• Journal of Preventive Medicine and Public Health
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• v.53 no.6
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• pp.476-486
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• 2020

Objectives: The objective of this study was to estimate the risk of lung cancer in relation to angiotensin II receptor blocker (ARB) use among patients with hypertension from the Korean National Health Insurance Service-National Health Screening Cohort. Methods: We conducted a retrospective cohort study of patients with hypertension who started to take antihypertensive medications and had a treatment period of at least 6 months. We calculated the weighted hazard ratios (HRs) and their 95% confidence intervals (CIs) of lung cancer associated with ARB use compared with calcium channel blocker (CCB) use using inverse probability treatment weighting. Results: Among a total of 60 469 subjects with a median follow-up time of 7.8 years, 476 cases of lung cancer were identified. ARB use had a protective effect on lung cancer compared with CCB use (HR, 0.75; 95% CI, 0.59 to 0.96). Consistent findings were found in analyses considering patients who changed or discontinued their medication (HR, 0.50; 95% CI, 0.32 to 0.77), as well as for women (HR, 0.56; 95% CI, 0.34 to 0.93), patients without chronic obstructive pulmonary disease (HR, 0.75; 95% CI, 0.56 to 1.00), never-smokers (HR, 0.64; 95% CI, 0.42 to 0.99), and non-drinkers (HR, 0.69; 95% CI, 0.49 to 0.97). In analyses with different comparison antihypertensive medications, the overall protective effects of ARBs on lung cancer risk remained consistent. Conclusions: The results of the present study suggest that ARBs could decrease the risk of lung cancer. More evidence is needed to establish the causal effect of ARBs on the incidence of lung cancer.

• Journal of Life Science
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• v.18 no.7
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• pp.918-923
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• 2008

The angiotensin II receptor ($AT_1R$) antagonists are effective in treating patients with hypertension and showed beneficial effects in diabetes and other metabolic diseases. The beneficial effects of $AT_1R$ antagonists are mainly considered to be from inhibition of Ang $II-AT_1R$ signaling pathway such as the activation of NADPH oxidase and the generation of reactive oxygen species. In this study, we examined whether antagonist of the $AT_1R$ could account for phosphorylation of proteins in cells using antibody array. We have selected 6 proteins with Ser/Thr-phosphorylation sites and 12 proteins with Tyr-phosphorylation sites based on literature search. Upon $AT_1R$ antagonist losartan treatment to serum-starved COS-1 cells, there was ${\sim}20%$ increase of Ser phosphorylation in small GTPase RhoA. RhoA is known to be responsible for cytoskeleton rearrangement and is down-regulated upon Ser phosphorylation in vivo. Our finding provides a new insight into the mechanism and signaling pathway of the $AT_1R$ antagonist in cells.

• YAKHAK HOEJI
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• v.58 no.2
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• pp.141-149
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• 2014

Background: Oriental lifestyle for treating diseases has been developed and well-accepted for a long time among Koreans. Sasang Constitution theory, originated from Korean traditional medicine, suggests that medication treatment should be differentiated by each patient's body classification (So-yang [SY], So-eum [SE], Tae-yang [TY], and Tae-eum [TE]), in contrary to western medicine's theory that medication should be applied equally by disease indication without such classification. However, the pharmacotherapeutic outcomes of these theories have not been compared to date. In this study, we aimed to compare the two theories by evaluating blood pressure (BP), which is lowered as a therapeutic outcome, among hypertensive patients taking angiotensin II receptor blockers (ARBs) or calcium channel blockers (CCBs), two most commonly used antihypertensive classes in Korea. Methods: From April 2006 to June 2012, we retrospectively collected data on hypertensive patients with Sasang Constitution classification at Kyunghee University Hospital at Gangdong, one of the East-West collaborative medical centers in Korea. We collected information on age, gender, underlying diseases, antihypertensive drugs (ARB, CCB, ARB+CCB), and BP by reviewing the electronic medical records. We excluded patients with missing blood pressure at baseline or follow-up, or those who had a change in their antihypertensive drug class during follow-up. Results: We selected a total of 573 patients (SY: 165, SE: 158, TY: 0, TE: 250). Baseline BPs were on average 139.0/82.0 mmHg for SY, 137.8/78.5 mmHg for SE, and 138.7/79.2 mmHg for TE. In all three groups, CCBs were the most prescribed, followed by combination therapy with ARB+CCB, then ARBs. BP reduction after 1 month of initial medication was significantly different among the drug classes, but not in Sasang constitutional classification (ARB [SY: -12.4/-4.7, SE: -12.3/-2.5, TE: -8.6/-1.8], CCB [SY: -12.3/-5.4, SE: -13.0/-2.3, TE: -10.8/-6.0], ARB+CCB [SY: -15.6/-6.7, SE: -18.4/-8.1, TE: -20.2/-6.7], drug [$P{\leq}0.05$/P>0.05], constitutional type [P>0.05/P>0.05]). Conclusion: We observed significant differences in reduction of blood pressure by classes of drugs (ARB+CCB>CCB>ARB) but not by Sasang constitutional classification. Therefore, current approach of antihypertensive pharmacotherapy assisted by Western medicine is appropriate for treatment of hypertension. However, further larger scale or prospective studies are required in order to confirm these results.

