Yoshihiro Fukumoto
Kurume University
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Featured researches published by Yoshihiro Fukumoto.
Journal of Cardiovascular Pharmacology | 1996
Hiroaki Shimokawa; H. Yasutake; Fujii K; Owada Mk; Ryuichi Nakaike; Yoshihiro Fukumoto; Takayanagi T; Nagao T; Kensuke Egashira; Fujishima M; Akira Takeshita
Endothelium-dependent relaxations are achieved by a combination of endothelium-derived prostacyclin (PGI2), nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). However, it remains to be fully clarified whether the relative contribution of these three mechanisms to endothelium-dependent relaxations varies as a function of the vessel size. This study was designed to clarify this point. Acetylcholine (ACh)-induced endothelium-dependent relaxations were examined in isolated blood vessels taken from the aorta and the proximal and distal mesenteric arteries of the rat. The contributions of PGI2, NO, and EDHF were evaluated by the inhibitory effects of indomethacin, N omega-nitro-L-arginine methyl ester (L-NAME) in the presence of indomethacin, and KCl in the presence of indomethacin and L-NAME, respectively. The membrane potentials were recorded with microelectrodes. The expression of endothelial No synthase (eNOS) was examined by both immunostaining and immunoblotting. The contribution of PGI2 was negligible in three different-sized blood vessels. The contribution of NO was most prominent in the aorta, whereas that of EDHF was most prominent in the distal mesenteric arteries. The resting membrane potential was significantly deeper and the ACh-induced hyperpolarization was greater in the distal mesenteric arteries than those in the aorta. The expression of eNOS was the highest in the aorta and the lowest in the distal mesenteric arteries. These results indicate that the importance of EDHF increases as the vessel size decreases in endothelium-dependent relaxations in the rat mesenteric circulation.
Circulation | 2001
Yoshihiro Fukumoto; Peter Libby; Elena Rabkin; Christopher C. Hill; Makoto Enomoto; Yasuhiko Hirouchi; Masashi Shiomi; Masanori Aikawa
Background —Acute coronary syndromes often result from rupture of vulnerable plaques. The collagen content of plaques probably regulates their stability. This study tested whether HMG-CoA reductase inhibitors (statins) alter interstitial collagen gene expression or matrix metalloproteinase (MMP) levels in rabbit atheroma. Methods and Results —We administered equihypocholesterolemic doses of pravastatin (a hydrophilic statin, 50 mg · kg−1 · d−1, n=9), fluvastatin (a cell-permeant lipophilic statin, 20 mg · kg−1 · d−1, n=10), or placebo (n=10) to mature Watanabe heritable hyperlipidemic rabbits for 52 weeks. The fluvastatin group achieved a much higher peak plasma concentration (23.7 &mgr;mol/L) than did the pravastatin group (1.3 &mgr;mol/L) under these conditions. Immunohistochemistry revealed that MMP-1, MMP-3, and MMP-9 expression by macrophages in the intima was lower in both the pravastatin and fluvastatin groups than in the placebo group, whereas there was no difference in macrophage numbers. Numbers of intimal smooth muscle cells (SMCs) (identified by immunohistochemistry) and expression of type I procollagen mRNA (detected by in situ hybridization), however, were significantly higher in the pravastatin group than in the fluvastatin group. Treatment with pravastatin, but not fluvastatin, preserved interstitial collagen content in vivo (detected by picrosirius red polarization). In vitro, fluvastatin, but not pravastatin, decreased numbers of rabbit and human aortic SMCs without altering procollagen I mRNA expression. Conclusions —This study showed that statins can reduce MMP expression in atheroma and that cell-permeant statins can decrease SMC number and collagen gene expression in vivo.
American Journal of Physiology-heart and Circulatory Physiology | 2011
Kimio Satoh; Yoshihiro Fukumoto; Hiroaki Shimokawa
Rho-kinase (ROCKs) belongs to the family of serine/threonine kinases and is an important downstream effector of the small GTP-binding protein RhoA. There are two isoforms of Rho-kinase, ROCK1 and ROCK2, and they have different functions with ROCK1 for circulating inflammatory cells and ROCK2 for vascular smooth muscle cells. It has been demonstrated that the RhoA/Rho-kinase pathway plays an important role in various fundamental cellular functions, including contraction, motility, proliferation, and apoptosis, leading to the development of cardiovascular disease. The important role of Rho-kinase in vivo has been demonstrated in the pathogenesis of vasospasm, arteriosclerosis, ischemia-reperfusion injury, hypertension, pulmonary hypertension, stroke, and heart failure. Furthermore, the beneficial effects of fasudil, a selective Rho-kinase inhibitor, have been demonstrated for the treatment of several cardiovascular diseases in humans. Thus the Rho-kinase pathway is an important new therapeutic target in cardiovascular medicine.
