-
Sumiko Yoshida,
Ken-Ichi Aihara,
Yasumasa Ikeda,
Yuka Sumitomo-Ueda,
Ryoko Uemoto,
Kazue Ishikawa,
Takayuki Ise, Shusuke Yagi,
Takashi Iwase,
Yasuhiro Mouri,
Matomo Sakari,
Takahiro Matsumoto,
Ken-Ichi Takeyama,
Masashi Akaike,
Mitsuru Matsumoto,
Masataka Sata,
Kenneth Walsh,
Shigeaki Kato,
Toshio Matsumoto
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Hypoandrogenemia is associated with an increased risk of ischemic diseases. Since actions of androgens are exerted through androgen receptor (AR) activation, we studied hind limb ischemia in AR knockout (KO) mice to elucidate the role of AR in response to ischemia. METHODS AND RESULTS: Both male and female ARKO mice exhibited impaired blood flow recovery, more cellular apoptosis and a higher incidence of autoamputation after ischemia. In ex vivo and in vivo angiogenesis studies, AR-deficient vascular endothelial cells showed reduced angiogenic capability. In ischemic limbs of ARKO mice, reductions in the phosphorylation of the Akt protein kinase and endothelial nitric oxide synthase (eNOS) were observed despite a robust increase in hypoxia-inducible factor 1α and vascular endothelial cell growth factor (VEGF) gene expression. In in vitro studies, siRNA-mediated ablation of AR in vascular endothelial cells blunted VEGF-stimulated phosphorylation of Akt and eNOS. Immunoprecipitation experiments documented an association between AR and kinase insert domain protein receptor (KDR) that promoted the recruitment of downstream signaling components. CONCLUSIONS: These results document a physiological role of AR in gender-independent angiogenic potency and provide evidence for a novel cross-talk between androgen/AR signaling and VEGF/KDR signaling pathways.
Circulation 05/2013; · 14.74 Impact Factor
-
Takayuki Ise,
Ken-Ichi Aihara,
Yuka Sumitomo-Ueda,
Sumiko Yoshida,
Yasumasa Ikeda, Shusuke Yagi,
Takashi Iwase,
Hirotsugu Yamada,
Masashi Akaike,
Masataka Sata,
Toshio Matsumoto
-
[show abstract]
[hide abstract]
ABSTRACT: Because dementia is associated with both deterioration in the quality of life and poor prognosis, the prevention of cognitive impairment (CI) is a critical problem in public health promotion. Hypertension is a risk factor for the aggravation of CI, and the renin-angiotensin-aldosterone system (RAAS) is a key player in the increased incidence and development of hypertension. Therefore, the RAAS is considered to be a promoting factor for CI development. Conversely, recent studies have shown that lowering blood pressure with RAAS inhibitors decreases the incidence of CI, dementia and cardiovascular disease. Blood-brain barrier-penetrating RAAS inhibitors appear to have advantages in preventing cognitive decline because they can suppress the RAAS in the hippocampus, which has an important role in cognition. Thus, RAAS blockage is a notable strategy for preventing CI.Hypertension Research advance online publication, 23 May 2013; doi:10.1038/hr.2013.51.
Hypertension Research 05/2013; · 2.58 Impact Factor
-
Takeshi Soeki,
Toshiyuki Niki,
Etsuko Uematsu,
Sachiko Bando,
Tomomi Matsuura,
Kenya Kusunose,
Takayuki Ise,
Yuka Ueda,
Noriko Tomita,
Koji Yamaguchi, [......],
Daiju Fukuda,
Yoshio Taketani,
Takashi Iwase,
Hirotsugu Yamada,
Tetsuzo Wakatsuki,
Masashi Akaike,
Michio Shimabukuro,
Ichiro Kishimoto,
Kenji Kangawa,
Masataka Sata
[show abstract]
[hide abstract]
ABSTRACT: Vagal nerve stimulation has been postulated to confer an antifibrillatory effect. We studied whether ghrelin administration would exert an antiarrhythmic effect via modulation of autonomic nerve activity in rats after acute myocardial ischemia (MI). Male Sprague-Dawley rats were exposed to 30 min of ischemia following ligation of the left coronary artery. Animals were then randomized to receive either ghrelin (n = 26) or saline (n = 26) during the period of coronary ligation. Power spectral analysis of heart-rate variability revealed that the administration of ghrelin increased the high-frequency (HF) power and decreased the low-frequency (LF)/HF ratio. Ventricular tachyarrhythmias were less frequent in rats after MI who received ghrelin in comparison with rats that received saline. Immunoblotting and immunohistochemistry revealed that rats given saline alone during MI exhibited a marked reduction in phosphorylated connexin-43 within the left ventricle, whereas those that received ghrelin displayed only minor reductions in comparison with sham-operated rats. These effects of ghrelin were diminished by the coadministration of atropine or the blockade of vagal afferents. These data demonstrate that the beneficial effect of ghrelin might be mediated by modulation of cardiac autonomic nerve activity.
