. It also increased BP and Ang II-induced aortic contraction. Basal expression of p-CPI-17 and myosin light chain (MLC) kinase was increased by HFD along with increased phosphorylation of MLC. Ang II-induced phosphorylation of CPI-17 and MLC were also higher in HFD group than control group. In conclusion HFD-induced hypertension is through at least in part by increased vascular contractility via increased expression and activation of contractile proteins and subsequent MLC phosphorylation induced by increased Ang II.