Circulation Research | 2007
Makoto Nakano; Kimio Satoh; Yoshihiro Fukumoto; Yoshitaka Ito; Yutaka Kagaya; Naoto Ishii; Kazuo Sugamura; Hiroaki Shimokawa
We have recently demonstrated that endogenous erythropoietin (Epo)/Epo receptor (EpoR) system plays an important protective role in hypoxia-induced pulmonary hypertension. However, it remains to be examined whether vascular EpoR system contributes to angiogenesis in response to ischemia. We examined angiogenesis in EpoR−/−-rescued mice that lack EpoR in most organs including cardiovascular system except erythroid-lineage cells. Two weeks after femoral artery ligation, blood flow recovery, activation of VEGF/VEGF receptor system, and mobilization of endothelial progenitor cells were all impaired in EpoR−/−-rescued mice as compared with wild-type (WT) mice. Bone marrow (BM) transplantation with WT-BM cells in EpoR−/−-rescued mice partially but significantly improved blood flow recovery after hindlimb ischemia. The extent of VEGF upregulation and the number of BM-derived cells in ischemic tissue were significantly less in EpoR−/−-rescued mice compared with WT mice even after BM reconstitution with WT-BM cells. Similarly, the recovery of blood flow was significantly impaired in recipient EpoR−/−-rescued mice that had been transplanted with WT-BM or EpoR−/−-rescued-BM as compared with recipient WT mice. Furthermore, the Matrigel implantation assay and aortic ring assay showed that microvessel growth in vitro was significantly reduced in EpoR−/−-rescued mice as compared with WT mice. These results indicate that vascular EpoR system also plays an important role in angiogenesis in response to hindlimb ischemia through upregulation of VEGF/VEGF receptor system, both directly by enhancing neovascularization and indirectly by recruiting endothelial progenitor cells and BM-derived proangiogenic cells.
European Heart Journal | 2012
Tatsuo Aoki; Yoshihiro Fukumoto; Satoshi Yasuda; Yasuhiko Sakata; Kenta Ito; Jun Takahashi; Satoshi Miyata; Ichiro Tsuji; Hiroaki Shimokawa
AIMS While previous studies reported a short-term increase in individual cardiovascular disease (CVD) after great earthquakes, mid-term occurrences of all types of CVDs after great earthquakes are unknown. We addressed this important issue in our experience with the Great East Japan Earthquake (11 March 2011). METHODS AND RESULTS We retrospectively examined the impact of the Earthquake on the occurrences of CVDs and pneumonia by comparing the ambulance records made by doctors in our Miyagi Prefecture, the centre of the disaster area, during the periods of 2008-11 (n = 124,152). The weekly occurrences of CVDs, including heart failure (HF), acute coronary syndrome (ACS), stroke, cardiopulmonary arrest (CPA), and pneumonia were all significantly increased after the Earthquake compared with the previous 3 years. The occurrences of ACS and CPA showed the rapid increase followed by a sharp decline, whereas those of HF and pneumonia showed a prolonged increase for more than 6 weeks and those of stroke and CPA showed a second peak after the largest aftershock (7 April 2011). Furthermore, the occurrence of CPA was increased in the first 24 h after the Earthquake, followed by other diseases later on. These increases were independent of age, sex, or residence area (seacoast vs. inland). CONCLUSION These results indicate that the occurrences of all types of CVDs and pneumonia were increased in somewhat different time courses after the Earthquake, including the first observation of the marked and prolonged increase in HF, emphasizing the importance of intensive medical management of all types of CVDs after great earthquakes.
