Koichi Yoshimura

Yamaguchi University, Yamaguti, Yamaguchi, Japan

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Publications (41)110.63 Total impact

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    ABSTRACT: Abdominal aortic aneurysm (AAA) is considered a chronic inflammatory disease; however, the molecular basis underlying the sterile inflammatory response involved in the process of AAA remains unclear. We previously showed that the inflammasome, which regulates the caspase-1-dependent interleukin-1β production, mediates the sterile cardiovascular inflammatory responses. Therefore, we hypothesized that the inflammasome is a key mediator of initial inflammation in AAA formation.
    Arteriosclerosis Thrombosis and Vascular Biology 11/2014; · 6.34 Impact Factor
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    ABSTRACT: Background Kawasaki disease (KD) is the most common systemic vasculitis of unknown etiology in children, and can cause the life-threatening complication of coronary artery aneurysm. Although a novel treatment strategy for patients with KD-caused vascular lesions is eagerly awaited, their molecular pathogenesis remains largely unknown. c-Jun N-terminal kinase (JNK) is a signaling molecule known to have roles in inflammation and tissue remodeling. The aim of this study was to elucidate significant involvement of JNK in the development of vascular lesions in a mouse model of KD. Methods and results We injected Candida albicans cell wall extract (CAWE) into 4-week-old C57BL/6 mice. Macroscopically, we found that CAWE caused the development of bulging lesions at coronary artery, carotid artery, celiac artery, iliac artery and abdominal aorta. Histological examination of coronary artery and abdominal aorta in CAWE-treated mice showed marked inflammatory cell infiltration, destruction of elastic lamellae, loss of medial smooth muscle cells and intimal thickening, which are similar to histological features of vascular lesions of patients with KD. To find the role of JNK in lesion formation, we evaluated the effects of JNK inhibitor, SP600125, on abdominal aortic lesions induced by CAWE. Interestingly, treatment with SP600125 significantly decreased the incidence of lesions and also protected against vascular inflammation and tissue destruction histologically, compared with the placebo treatment. Conclusions Our findings suggest that JNK is crucial for the development of CAWE-induced vascular lesions in mice, and potentially represents a novel therapeutic target for KD.
    Cardiovascular Pathology 08/2014; · 2.35 Impact Factor
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    ABSTRACT: Acute aortic dissection (AAD) is caused by the disruption of intimomedial layer of the aortic walls, which is immediately life-threatening. Although recent studies indicate the importance of proinflammatory response in pathogenesis of AAD, the mechanism to keep the destructive inflammatory response in check is unknown. Here, we report that induction of tenascin-C (TNC) is a stress-evoked protective mechanism against the acute hemodynamic and humoral stress in aorta. Periaortic application of CaCl2 caused stiffening of abdominal aorta, which augmented the hemodynamic stress and TNC induction in suprarenal aorta by angiotensin II infusion. Deletion of Tnc gene rendered mice susceptible to AAD development upon the aortic stress, which was accompanied by impaired TGFβ signaling, insufficient induction of extracellular matrix proteins and exaggerated proinflammatory response. Thus, TNC works as a stress-evoked molecular damper to maintain the aortic integrity under the acute stress.
    Scientific Reports 01/2014; 4:4051. · 5.08 Impact Factor
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    ABSTRACT: Abdominal aortic aneurysms (AAAs) are characterized by chronic inflammation, which contributes to the pathological remodeling of the extracellular matrix. Although mechanical stress has been suggested to promote inflammation in AAA, the molecular mechanism remains uncertain. Periostin is a matricellular protein known to respond to mechanical strain. The aim of this study was to elucidate the role of periostin in mechanotransduction in the pathogenesis of AAA. We found significant increases in periostin protein levels in the walls of human AAA specimens. Tissue localization of periostin was associated with inflammatory cell infiltration and destruction of elastic fibers. We examined whether mechanical strain could stimulate periostin expression in cultured rat vascular smooth muscle cells. Cells subjected to 20% uniaxial cyclic strains showed significant increases in periostin protein expression, focal adhesion kinase (FAK) activation, and secretions of monocyte chemoattractant protein-1 (MCP-1) and the active form of matrix metalloproteinase (MMP)-2. These changes were largely abolished by a periostin-neutralizing antibody and by the FAK inhibitor, PF573228. Interestingly, inhibition of either periostin or FAK caused suppression of the other, indicating a positive feedback loop. In human AAA tissues in ex vivo culture, MCP-1 secretion was dramatically suppressed by PF573228. Moreover, in vivo, periaortic application of recombinant periostin in mice led to FAK activation and MCP-1 upregulation in the aortic walls, which resulted in marked cellular infiltration. Our findings indicated that periostin plays an important role in mechanotransduction that maintains inflammation via FAK activation in AAA.
