The protective effect of resveratrol on vascular aging by modulation of the renin–angiotensin system

Kim, Eun Nim,Kim, Min Young,Lim, Ji Hee,Kim, Yaeni,Shin, Seok Joon,Park, Cheol Whee,Kim, Yong-Soo,Chang, Yoon Sik,Yoon, Hye Eun,Choi, Bum Soon Elsevier Scientific Publ. Co 2018 Atherosclerosis Vol.270 No.-

<P><B>Abstract</B></P> <P><B>Background and aims</B></P> <P>This study evaluated the effects of resveratrol on arterial aging and the renin–angiotensin system (RAS) in mice and vascular smooth muscle cells (VSMCs).</P> <P><B>Methods</B></P> <P>Aging mice were divided into control and resveratrol groups. Histological changes, inflammation, oxidative stress, RAS components, and the expression of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1), peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α), and anti-oxidative enzymes was measured in thoracic aortas of 24-month-old mice. The effect of resveratrol on fibrosis, cell senescence, and RAS components was also investigated in VSMCs stimulated by angiotensin (Ang) II.</P> <P><B>Results</B></P> <P>Aorta media thickness, inflammation, fibrosis, and oxidative stress were significantly lower in the resveratrol group than in the control group. Resveratrol treatment decreased serum Ang II level and the aortic expression of prorenin receptor (PRR) and angiotensin converting enzyme (ACE), and increased serum Ang-(1–7) level and the expression of ACE2, Ang II type 2 receptor (AT2R), and Mas receptor (MasR). Resveratrol increased the expression of phosphorylated AMPK, SIRT1, PGC-1α, phosphorylated endothelial nitric oxide synthase and superoxide dismutase 1 and 2, and decreased that of NADPH oxidase 2 and 4. In Ang II-stimulated VSMCs, resveratrol treatment markedly decreased the number of senescence associated β-galactosidase stained cells and pro-fibrotic protein expression and increased the expression of AT2R and MasR.</P> <P><B>Conclusions</B></P> <P>Resveratrol protects against arterial aging and this effect is associated with reduced activity of the PRR–ACE–Ang II axis and stimulation of the ACE2–Ang-(1–7)–ATR2–MasR axis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Resveratrol protected against arterial aging by attenuating inflammation and oxidative stress. </LI> <LI> Resveratrol reduced the activity of the prorenin receptor-angiotensin converting enzyme-angiotensin II axis in aorta of aging mice. </LI> <LI> Resveratrol stimulated the activity of the angiotensin converting enzyme 2-angiotensin-(1–7)-angiotensin II type 2 receptor-Mas receptor axis both<I>in vivo</I> and <I>in vitro</I>. </LI> </UL> </P>

PTEN differentially regulates expressions of ICAM-1 and VCAM-1 through PI3K/Akt/GSK-3β/GATA-6 signaling pathways in TNF-α-activated human endothelial cells

Tsoyi, K.,Jang, H.J.,Nizamutdinova, I.T.,Park, K.,Kim, Y.M.,Kim, H.J.,Seo, H.G.,Lee, J.H.,Chang, K.C. Elsevier Scientific Publ. Co 2010 Atherosclerosis Vol.213 No.1

Phosphotase and tensin homolog deleted on chromosome 10 (PTEN) is a potent negative regulator of PI3K/Akt pathway. Here, we tried to elucidate the role of PTEN in the regulation of endothelial adhesion molecules, vascular cell adhesion molecule (VCAM)-1 and intracellular adhesion molecule (ICAM)-1, induced by TNF-α in human endothelial cells (ECs). Transfection with PTEN overexpressing vector resulted in the significant decrease in phosphorylation of Akt in TNF-α-treated ECs. PTEN strongly inhibited VCAM-1 but not ICAM-1, however this inhibitory effect was reversed by co-trasfection with constitutively active-Akt (CA-Akt-HA) in TNF-α-stimulated ECs. Additionally, silencing of PTEN with specific siRNA showed significant increase of phosphor-Akt compared with TNF-α alone treated ECs. siPTEN significantly upregulated VCAM-1 but was indifferent to ICAM-1 in TNF-α-treated cells. Further, chromatin immunoprecipitation (ChIP) assay showed that PTEN targets GATA-6 but not IRF-1 binding to VCAM-1 promoter. In addition, GATA-6 is associated with glycogen synthesis kinase-3beta (GSK-3β) which is in turn regulated by PTEN-dependent Akt activity. Finally, PTEN significantly prevented monocyte adhesion to TNF-α-induced ECs probably through VCAM-1 regulation. It is concluded that PTEN selectively inhibits expression of VCAM-1 but not ICAM-1 through modulation of PI3K/Akt/GSK-3β/GATA-6 signaling cascade in TNF-α-treated ECs.