Heart and Vessels | 2010
Hiroshi Fujita; Yoshihiro Fukumoto; Kenya Saji; Koichiro Sugimura; Jun Demachi; Jun Nawata; Hiroaki Shimokawa
We have previously demonstrated that long-term inhibition of Rho-kinase ameliorates pulmonary arterial hypertension (PAH) in animal models. In the present study, we examined acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, as a more feasible option to locally deliver the drug for PAH. We examined 15 patients with PAH (13 women and 2 men, 45 ± 4 years old), including idiopathic PAH (n = 5), PAH associated with connective tissue disease (n = 6), PAH with congenital heart disease (n = 3), and portal PAH (n = 1). In those patients, we performed right heart catheterization with a Swan-Ganz catheter in the two protocols with inhalation of nitric oxide (NO) (40 ppm, 10 min) and fasudil (30 mg, 10 min) with a sufficient interval (>30 min). Both NO and fasudil inhalation significantly reduced mean pulmonary arterial pressure (PAP) (NO: P < 0.01, fasudil: P < 0.05) and tended to decrease pulmonary vascular resistance (NO: P = 0.07, fasudil: P = 0.1), but did not affect cardiac index. The ratio of pulmonary to systemic vascular resistance was significantly reduced both in NO and fasudil inhalation (NO: P < 0.01, fasudil: P < 0.05), indicating that both NO and fasudil inhalation selectively affect lung tissues. Interestingly, there was no correlation in the vasodilator effects between NO and fasudil, and a positive correlation with serum levels of high-sensitivity C-reactive protein was noted for fasudil but not for NO. These results suggest that inhalation of fasudil is as effective as NO in patients with PAH, possibly through different mechanisms.
Journal of The American Society of Nephrology | 2009
Takafumi Toyohara; Takehiro Suzuki; Ryo Morimoto; Yasutoshi Akiyama; Tomokazu Souma; Hiromi O. Shiwaku; Yoichi Takeuchi; Eikan Mishima; Michiaki Abe; Masayuki Tanemoto; Satohiro Masuda; Hiroaki Kawano; Koji Maemura; Masaaki Nakayama; Hiroshi Sato; Tsuyoshi Mikkaichi; Hiroaki Yamaguchi; Shigefumi Fukui; Yoshihiro Fukumoto; Hiroaki Shimokawa; Ken-ichi Inui; Tetsuya Terasaki; Junichi Goto; Sadayoshi Ito; Takanori Hishinuma; Isabelle Rubera; Michel Tauc; Yoshiaki Fujii-Kuriyama; Hikaru Yabuuchi; Yoshinori Moriyama
Hypertension in patients with chronic kidney disease (CKD) strongly associates with cardiovascular events. Among patients with CKD, reducing the accumulation of uremic toxins may protect against the development of hypertension and progression of renal damage, but there are no established therapies to accomplish this. Here, overexpression of human kidney-specific organic anion transporter SLCO4C1 in rat kidney reduced hypertension, cardiomegaly, and inflammation in the setting of renal failure. In addition, SLCO4C1 overexpression decreased plasma levels of the uremic toxins guanidino succinate, asymmetric dimethylarginine, and the newly identified trans-aconitate. We found that xenobiotic responsive element core motifs regulate SLCO4C1 transcription, and various statins, which act as inducers of nuclear aryl hydrocarbon receptors, upregulate SLCO4C1 transcription. Pravastatin, which is cardioprotective, increased the clearance of asymmetric dimethylarginine and trans-aconitate in renal failure. These data suggest that drugs that upregulate SLCO4C1 may have therapeutic potential for patients with CKD.
Cardiovascular Research | 2009
Kimio Satoh; Yoshihiro Fukumoto; Makoto Nakano; Koichiro Sugimura; Jun Nawata; Jun Demachi; Akihiko Karibe; Yutaka Kagaya; Naoto Ishii; Kazuo Sugamura; Hiroaki Shimokawa
AIMS Mobilization of stem cells/progenitors is regulated by the interaction between stromal cell-derived factor-1 (SDF-1) and its ligand, CXC chemokine receptor 4 (CXCR4). Statins have been suggested to ameliorate pulmonary arterial hypertension (PAH); however, the mechanisms involved, especially their effects on progenitors, are largely unknown. Therefore, we examined whether pravastatin ameliorates hypoxia-induced PAH in mice, and if so, which type of progenitors and what mechanism(s) are involved. METHODS AND RESULTS Chronic hypoxia (10% O(2) for 5 weeks) increased the plasma levels of SDF-1 and mobilization of CXCR4(+)/vascular endothelial growth factor receptor (VEGFR)2(+)/c-kit(+) cells from bone marrow (BM) to pulmonary artery adventitia in Balb/c mice in vivo, both of which were significantly suppressed by simultaneous oral treatment with pravastatin (2 mg/kg/day). Furthermore, in vitro experiments demonstrated that hypoxia enhances differentiation of VEGFR2(+)/c-kit(+) cells into alpha-smooth muscle actin(+) cells. Importantly, pravastatin ameliorated hypoxia-induced PAH associated with a decrease in the number of BM-derived progenitors accumulating in the pulmonary artery adventitia. The expression of intercellular adhesion molecule-1 (ICAM-1) and its ligand, CD18 (beta2-integrin), were enhanced by hypoxia and were again suppressed by pravastatin. CONCLUSIONS These results suggest that pravastatin ameliorates hypoxia-induced PAH through suppression of SDF-1/CXCR4 and ICAM-1/CD18 pathways with a resultant reduction in the mobilization and homing of BM-derived progenitor cells.