    PLoS ONE 01/2013; 8(11):e79753. · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: The precise pathologic mechanisms underlying human thoracic aortic aneurysms (TAAs) remain uncertain, except that matrix metalloproteinase-9 (MMP-9) is considered a key enzyme for the degradation of extracellular matrix in aneurysm walls. The aim of this study was to elucidate the significance of the angiotensin II (AngII) pathway to MMP-9 production in human TAA walls. METHODS AND RESULTS: We examined the activation of Smad2, a common downstream molecule of AngII and transforming growth factor β (TGF-β) pathways, and the expression of MMP-9 in human nonsyndromic TAA walls. We observed significant increases in Smad2 activation and MMP-9 expression, associated with disruption of elastic lamellae. Using human TAA walls in ex vivo culture, we investigated whether AngII and/or TGF-β pathways are essential for MMP-9 production. Unexpectedly, TGF-β receptor inhibitor had no effect on MMP-9 production. We used PD98059, an inhibitor of extracellular signal-regulated kinase (ERK) activation, and demonstrated that PD98059 dramatically reduced MMP-9 production with attenuation of Smad2 activation. Moreover, exogenous AngII resulted in increases in Smad2 activation and MMP-9 production, in an ERK-dependent manner. CONCLUSION: Our findings indicate that the AngII/ERK pathway has an important role in the production of MMP-9 in human nonsyndromic TAA walls.
    Journal of Surgical Research 01/2013; · 2.02 Impact Factor
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    ABSTRACT: Recently, we reported that angiopoietin-like protein 2 (Angptl2) functions in various chronic inflammatory diseases. In the present study, we asked whether Angptl2 and its associated chronic inflammation contribute to abdominal aortic aneurysm (AAA). Immunohistochemistry revealed that Angptl2 is abundantly expressed in infiltrating macrophages within the vessel wall of patients with AAA and in a CaCl(2)-induced AAA mouse model. When Angptl2-deficient mice were used in the mouse model, they showed decreased AAA development compared with wild-type mice, as evidenced by reduction in aneurysmal size, less severe destruction of vessel structure, and lower expression of proinflammatory cytokines and matrix metalloproteinase-9. However, no difference in the number of infiltrating macrophages within the aortic aneurysmal vessel wall was observed between genotypes. AAA development was also significantly suppressed in wild-type mice that underwent Angptl2-deficient bone marrow transplantation. Expression levels of proinflammatory cytokines and metalloproteinase-9 in Angptl2-deficient macrophages were significantly decreased, and those decreases were rescued by treatment of Angptl2 deficient macrophages with exogenous Angptl2. Macrophage-derived Angptl2 contributes to AAA development by inducing inflammation and degradation of extracellular matrix in the vessel wall, suggesting that targeting the Angptl2-induced inflammatory axis in macrophages could represent a new strategy for AAA therapy.