Heart and Vessels 03/2013; · 2.05 Impact Factor
-
Michio Shimabukuro,
Chisayo Kozuka,
Shin-Ichiro Taira,
Koichi Yabiku,
Munkhbaatar Dagvasumberel,
Masayoshi Ishida,
Sachiko Matsumoto, Shusuke Yagi,
Daiju Fukuda,
Ken Yamakawa,
Moritake Higa,
Takeshi Soeki,
Hisashi Yoshida,
Hiroaki Masuzaki,
Masataka Sata
[show abstract]
[hide abstract]
ABSTRACT: The obesity epidemic is a global public health concern that increases the likelihood of morbidity and mortality of metabolic and cardiovascular disease (CVD) and threatens to reduce life expectancy around the world. The concept of the metabolic syndrome (MetS) takes into account that visceral fat plays an essential role in the development of metabolic and cardiovascular diseases. However, MetS cannot be used to assess global CVD risk but is at best one more modifiable CVD risk factor. Thus, global cardiometabolic risk (the global risk of cardiovascular disease resulting from traditional risk factors combined with the additional contribution of the metabolic syndrome and/or insulin resistance) should be considered individually. There is solid evidence supporting the notion that excess abdominal fat is predictive of insulin resistance and the presence of related metabolic abnormalities currently referred to as MetS. Despite the fact that abdominal obesity is a highly prevalent feature of MetS, the mechanisms by which abdominal obesity is causally related to MetS are not fully elucidated. Besides visceral fat accumulation, ectopic lipid deposition, especially in liver and skeletal muscle, has been implicated in the pathophysiology of diabetes, insulin resistance and obesity-related disorders. Also, ectopic fat deposition could be deteriorated in the heart components such as (1) circulatory and locally recruited fat, (2) intra- and extra-myocellular fat, (3) perivascular fat, and (4) pericardial fat. In this review, the contribution of ectopic lipid deposition to global cardiometabolic risk is reviewed and also discussed are potential underlying mechanisms including adipocytokine, insulin resistance and lipotoxicity. J. Med. Invest. 60: 1-14, February, 2013.
The Journal of Medical Investigation 01/2013; 60(1-2):1-14.
-
Yoichiro Hirata,
Hirotsugu Kurobe,
Etsuko Uematsu, Shusuke Yagi,
Takeshi Soeki,
Hirotsugu Yamada,
Daiju Fukuda,
Michio Shimabukuro,
Mizuho Nakayama,
Kunio Matsumoto,
Yoshiki Sakai,
Tetsuya Kitagawa,
Masataka Sata
[show abstract]
[hide abstract]
ABSTRACT: Injury to the heart can result in cardiomyocyte hypertrophy, fibrosis, and cell death. Myocarditis sometimes progresses to dilated cardiomyopathy. We previously reported that ONO-1301, a synthetic prostacyclin agonist with thromboxane-synthase inhibitory activity, promotes production of hepatocyte growth factor (HGF) from various cell types and ameliorates ischemia-inducedleft ventricle dysfunction in the mouse, rat and pig. Here, we investigatedthe therapeutic efficacy of ONO-1301 in a rat model of myosin-induced experimental autoimmune myocarditis, in which the heart transits from an acute inflammatory phase to a chronic dilated cardiomyopathy phase. Four weeks after myosin injection to Wistar rats, ONO-1301 (6mg/kg/day) was orally administered for 4 weeks (ONO-1301 group). Hemodynamic parameters and plasma brain natriuretic peptide (BNP) level were significantly improved by ONO-1301.Histological analysis revealed that capillary density in the myocardium was significantly increased by ONO-1301. ONO-1301 increased circulating endothelial progenitor cells (EPC) as determined by FACS analysis. These beneficial effects of ONO-1301 were partialy abrogated by a neutralizing anti-HGF antibody(8mg/kg/dose). These findings indicatebneficial effects of ONO-1301 in a ratexperimental autoimmune myocarditis model.