Statin and clinical outcomes of primary prevention in individuals aged >75 years: The SCOPE-75 study

Kim, Kyu,Lee, Chan Joo,Shim, Chi-Young,Kim, Jung-Sun,Kim, Byeong-Keuk,Park, Sungha,Chang, Hyuk-Jae,Hong, Geu-Ru,Ko, Young-Guk,Kang, Seok-Min,Choi, Donghoon,Ha, Jong-Won,Hong, Myeong-Ki,Jang, Yangsoo,L Elsevier Scientific Publ. Co 2019 Atherosclerosis Vol.284 No.-

<P><B>Abstract</B></P> <P><B>Background and aims</B></P> <P>Limited data is available on the benefit of statin for primary prevention in the elderly. The aim of this study is to investigate whether statin for primary prevention is effective in lowering the cardiovascular risk and all-cause death in individuals aged >75 years.</P> <P><B>Methods</B></P> <P>This was a retrospective, propensity score-matched study and data were acquired between 2005 and 2016 in a tertiary university hospital. Of the 6414 patients screened, 1559 statin-naïve patients without a history of atherosclerotic cardiovascular disease before the index visit were included. After propensity score matching, 1278 patients (639 statin users, 639 statin non-users) were finally analyzed. Primary outcome variables included major adverse cardiovascular and cerebrovascular events (MACCE) and all-cause death. MACCE included cardiovascular death, nonfatal myocardial infarction, coronary revascularization, and nonfatal stroke or transient ischemic attack.</P> <P><B>Results</B></P> <P>At a median follow-up of 5.2 years, statin users had lower rates of MACCE (2.15 <I>vs.</I> 1.25 events/100 person-years; hazard ratio, 0.59; <I>p</I> = 0.005) and all-cause death (1.19 <I>vs.</I> 0.65 events/100 person-years; hazard ratio, 0.56; <I>p</I> = 0.02), as well as lower levels of low-density lipoprotein-cholesterol than did non-users. The Kaplan-Meier curves revealed lower event rates in statin users (hazard ratio: 0.59 for MACCE and 0.56 for all-cause death). The incidence of myocardial infarction and coronary revascularization were lower in statin users.</P> <P><B>Conclusions</B></P> <P>Statin therapy for primary prevention was clearly associated with lower risk of cardiovascular events and all-cause death in individuals aged >75 years. These results support more active statin use in this population.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Effect of statins for primary prevention was analyzed in individuals aged >75 years. </LI> <LI> Statin was associated with lower cardiovascular risk and all-cause death. </LI> <LI> Rates of MI and coronary revascularization were lower in statin users. </LI> <LI> These results support a more active statin use in this population. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Different prognostic value of white blood cell subtypes in patients with acute cerebral infarction

Kim, J.,Song, T.J.,Park, J.H.,Lee, H.S.,Nam, C.M.,Nam, H.S.,Kim, Y.D.,Heo, J.H. Elsevier Scientific Publ. Co 2012 Atherosclerosis Vol.222 No.2

Objective: We aimed to investigate the relationship of each white blood cells (WBC) subtype with neurologic severity and outcome in acute stroke. Methods: We included 779 patients with first-ever acute cerebral infarction within 72h after symptom onset. We investigated the association between counts for WBC subtypes in peripheral blood at admission and (1) initial stroke severity; (2) early change in stroke severity within one week; and (3) functional outcome at three months. Results: Higher total WBC and neutrophil counts were associated with more severe stroke at admission (p<0.001). In contrast, lower lymphocyte counts were associated with a lesser improvement during the first week after admission (p<0.05) and with poor functional outcome at three months (OR=0.706 per 1000 lymphocyte counts/mm<SUP>3</SUP>, p=0.020). Conclusions: Our study merits further investigation on the role of each WBC subtype in ischemic injury and different prognostic value of WBC subtypes measured at admission in acute stroke.