Journal of Cardiovascular Pharmacology | 2007
Bao Hua Jiang; Shunsuke Tawara; Kohtaro Abe; Aya Takaki; Yoshihiro Fukumoto; Hiroaki Shimokawa
Pulmonary arterial hypertension is a progressive and fatal disease for which Rho-kinase may be substantially involved. In this study, we examined the acute vasodilator effects of fasudil, a Rho-kinase inhibitor, in monocrotaline (MCT)-induced pulmonary hypertension (PH) in rats. Three weeks after a single subcutaneous injection of MCT (60 mg/kg), hemodynamic variables were measured under conscious and free-moving conditions before and after oral administration of fasudil. MCT caused a significant elevation of mean pulmonary arterial pressure (mPAP). Although a low dose of fasudil (3 mg/kg) had no effect on mPAP, a middle dose (10 mg/kg) caused a significant reduction in mPAP without change in mean systemic arterial pressure (mSAP), and a high dose (30 mg/kg) significantly reduced both mPAP and mSAP. Rho-kinase activity was significantly increased by MCT injection in pulmonary arteries but not in the aorta. Fasudil (10 mg/kg) inhibited only the Rho-kinase activity in pulmonary arteries without any effect in the aorta. Plasma concentration of hydroxyfasudil, a metabolite of fasudil, was within its clinical range in humans. These results demonstrate that fasudil exerts effective and selective vasodilatation of pulmonary arteries in rats with MCT-induced PH at a given dose, suggesting its usefulness for the treatment of the fatal disorder.
Arteriosclerosis, Thrombosis, and Vascular Biology | 2013
Toru Shimizu; Yoshihiro Fukumoto; Shin-ichi Tanaka; Kimio Satoh; Shohei Ikeda; Hiroaki Shimokawa
Objective—Rho/Rho-kinase (ROCK) pathway in vascular smooth muscle cells (VSMCs) plays an important role in the pathogenesis of cardiovascular diseases, including pulmonary arterial hypertension (PAH). Rho-kinase has 2 isoforms, ROCK1 and ROCK2, with different functions in different cells; ROCK1 for circulating inflammatory cells and ROCK2 for the vasculature. In the present study, we aimed to examine whether ROCK2 in VSMC is involved in the pathogenesis of PAH. Approach and Results—In patients with PAH, the expression of ROCK2 was increased in pulmonary arterial media and primary pulmonary arterial smooth muscle cells when compared with controls. To investigate the role of ROCK2 in VSMC, we generated VSMC-specific heterozygous ROCK2-deficient (ROCK2+/−) mice and VSMC-specific ROCK2-overexpressing transgenic (ROCK2-Tg) mice. The extent of hypoxia-induced pulmonary hypertension was reduced in ROCK2+/− mice and was enhanced in ROCK2-Tg mice compared with respective littermates. The protein expression of ROCK activity and phosphorylated extracellular signal–regulated kinase and the number of Ki67-positive proliferating cells in the lung were reduced in ROCK2+/− mice and were increased in ROCK2-Tg mice compared with respective littermates. In cultured mouse aortic VSMC, migration and proliferation activities were reduced in ROCK2+/− mice, and migration activity was increased in ROCK2-Tg mice compared with respective littermates. In addition, in primary pulmonary arterial smooth muscle cells from a patient with PAH, ROCK2 was required for migration and proliferation through ROCK and extracellular signal–regulated kinase activation. Conclusions—ROCK2 in VSMC contributes to the pathogenesis of PAH.