European journal of pharmacology 12/2012; · 2.59 Impact Factor
-
Dagvasumberel Munkhbaatar,
Michio Shimabukuro,
Takeshi Nishiuchi,
Junji Ueno,
Shoichiro Takao,
Daiju Fukuda,
Yoichiro Hirata,
Hirotsugu Kurobe,
Takeshi Soeki,
Takashi Iwase, [......],
Toshiyuki Niki,
Koji Yamaguchi,
Yoshio Taketani, Shusuke Yagi,
Noriko Tomita,
Hirotsugu Yamada,
Tetsuzo Wakatsuki,
Masafumi Harada,
Tetsuya Kitagawa,
Masataka Sata
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Growing evidence suggests that epicardial adipose tissue (EAT) may contribute to the development of coronary artery disease (CAD). In this study, we explored gender disparities in EAT volume (EATV) and its impact on coronary atherosclerosis. METHODS: The study population consisted of 90 consecutive subjects (age: 63 +/- 12 years; men: 47, women: 43) who underwent 256-slice multi-detector computed tomography (MDCT) coronary angiography. EATV was measured as the sum of cross-sectional epicardial fat area on CT images, from the lower surface of the left pulmonary artery origin to the apex. Subjects were segregated into the CAD group (coronary luminal narrowing > 50%) and non-CAD group. RESULTS: EATV/body surface area (BSA) was higher among men in the CAD group than in the non-CAD group (62 +/- 13 vs. 33 +/- 10 cm3/m2, p < 0.0001), but did not differ significantly among women in the 2 groups (49 +/- 18 vs. 42 +/- 9 cm3/m2, not significant). Multivariate logistic analysis showed that EATV/BSA was the single predictor for >50% coronary luminal narrowing in men (p < 0.0001). Predictors excluded were age, body mass index, hypertension, diabetes mellitus, and hyperlipidemia. CONCLUSIONS: Increased EATV is strongly associated with coronary atherosclerosis in men.
Cardiovascular Diabetology 09/2012; 11(1):106. · 3.35 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cilnidipine, an L/N-type calcium channel blocker (CCB), has been reported to have more beneficial effects on proteinuria progression in hypertensive patients than amlodipine, an L-type CCB. The N-type calcium channel blockade that inhibits renal sympathetic nerve activity might reduce glomerular hypertension by facilitating vasodilation of the efferent arterioles. However, the precise mechanism of the renoprotective effect of cilnidipine remains unknown. Because cilnidipine exerted significantly higher antioxidant activity than amlodipine in cultured human mesangial cells, we hypothesized that cilnidipine might exert a renoprotective effect by suppressing oxidative stress. A total of 35 hypertensive patients receiving a renin-angiotensin system inhibitor were randomly assigned to a cilnidipine (n=18; 10 mg per day cilnidipine titrated to 20 mg per day) or amlodipine (n=17; 5 mg per day amlodipine titrated to 10 mg per day) group; the target blood pressure (BP) was set at 130/85 mmHg. After 6 months of treatment, systolic and diastolic BPs were significantly reduced in both of the groups, without any significant difference between the groups. The urinary albumin, 8-hydroxy-2'-deoxyguanosine (OHdG) and liver-type fatty-acid-binding protein (L-FABP) to creatinine ratios significantly decreased in the cilnidipine group (P<0.05) compared with those in the amlodipine group. The reductions in urinary albumin, 8-OHdG and L-FABP were not correlated with the change in systolic BP. In conclusion, cilnidipine, but not amlodipine, ameliorated urinary albumin excretion and decreased urinary 8-OHdG and L-FABP in the hypertensive patients. Cilnidipine probably exerts a greater renoprotective effect through its antioxidative properties.Hypertension Research advance online publication, 5 July 2012; doi:10.1038/hr.2012.96.