Optimal pharmacologic approach to patients with hypertriglyceridemia and low high-density lipoprotein-cholesterol: Randomized comparison of fenofibrate 160mg and niacin 1500mg

Wi, J.,Kim, J.Y.,Park, S.,Kang, S.M.,Jang, Y.,Chung, N.,Shim, W.H.,Cho, S.Y.,Lee, S.H. Elsevier Scientific Publ. Co 2010 Atherosclerosis Vol.213 No.1

Objectives: Atherogenic dyslipidemia is emerging as a target of lipid-modifying therapy. However, an optimal pharmacologic approach has not yet been established. The aim of this study is to compare the efficacy and tolerability of the typical doses of fenofibrate and niacin. Methods: After an eight-week dietary run-in, 201 patients who had triglyceride (TG) levels of 150-499mg/dL, high-density lipoprotein-cholesterol (HDL-C) levels of <45mg/dL and low-density lipoprotein-cholesterol (LDL-C) levels of <130mg/dL were randomly assigned to one of two treatment groups for 16 weeks: fenofibrate 160mg or niacin extended release 1500mg (starting at 500mg and up-titrated at the fifth and ninth weeks). Results: One hundred forty patients completed the study. The percent reductions in apoB/A1 were not different between the two groups (-20% and -22% in the fenofibrate and niacin groups, respectively, p=0.47). The effects of the two regimens on HDL-C were similar (24% and 20%, respectively, p=0.22), while fenofibrate reduced TG more than did niacin (-53% and -48%, respectively, p=0.045). Niacin was more effective at lowering LDL-C, Lp (a), and hs-CRP. However, niacin worsened the parameters of glycemic control, whereas fenofibrate improved them. Niacin showed more frequent adverse events including pruritus and skin flushing. Conclusions: These two regimens have largely comparable lipid-modifying effects. However, their effects on glucose metabolism and inflammation, and their adverse events need to be considered additionally. Our results underscore more individualized pharmacologic approaches to patients with atherogenic dyslipidemia.

Cellular factors involved in CXCL8 expression induced by glycated serum albumin in vascular smooth muscle cells

Choi, K.H.,Park, J.w.,Kim, H.Y.,Kim, Y.H.,Kim, S.M.,Son, Y.H.,Park, Y.C.,Eo, S.K.,Kim, K. Elsevier Scientific Publ. Co 2010 Atherosclerosis Vol.209 No.1

Glycated serum albumin (GSA) promotes vascular complications in diabetes. The aim of this study was to determine if GSA induces chemokine, particularly CXCL8 (IL-8), and to determine intracellular signaling pathways activated by GSA in vascular smooth muscle cells (VSMCs). GSA increased IL-8 transcription via promoter activation and enhanced CXCL8 release from VSMCs. GSA-induced promoter activation of the IL-8 gene was suppressed by dominant-negative mutants of TLR-4, MyD88, and TRIF, but not by a dominant-negative form of TLR-2. In addition, IL-8 up-regulation in response to GSA was inhibited by resveratrol, curcumin, diphenyleneiodium, U0126, and SB202190. Mutation at the NF-κB- or C/EBP-binding site, but not at the AP-1-binding site, in the IL-8 promoter region suppressed GSA-induced promoter activation. Moreover, gene delivery of IκB suppressed CXCL8 release. This study suggests that GSA induces expression of IL-8 in VSMCs and that TLR-4, mitogen-activated protein kinases, NF-κB, and NADPH oxidase are involved in that process.