• Proceedings of the PSK Conference
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• 2000.04a
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• pp.139.1-139.1
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• 2000

• Clinical and Experimental Pediatrics
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• v.59 no.1
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• pp.8-15
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• 2016

Purpose: Nephrogenesis is normally accompanied by a tightly regulated and efficient vascularization. We investigated the effect of angiotensin II inhibition on angiogenesis in the developing rat kidney. Methods: Newborn rat pups were treated with enalapril (30 mg/kg/day) or vehicle (control) for 7 days after birth. Renal histological changes were checked using Hematoxylin & Eosin staining. We also investigated the intrarenal expression of vascular endothelial growth factor (VEGF)-A, VEGF receptor 1 (VEGFR1), VEGFR2, platelet-derived growth factor (PDGF)-B, and PDGF receptor-${\beta}$ with Western blotting and immunohistochemical staining at postnatal day 8. Expression of the endothelial cell marker CD31 was examined to determine glomerular and peritubular capillary density. Results: Enalapril-treated rat kidneys showed disrupted tubules and vessels when compared with the control rat kidneys. In the enalapril-treated group, intrarenal VEGF-A protein expression was significantly higher, whereas VEGFR1 protein expression was lower than that in the control group (P<0.05). The expression of VEGFR2, PDGF-B, and PDGF receptor-${\beta}$ was not different between the 2 groups. The increased capillary CD31 expression on the western blots of enalapril-treated rat kidneys indicated that the total endothelial cell protein level was increased, while the cortical capillary density, assessed using CD31 immunohistochemical staining, was decreased. Conclusion: Impaired VEGF-VEGFR signaling and altered capillary repair may play a role in the deterioration of the kidney vasculature after blocking of angiotensin II during renal development.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.5
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• pp.299-304
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• 2010

Losartan is a selective angiotensin II (Ang II) type 1 ($AT_1$) receptor antagonist which inhibits vascular smooth muscle cells (VSMCs) contraction and proliferation. We hypothesized that losartan may prevent cell proliferation by activating AMP-activated protein kinase (AMPK) in VSMCs. VSMCs were treated with various concentrations of losartan. AMPK activation was measured by Western blot analysis and cell proliferation was measured by MTT assay and flowcytometry. Losartan dose- and time-dependently increased the phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase (ACC) in VSMCs. Losartan also significantly decreased the Ang II- or 15% FBS-induced VSMC proliferation by inhibiting the expression of cell cycle associated proteins, such as p-Rb, cyclin D, and cyclin E. Compound C, a specific inhibitor of AMPK, or AMPK siRNA blocked the losartan-induced inhibition of cell proliferation and the $G_0/G_1$ cell cycle arrest. These data suggest that losartan-induced AMPK activation might attenuate Ang II-induced VSMC proliferation through the inhibition of cell cycle progression.

• 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
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• v.29 no.1
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• pp.91-102
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• 1995

The role of neurohumoral mechanisms in the regulation of cardiovascular functions and the effects of ethanol (EOH) on these mechanisms were examined in hemorrhaged conscious Wistar rats. The rats were bled at a constant rate (2 ml/kg/min) through the femoral artery until mean arterial pressure (MAP) was reduced by 30 mmHg. We studied the responses to hemorrhage 1) under normal conditions (Normal), and after pretreatments with 2) neural blockade (NB), pentolinium, 3) arginine vasopressin V1-receptor antagonist (AVPX) + NB, 4) angiotensin II ATI-receptor antagonist (AngIIX) + NB, 5) combined humoral blockade (HB), and 6) neurohumoral blockade. Intravenous administration of 30% EOH (6.3 ml/kg) attenuated the baroreceptor reflex sensitivity, and enhanced the depressor action of AngIIX. During hemorrhage, NB produced a faster fall ill MAP than Normal both in the saline and EOH groups. However, HB accelerated the rate of fall in MAP only in the EOH group. The recovery from hemorrhagic hypotension was not different between NB and Normal rats, but was attenuated in HB rats in the saline group. Under NB, AngIIX, but not AVPX, retarded the recovery rate compared with NB alone. EOH attenuated the recovery of MAP after hemorrhage in Normal rats, but completely abolished the recovery in HB rats. We conclude that 1) the maintenance of MAP during hemorrhage is mediated almost entirely by the autonomic functions, 2) angiotensin II plays an important role in the recovery from hemorrhagic hypotension, but AVP assumes little importance, 3) AVP release largely depends on the changes in blood volume, whereas renin release depends on the changes in blood pressure rather than blood volume, and 4) EOH increases the dependence of cardiovascular regulation on angiotensin II and impairs the recovery from hemorrhagic hypotension through the attenuation of autonomic functions.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.1
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• pp.55-63
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• 1997