Hypertension Research 07/2012; · 2.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cardiovascular disease and renal disease have a close relationship that forms a vicious cycle as a cardiorenal syndrome (CRS). Oxidative stress, endothelial dysfunction, and vascular inflammation could be therapeutic targets when the renin-angiotensin-aldosterone system is activated by accumulation of conventional cardiovascular risk factors; however, a strategy for management of CRS has not been established yet. Statins, HMG-CoA reductase inhibitors, have not only cholesterol-lowering effects but also pleiotropic effects on cardiovascular systems, including anti-inflammatory and antioxidant effects and improvement of nitric oxide bioavailability. Since recent studies have indicated that statins have beneficial effects on chronic kidney disease and heart failure as well as coronary artery disease in cholesterol-lowering-dependent/independent manners, treatment with statins might be a successful strategy for preventing deterioration of CRS.
International journal of vascular medicine 01/2012; 2012:162545.
-
Koji Yamaguchi,
Tetsuzo Wakatsuki,
Toshiyuki Niki,
Kenya Kusunose,
Kunihiko Koshiba, Shusuke Yagi,
Yoshio Taketani,
Takashi Iwase,
Noriko Tomita,
Hirotsugu Yamada,
Takeshi Soeki,
Masashi Akaike,
Masataka Sata
[show abstract]
[hide abstract]
ABSTRACT: Late stent thrombosis (LST) after sirolimus-eluting stent (SES) implantation has been demonstrated previously. Although incomplete neointimal coverage after SES implantation has been reported, local long-term hypercoagulability remains unknown.
We evaluated the local persistent coagulative response in eighty-three consecutive patients with stable angina, treated with either SES (n=51) or BMS (n=32) implantation for isolated de novo left anterior descending (LAD) stenosis. We measured prothrombin fragment F1+2 (frF1+2) and D-dimer levels sampled in the coronary sinus (CS) and sinus of Valsalva (V). The transcardiac gradient (Δ) was defined as the CS level minus V level.
The ΔfrF1 + 2 and ΔD-dimer were significantly greater in the SES group than in the BMS group (0.50 ± 0.35 vs -0.14 ± 0.15 nmol/l, p=0.009 and 0.24 ± 0.21 vs -0.05 ± 0.16 μg/ml, p=0.041, respectively). We selected the hypocoagulative [ΔfrF1 + 2<0.15 (mean value-SD) nmol/l, n=21] and hypercoagulative [ΔfrF1 + 2>0.85 (mean value+SD) nmol/l, n=14] groups out of the SES patients. Multivariate analysis was performed to identify independent predictors of local hypercoagulability. Total SES length was the only independent predictor of local hypercoagulability. There was a significant positive correlation between the ΔfrF1 + 2 and total stent length in the SES group (r=0.57, p<0.05).
An increased local coagulative response was observed in the convalescent phase after SES implantation as compared to BMS. Careful long-term follow-up of patients after longer SES implantation is recommended in order to avoid LST.
International journal of cardiology 12/2011; 153(3):272-6. · 7.08 Impact Factor
-
Takeshi Soeki,
Toshiyuki Niki,
Kenya Kusunose,
Sachiko Bando,
Yoichiro Hirata,
Noriko Tomita,
Koji Yamaguchi,
Kunihiko Koshiba, Shusuke Yagi,
Yoshio Taketani,
Takashi Iwase,
Hirotsugu Yamada,
Tetsuzo Wakatsuki,
Masashi Akaike,
Masataka Sata
[show abstract]
[hide abstract]
ABSTRACT: Inflammation is a critical contributing factor to the development and progression of atherosclerosis. Pentraxin 3 (PTX3) is produced abundantly in atherosclerotic lesions while C-reactive protein (CRP) is mainly produced in the liver. In this study, we investigated whether plasma levels of PTX3 might be a sensitive marker both for the severity of coronary artery disease and vulnerable plaques. Next, we determined whether assays for inflammatory molecules can be used to monitor the therapeutic effects of telmisartan on stabilization of vulnerable atherosclerotic plaques.