Effects of low serum triglyceride on stroke mortality: A prospective follow-up study

Ryu, W.S.,Lee, S.H.,Kim, C.K.,Kim, B.J.,Yoon, B.W. Elsevier Scientific Publ. Co 2010 Atherosclerosis Vol.212 No.1

Background: Low serum triglyceride (TG) has been suggested as a predictor of mortality after cardiovascular disease. However, the relationship between the level of TGs and the outcome after stroke remains to be elucidated. We hypothesized that the influence of TG levels on post-stroke mortality varies according to stroke mechanism: cardioembolic (CE) vs. non-CE causes. Methods: We prospectively enrolled a consecutive series of patients with first-ever acute ischemic stroke for 5 years (n=1067), and followed them until the end of 2007 to obtain information on mortality and cause of death. We divided the level of TG into the quartiles, and classified the patients into CE (n=226) and non-CE stroke groups (n=841). The influence of TG level on mortality (all-cause death and vascular death) was examined by univariate and multivariate analyses using Cox regression. Result: All-cause death and vascular death rates showed inverse relationships to the quartiles of TG levels in all patients (p<0.001, both) and also in non-CE stroke group (p<0.001, both), but not in CE stroke group (p=0.17 and p=0.37, respectively). In the Cox-regression analysis, compared with the highest quartile, the adjusted hazard ratio (HR) of the lowest quartile for all-cause death was 2.58 [95% confidence interval (CI), 1.38-4.82] and that for vascular death was 3.50 (95% CI, 1.39-8.82) in non-CE stroke group. These same associations, however, were not significant in CE stroke group. Conclusion: Our results indicate that low serum TG is an independent predictor of mortality after ischemic stroke brought on by non-CE causes.

Relationship between HDL₃ subclasses and waist circumferences on the prevalence of metabolic syndrome: KMSRI-Seoul Study

Lee, M.,Jang, Y.,Kim, K.,Cho, H.,Jee, S.h.,Park, Y.,Kim, M.K. Elsevier Scientific Publ. Co 2010 Atherosclerosis Vol.213 No.1

Objective: Limited information is available on the association of HDL subtypes and the risk of metabolic syndrome (MetSyn). The objective of the present study was to investigate the association of HDL subspecies with the prevalence of MetSyn in new outpatients. Methods: Five hundred forty-one new outpatients (366 males and 175 females) were enrolled in two hospitals participating in the KMSRI-Seoul Study. The new criteria for the Korean MetSyn based on the 2005 KHANES were used. Medical questionnaires, anthropometric measurements, 3-day recall dietary assessments, and blood biomarker analyses were performed. Unconditional logistic regression models were used to estimate crude and odds ratios (ORs) and 95% confidence intervals (CIs) with multivariate adjustments. The proportions of HDL subtypes were measured after subtypes were identified by 4-30% gradient gel electrophoresis. Results: Of the subjects, 50.8% were classified as MetSyn; blood pressure (BP) and fasting blood sugar (FBS) among the five criteria did not differ by gender. Increasing the HDL<SUB>2b</SUB> subtype significantly reduced the risk of MetSyn in males and females. The association of small size HDL<SUB>3b</SUB> with the risk of MetSyn was stronger in females than in males: adjusted ORs (95% CIs) for the 3rd tertile of HDL<SUB>3b</SUB> compared to the 1st tertile were 3.79 (CI, 2.00-7.18) in males and 11.2 (CI, 2.1-59.6) in females. However, a decreased waist circumference (WC), BP, and triglycerides (TG) were observed with increased large HDL particles in males. Conclusions: Small-sized HDL was associated with increased MetSyn risk factors and closely related to WC, BP, TG, and HOMA-IR, particularly in males.