The present study was designed to quantify the alterations of renal renin, angiotensin type I receptor ($AT_1$), $TGF-{\beta}1$, and fibronectin gene expression in rats with unilateral ureteral obstruction (UUO). We also investigated the change of $AT_1$ density during UUO. Reverse transcription-polymerase chain reaction (RT-PCR) technique and receptor binding assay were used to detect mRNA expression and receptor density, respectively. At one day after UUO, renin mRNA level of the obstructed kidneys was decreased transiently and then subsequently increased to the level of sham kidneys. In the contralateral kidneys of the same rats, on the contrary, renin mRNA level was gradually decreased. Then, at 9 days after UUO, it was significantly lower than that of sham kidneys. The expressions of both $AT_1$ subtypes, called $AT_{1A}$ and $AT_{1B}$, mRNAs did not change at any time. UUO led to a significant decrease in $AT_1$ density in the obstructed kidneys compared with the sham kidneys at 1 and 3 days $(66\;{\pm}\;11.6%\;(p<0.005)\;and\;73\;{\pm}\;4.0%$ (p<0.01), respectively). Thereafter, $AT_1$ density was gradually increased and at 9 days it showed a marked elevation in the obstructed kidneys compared to the sham kidneys. In contrast, in the contralateral kidneys $AT_1$ density was significantly reduced from 3 to 9 days after UUO. The $TGF-{\beta}$1 mRNA level of the obstructed kidneys was unexpectedly decreased at 6 days after UUO. Then, at 9 days it was followed by a significant increase in the obstructed kidneys, whereas it showed an obvious decrease in the contralateral kidneys. In addition, fibronectin mRNA level was also significantly increased in the obstructed kidneys after UUO compared to the sham or the contralateral kidneys of the same rats. These results suggest a differential regulation of renal renin, $AT_1$ receptor, $TGF-{\beta}$1 and fibronectin mRNA levels at different stages of UUO.

• IMMUNE NETWORK
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• v.9 no.3
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• pp.106-113
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• 2009

Background: We previously demonstrated remarkable differences in the expression of IL-8/CXCL8 in aortic tissues and vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) compared to VSMC from normotensive Wistar-Kyoto rats (WKY). In the present study, we investigated the direct effect of IL-8/CXCL8 on expression of 12-lipoxygenase (LO), a hypertensive modulator, in SHR VSMC. Methods: Cultured aortic VSMC from SHR and WKY were used. Expression of 12-LO mRNA was determined by real-time polymerase chain reaction. Phosphorlyation of ERK1/2 and production of 12-LO and angiotensin II subtype 1 ($AT_1$) receptor were assessed by Western blots. IL-8/CXCL8-stimulated DNA synthesis was determined by measuring incorporation of [$^3H$]-thymidine. And effect of IL-8/CXCL8 on vascular tone was determined by phenylephrine-induced contraction of thoracic aortic rings. Results: Treatment with IL-8/CXCL8 greatly increased 12-LO mRNA expression and protein production compared to treatment with angiotensin II. IL-8/CXCL8 also increased the expression of the $AT_1$ receptor. The increase in 12-LO induced by IL-8/CXCL8 was inhibited by treatment with an $AT_1$ receptor antagonist. The induction of 12-LO mRNA production and the proliferation of SHR VSMC by IL-8/CXCL8 was mediated by the ERK pathway. The proliferation of SHR VSMC and the vascular contraction in the thoracic aortic ring, both of which were induced by IL-8/CXCL8, were inhibited by baicalein, a 12-LO inhibitor. Conclusion: These results suggest that the potential role of IL-8/CXCL8 in hypertensive processes is likely mediated through the 12-LO pathway.