We measured PTX3 concentrations in the peripheral and coronary sinus plasma of 40 patients with angina pectoris (AP) and 20 control subjects. Next, in 28 patients with AP, we determined the correlation between levels of inflammatory molecules and the computed tomography (CT) density of plaques as a quantitative index of plaque vulnerability. There was no significant difference in peripheral plasma PTX3 concentrations between patients with AP and control subjects, while coronary sinus plasma PTX3 concentrations were significantly higher in AP patients than control subjects. The concentrations of PTX3 in coronary sinus and peripheral plasma correlated with Gensini scores as an index of severity of coronary atherosclerosis. Interestingly, there was a significantly negative correlation between plasma PTX3 concentrations and CT density (r=-0.67, p<0.01). On the other hand, CT density did not correlate with the peripheral plasma concentrations of monocyte chemoattractant protein-1 (MCP-1) or high-sensitivity CRP (hsCRP). Furthermore, telmisartan treatment for 6 months decreased plasma concentrations of PTX3 but not those of MCP-1 or hsCRP in 12 patients with essential hypertension. Multivariate regression analysis revealed that changes in PTX3 levels were independent of blood pressure changes.
PTX3 is likely more specific than hsCRP as an indicator of coronary plaque vulnerability that could lead to plaque rupture.
Journal of Cardiology 06/2011; 58(2):151-7. · 1.28 Impact Factor
-
Shusuke Yagi,
Masashi Akaike,
Ken-Ichi Aihara,
Takashi Iwase,
Kazue Ishikawa,
Sumiko Yoshida,
Yuka Sumitomo-Ueda,
Kenya Kusunose,
Toshiyuki Niki,
Koji Yamaguchi,
Kunihiko Koshiba,
Yoshio Taketani,
Noriko Tomita,
Hirotsugu Yamada,
Takeshi Soeki,
Tetsuzo Wakatsuki,
Toshio Matsumoto,
Masataka Sata
[show abstract]
[hide abstract]
ABSTRACT: The aim of the present study was to evaluate the factors that modulate the protective action of statins on cardiorenal function, regardless of the lipid-lowering effect. To treat abnormal serum lipid profiles, low-dose pitavastatin (1.0 mg/day) was administered to 65 hyperlipidemic patients. The exclusion criteria included left ventricular ejection fraction <40% and apparent renal disease. Age- and gender-matched patients with hyperlipidemia (n = 40) served as the controls. After 12 to 16 weeks of pitavastatin treatment, pitavastatin had decreased low-density lipoprotein cholesterol (from 143.5 ± 31.4 to 98.2 ± 19.4 mg/dl, p <0.01), triglycerides (from 157.7 ± 57.2 to 140.5 ± 60.7 mg/dl, p <0.01), E/e' (from 10.8 ± 6.2 to 9.0 ± 4.5, p <0.05), a parameter of left ventricular diastolic function, and albuminuria (from 47.6 ± 55.9 to 28.5 ± 40.0 mg/g creatinine, p <0.01). Furthermore, pitavastatin decreased serum transforming growth factor-β1 (from 709 ± 242 to 550 ± 299 pg/ml, p <0.01), urinary 8-hydroxy-2'-deoxyguanosine (from 6.6 ± 4.1 to 5.0 ± 3.1 μg/g creatinine, p <0.01), an oxidative stress marker, and increased urinary nitrate and nitrite (from 22.5 ± 14.6 to 29.4 ± 27.6 nmol/g creatinine, p <0.05). No such changes were observed in the controls. Multiple regression analysis in the pitavastatin group revealed the effect of pitavastatin on cardiorenal function was associated with suppression of oxidative stress, but not on low-density lipoprotein cholesterol reduction. In conclusion, pitavastatin decreases E/e' and albuminuria, which is associated with suppression of oxidative stress.