Participation of 5-lipoxygenase-derived LTB₄ in 4-hydroxynonenal-enhanced MMP-2 production in vascular smooth muscle cells

Seo, K.W.,Lee, S.J.,Kim, C.E.,Yun, M.R.,Park, H.M.,Yun, J.W.,Bae, S.S.,Kim, C.D. Elsevier Scientific Publ. Co 2010 Atherosclerosis Vol.208 No.1

5-Lipoxygenase (5-LO) has been suggested as a modulator of atherosclerotic plaque instability, however, its role in MMP production in vascular smooth muscle cells (VSMC) is still unclear. Thus, this study investigated the role of 5-LO in HNE-enhanced MMP-2 production in VSMC, and the mechanisms by which this enzyme could be activated by HNE. VSMC stimulated with HNE (1μM) produced MMP-2, which was markedly attenuated in 5-LO-deficient VSMC as well as in cells pretreated with a FLAP inhibitor, MK886, confirming a role for 5-LO metabolites in HNE-enhanced MMP-2 production. Related to these results, HNE increased nuclear translocation of 5-LO promoting 5-LO activity, which was attenuated not only by SB203580, a p38 MAPK inhibitor, but also by PD98059, an ERK inhibitor. In parallel, phosphorylation of p38 MAPK and ERK occurred as early as 15min after exposure to HNE, suggesting a potential role for p38 MAPK and ERK pathways in HNE-induced activation of 5-LO. Among leukotriene (LT) receptor antagonists, U-75302, a BLT receptor antagonist, but not MK-571 and Rev-5901, cysLT receptor antagonists, showed an inhibitory effect on HNE-enhanced MMP-2 production. Moreover, MMP-2 production in VSMC was also significantly increased by LTB<SUB>4</SUB>, but not by LTC<SUB>4</SUB> and LTD<SUB>4</SUB>. Collectively, these data suggest that 5-LO mediates HNE-enhanced MMP-2 production via LTB<SUB>4</SUB>-BLT receptor pathways, consequently leading to atherosclerotic plaque instability.

Independent inverse relationship between serum lycopene concentration and arterial stiffness

Kim, O.Y.,Yoe, H.Y.,Kim, H.J.,Park, J.Y.,Kim, J.Y.,Lee, S.H.,Lee, J.H.,Lee, K.P.,Jang, Y.,Lee, J.H. Elsevier Scientific Publ. Co 2010 Atherosclerosis Vol.208 No.2

Objective: Emerging evidence suggests a role of lycopene in the primary prevention of cardiovascular disease. This study aimed to investigate the association of serum lycopene concentration with brachial-ankle pulse wave velocity (baPWV), a marker of arterial stiffness and markers of oxidative stress and inflammation. Methods: healthy women (n=264, 31-75 yrs) were classified into tertiles according to serum lycopene concentration. Multivariate linear regression analyses were used to assess the relationship between serum lycopene and baPWV. Results: Subjects in middle tertile (T2) and upper tertile (T3) had lower baPWV (1263+/-23 and 1265+/-14cm/s vs. 1338+/-21cm/s; p=0.009) and lower oxidized LDL (oxLDL) (53+/-3 and 55+/-3U/L vs. 66+/-3U/L; p<0.001) than those in lower tertile (T1). Subjects in T3 showed higher LDL particle size (24.3+/-0.08nm vs. 24.0+/-0.07nm, p=0.005) and lower C-reactive protein (hs-CRP) (0.80+/-0.25mg/dL vs. 1.27+/-0.24mg/dL, p=0.015), compared with those in T1. Logistic regression analysis showed that baPWV decreased with the increment of lycopene concentration; log baPWV decreased by 0.21cm/s (95% CI -0.168;-0.045, p=0.001) per unit change in lycopene. After adjustment for age, BMI, smoking, drinking, menopause and blood pressure, the estimated effect was attenuated by 35%, but remained statistically significant [-0.13cm/s (95% CI -0.112;-0.018, p=0.006)]. Further adjustment for β-carotene, α-tocopherol, oxLDL, LDL particle size, and hs-CRP increased the strength of the association [β=-0.221 (95% CI -0.215;-0.012, p=0.029)]. Conclusion: This study supports the presence of an independent inverse relationship between circulating lycopene and baPWV. Additionally, reduced oxidative modification of LDL may be one of mediators on the mechanisms how lycopene reduces arterial stiffness.