The American journal of cardiology 03/2011; 107(11):1644-9. · 3.58 Impact Factor
-
Takayuki Ise,
Ken-Ichi Aihara,
Yuka Sumitomo-Ueda,
Sumiko Yoshida,
Yasumasa Ikeda, Shusuke Yagi,
Takashi Iwase,
Hirotsugu Yamada,
Masashi Akaike,
Masataka Sata,
Toshio Matsumoto
[show abstract]
[hide abstract]
ABSTRACT: Thrombin has a crucial role in cardiac remodeling through protease-activated receptor-1 activation in cardiac fibroblasts and cardiomyocytes. As heparin cofactor II (HCII) inhibits the action of tissue thrombin in the cardiovascular system, it is possible that HCII counteracts the development of cardiac remodeling. We investigated the relationships between plasma HCII activity and surrogate markers of cardiac geometry, including left atrial volume index (LAVI), relative wall thickness (RWT) and left ventricular mass index, and deceleration time (DcT) and the ratio of peak E velocity to early diastolic mitral annulus velocity (E/e' ratio) as surrogate markers of left ventricular diastolic dysfunction measured using echocardiography in 304 Japanese elderly individuals without systolic heart failure (169 men and 135 women; mean age: 65.4 ± 11.8 years). Mean plasma HCII activity in all participants was 95.8 ± 17.0% and there was no difference between the mean plasma HCII activities in males and females. Multiple regression analysis revealed that there were significant inverse relationships between plasma HCII activity and LAVI (coefficient: -0.2302, P<0.001), between HCII activity and RWT (coefficient: -0.0007, P<0.05), between HCII activity and DcT (coefficient: -0.5189, P<0.05) and between HCII activity and E/e' ratio (coefficient: -0.0558, P<0.01). Plasma HCII activity was independently and inversely associated with the development of cardiac remodeling, including cardiac concentric change, left atrial enlargement and left ventricular diastolic dysfunction. These findings suggest that cardiac tissue thrombin inactivation by HCII is a novel therapeutic target for cardiac remodeling and atherosclerosis.
Hypertension Research 02/2011; 34(2):225-31. · 2.58 Impact Factor
-
International journal of cardiology 02/2011; 147(3):472-5. · 7.08 Impact Factor
-
Shusuke Yagi,
Masashi Akaike,
Takashi Iwase,
Kenya Kusunose,
Toshiyuki Niki,
Koji Yamaguchi,
Kunihiko Koshiba,
Yoshio Taketani,
Noriko Tomita,
Hirotsugu Yamada,
Takeshi Soeki,
Tetsuzo Wakatsuki,
Masataka Sata
International journal of cardiology 02/2011; 148(1):125-7. · 7.08 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cognitive impairment leading to dementia is associated with high prevalence of hypertension, decreased quality of life and poor prognosis. Aldosterone is known as a risk factor for cardiovascular and cerebrovascular diseases. In addition, mineral corticoid receptors are abundantly expressed in the hippocampus, which plays a pivotal role in cognitive function; however, it has not been determined whether plasma aldosterone level is associated with cognitive impairment in patients with hypertension. We enrolled 68 patients with essential hypertension and assessed their cardiovascular risk factors, including blood pressure, hyperlipidemia, diabetes mellitus, obesity, smoking, history of cerebral infarction, renal function, parameters of inflammation, oxidative stress and nitric oxide bioavailability, a parameter of cerebral blood flow and carotid plaque by ultrasound examination, plasma renin activity and plasma aldosterone concentration (PAC). The mini-mental state examination (MMSE) was used to evaluate cognitive function. The relevance of cardiovascular risk factors and MMSE score was statistically evaluated. Multiple regression analysis showed that age (P < 0.01), PAC (P < 0.01) and history of cerebral infarction (P < 0.05) were inversely and independently associated with MMSE score. Mineral corticoid receptor antagonists, including spironolactone and eplerenone, increased MMSE score in seven patients with hypertension, but not in the controls. In conclusion, increased PAC is associated with impaired cognitive function and mineral corticoid receptor blockade may protect against not only cardiovascular mortality, but also cognitive impairment in patients with hypertension.
Hypertension Research 01/2011; 34(1):74-8. · 2.58 Impact Factor
-
Shunji Hashizume,
Masashi Akaike,
Hiroyuki Azuma,
Kazue Ishikawa,
Sumiko Yoshida,
Yuka Sumitomo-Ueda, Shusuke Yagi,
Yasumasa Ikeda,
Takashi Iwase,
Ken-ichi Aihara,
Masahiro Abe,
Masataka Sata,
Toshio Matsumoto
[show abstract]
[hide abstract]
ABSTRACT: Platelet-derived growth factor (PDGF)-BB plays a crucial role in atherosclerosis and vascular remodeling by promoting the migration and proliferation of vascular smooth muscle cells. The objective of this study was to clarify the pleiotropic effect of peroxisome proliferator-activated receptor α (PPARα) activators on PDGF-BB expression in megakaryocytes and platelets.
The expression of PPARα in a human erythroleukemia (HEL) cells was clearly detected by reverse transcriptase-PCR and immunofluorescence microscopy. The expression level of PPARα in HEL cells was unchanged regardless of differentiation into megakaryocytic cells by treatment with phorbol 12-myristate 13 acetate (TPA). The TPA-induced expression of PDGF-B mRNA and PDGF-BB protein levels in culture media was significantly decreased by treatment with PPARα activators, Wy14643 and fenofibric acid, in a dose-dependent manner. PDGF-BB expression induced by inflammatory cytokines, including interleukin-1β or interleukin-6, was also significantly suppressed by treatment with PPARα activators. Immunohistochemistry of human bone marrow showed the expression of PPARα in both the nucleus and cytoplasm of megakaryocytes. In addition, PDGF-BB levels in platelets were significantly decreased from 1,800±870 to 1,470±840 pg/10(5) platelets (mean±SD, p<0.05) by treatment with 300 mg fenofibrate once daily for 4 weeks in 13 patients with dyslipidemia.
Activation of PPARα in megakaryocytes reduces PDGF-BB expression in platelets. PPARα activators may exert vasculo-protective action through suppression of PDGF-BB production in a megakaryocyte/platelet pathway.
Journal of atherosclerosis and thrombosis 11/2010; 18(2):138-47. · 2.69 Impact Factor
-
Sumiko Yoshida,
Ken-ichi Aihara,
Hiroyuki Azuma,
Ryoko Uemoto,
Yuka Sumitomo-Ueda, Shusuke Yagi,
Yasumasa Ikeda,
Takashi Iwase,
Susumu Nishio,
Hiromi Kawano,
Junko Miki,
Hirotsugu Yamada,
Yoichiro Hirata,
Masashi Akaike,
Masataka Sata,
Toshio Matsumoto
[show abstract]
[hide abstract]
ABSTRACT: Dehydroepiandrosterone sulfate (DHEAS) is thought to be associated with life expectancy and anti-aging. However, its biological significance in atherosclerosis remains controversial. Therefore, the aim of this study was to determine whether DHEAS is associated with development of carotid atherosclerosis in subjects with cardiovascular risk factors.
A total of 419 Japanese individuals (208 males and 211 females) were recruited from Tokushima University Hospital, Japan. In all subjects, maximum intima-media thickness (max-IMT) in all carotid arteries, and mean-IMT and mean blood flow volume (BFV) in the common carotid arteries (CCA) were measured by ultrasonography; endothelial function was assessed by flow-mediated vasodilation of the brachial artery (%FMD). Serum DHEAS and classical cardiovascular risk factors were also evaluated. Statistical significance was determined by multiple regression analysis to elucidate independent determinants of max-IMT, mean-IMT, mean CCA-BFV, and %FMD.
Serum DHEAS levels were higher in males than in females. Multiple regression analysis revealed that DHEAS was an independent negative factor for both max-IMT and mean-IMT in males but not in females. In contrast, DHEAS was the sole positive factor for mean CCA-BFV in females but not in males. In addition, there was no significant relationship between %FMD and DHEAS regardless of sex and other confounding factors.
Although DHEAS is not involved in endothelial function, DHEAS is inversely associated with sex-dependent diverse carotid atherosclerosis such as increased max-IMT and mean-IMT in males and decreased CCA-BFV in females.
Atherosclerosis 09/2010; 212(1):310-5. · 3.79 Impact Factor
-
Yuka Sumitomo-Ueda,
Ken-Ichi Aihara,
Takayuki Ise,
Sumiko Yoshida,
Yasumasa Ikeda,
Ryoko Uemoto, Shusuke Yagi,
Takashi Iwase,
Kazue Ishikawa,
Yoichiro Hirata,
Masashi Akaike,
Masataka Sata,
Shigeaki Kato,
Toshio Matsumoto
[show abstract]
[hide abstract]
ABSTRACT: Heparin cofactor II (HCII), a serine protease inhibitor, inhibits tissue thrombin action after binding with dermatan sulfate proteoglycans in the extracellular matrix of the vascular system. We previously reported that heterozygous HCII-deficient (HCII(+/-)) humans and mice demonstrate acceleration of vascular remodeling, including atherosclerosis. However, the action of HCII on cardiac remodeling never has been determined. HCII(+/+) and HCII(+/-) mice at age 25 weeks were infused with angiotensin II (Ang II; 2.0 mg/kg/d) for 2 weeks by an osmotic mini-pump. Echocardiography revealed acceleration of cardiac concentric remodeling in HCII(+/-) mice and larger left atrial volume in HCII(+/-) mice than in HCII(+/+) mice. Histopathologic studies showed more prominent interstitial fibrosis in both the left atrium and left ventricle in HCII(+/-) mice than in HCII(+/+) mice. Daily urinary excretion of 8-hydroxy-2'-deoxyguanosine, a parameter of oxidative stress, and dihydroethidium-positive spots, indicating superoxide production in the myocardium, were markedly increased in Ang II-treated HCII(+/-) mice compared to those in HCII(+/+) mice. Cardiac gene expression levels of atrial natriuretic peptides and brain natriuretic peptides, members of the natriuretic peptide family, Nox 4, Rac-1, and p67(phox) as components of NAD(P)H oxidase, and transforming growth factor-beta1 and procollagen III were more augmented in HCII(+/-) mice than in HCII(+/+) mice. However, administration of human HCII protein attenuated all of those abnormalities in Ang II-treated HCII(+/-) mice. Moreover, human HCII protein supplementation almost abolished cardiac fibrosis in Ang II-treated HCII(+/+) mice. The results indicate that HCII has a protective role against Ang II-induced cardiac remodeling through suppression of the NAD(P)H oxidase-transforming growth factor-beta1 pathway.
Hypertension 09/2010; 56(3):430-6. · 6.21 Impact Factor
-
Yasumasa Ikeda,
Ken-ichi Aihara,
Masashi Akaike,
Takashi Sato,
Kazue Ishikawa,
Takayuki Ise, Shusuke Yagi,
Takashi Iwase,
Yuka Ueda,
Sumiko Yoshida,
Hiroyuki Azuma,
Kenneth Walsh,
Toshiaki Tamaki,
Shigeaki Kato,
Toshio Matsumoto
[show abstract]
[hide abstract]
ABSTRACT: Doxorubicin (Dox) has been used as a potent anticancer agent, but serious cardiotoxicity precludes its use in a wide range of patients. We have reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and protection from angiotensin II-induced cardiac remodeling. The present study was undertaken to clarify whether the androgen-AR system exerts a cardioprotective effect against Dox-induced cardiotoxicity. Male AR knockout (ARKO) and age-matched littermate male wild-type (WT) mice at 25 wk of age were given ip injections of Dox (20 mg/kg) or a vehicle. The survival rate and left ventricular function in Dox-treated male ARKO mice were reduced compared with those in Dox-treated male WT mice. Electron microscopic study showed prominent vacuole formation of myocardial mitochondria in Dox-treated male ARKO mice. Cardiac oxidative stress and apoptosis of cardiomyocytes were increased more prominently by Dox treatment in male ARKO mice than in male WT mice. In addition, Dox-induced reduction in the expression of cardiac mitochondria transcription factor A (Tfam) and phosphorylation of serine-threonine kinase (Akt) was more pronounced in male ARKO mice than in male WT mice. In cardiac myoblast cells, testosterone up-regulated Akt phosphorylation and Tfam expression and exerted an antiapoptotic effect against Dox-induced cardiotoxicity. Collectively, the results demonstrate that Dox-induced cardiotoxicity is aggravated in male ARKO mice via exacerbation of mitochondrial damage and superoxide generation, leading to enhanced apoptosis of cardiomyocytes. Thus, the androgen-AR system is thought to counteract Dox-induced cardiotoxicity partly through activation of the Akt pathway and up-regulation of Tfam to protect cardiomyocytes from mitochondrial damage and apoptosis.
Molecular Endocrinology 07/2010; 24(7):1338-48. · 4.54 Impact Factor