    Arteriosclerosis Thrombosis and Vascular Biology 05/2012; 32(6):1400-9. · 6.34 Impact Factor
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    ABSTRACT: The targeting of Ca(2+) cycling has emerged as a potential therapy for the treatment of severe heart failure. These approaches include gene therapy directed at overexpressing sarcoplasmic reticulum (SR) Ca(2+) ATPase, or ablation of phospholamban (PLN) and associated protein phosphatase 1 (PP1) protein complexes. We previously reported that PP1β, one of the PP1 catalytic subunits, predominantly suppresses Ca(2+) uptake in the SR among the three PP1 isoforms, thereby contributing to Ca(2+) downregulation in failing hearts. In the present study, we investigated whether heart-failure-inducible PP1β-inhibition by adeno-associated viral-9 (AAV9) vector mediated gene therapy is beneficial for preventing disease progression in genetic cardiomyopathic mice. We created an adeno-associated virus 9 (AAV9) vector encoding PP1β short-hairpin RNA (shRNA) or negative control (NC) shRNA. A heart failure inducible gene expression system was employed using the B-type natriuretic protein (BNP) promoter conjugated to emerald-green fluorescence protein (EmGFP) and the shRNA sequence. AAV9 vectors (AAV9-BNP-EmGFP-PP1βshRNA and AAV9-BNP-EmGFP-NCshRNA) were injected into the tail vein (2×10(11) GC/mouse) of muscle LIM protein deficient mice (MLPKO), followed by serial analysis of echocardiography, hemodynamic measurement, biochemical and histological analysis at 3 months. In the MLPKO mice, BNP promoter activity was shown to be increased by detecting both EmGFP expression and the induced reduction of PP1β by 25% in the myocardium. Inducible PP1βshRNA delivery preferentially ameliorated left ventricular diastolic function and mitigated adverse ventricular remodeling. PLN phosphorylation was significantly augmented in the AAV9-BNP-EmGFP-PP1βshRNA injected hearts compared with the AAV9-BNP-EmGFP-NCshRNA group. Furthermore, BNP production was reduced, and cardiac interstitial fibrosis was abrogated at 3 months. Heart failure-inducible molecular targeting of PP1β has potential as a novel therapeutic strategy for heart failure.
    PLoS ONE 01/2012; 7(4):e35875. · 3.53 Impact Factor
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    Koichi Yoshimura, Hiroki Aoki
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    ABSTRACT: Abdominal aortic aneurysm (AAA) is a common disease causing segmental expansion and rupture of the aorta with a high mortality rate. The lack of nonsurgical treatment represents a large and unmet need in terms of pharmacotherapy. Advances in AAA research revealed that activation of inflammatory signaling pathways through proinflammatory mediators shifts the balance of extracellular matrix (ECM) metabolism toward tissue degradation. This idea is supported by experimental evidence in animal models that pharmacologic intervention at each pathological step can prevent AAA development. Previously, we identified c-Jun N-terminal kinase (JNK), a pro-inflammatory signaling molecule, as a therapeutic target for AAA. Abnormal activation of JNK in AAA tissue regulates multiple pathological processes in a coordinated manner. Pharmacologic inhibition of JNK tips the ECM balance back towards repair rather than degradation. Interventions targeting signaling molecules such as JNK in order to manipulate multiple pathological processes may be an ideal therapeutic strategy for AAA. Furthermore, the development of biomarkers as well as appropriate drug delivery systems is essential to produce clinically practical pharmacotherapy for AAA.
    International journal of vascular medicine 01/2012; 2012:648167.
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    ABSTRACT: Abdominal aortic aneurysm (AAA) is a common disease caused by segmental weakening of the aortic walls and progressive aortic dilation leading to the eventual rupture of the aorta. Currently no biomarkers have been established to indicate the disease status of AAA. Tenascin-C (TN-C) is a matricellular protein that is synthesized under pathological conditions. In the current study, we related TN-C expression to the clinical course and the histopathology of AAA to investigate whether the pattern of TN-C expression could indicate the status of AAA. We found that TN-C and matrix metalloproteinase (MMP)-9 were highly expressed in human AAA. In individual human AAA TN-C deposition associated with the tissue destruction, overlapped mainly with the smooth muscle actin-positive cells, and showed a pattern distinct from macrophages and MMP-9. In the mouse model of AAA high TN-C expression was associated with rapid expansion of the AAA diameter. Histological analysis revealed that TN-C was produced mainly by vascular smooth muscle cells and was deposited in the medial layer of the aorta during tissue inflammation and excessive destructive activities. Our findings suggest that TN-C may be a useful biomarker for indicating the pathological status of smooth muscle cells and interstitial cells in AAA.
    Pathology International 10/2011; 61(10):559-64. · 1.72 Impact Factor
  • Koichi Yoshimura, Yasuhiro Ikeda, Hiroki Aoki
    Atherosclerosis 06/2011; 218(2):285-6. · 3.71 Impact Factor
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    ABSTRACT: We sought to examine the effect of resveratrol (3,4',5-trihydroxy-trans-stilbene), a plant-derived polyphenolic compound, on the development of abdominal aortic aneurysm (AAA). AAA was induced in mice by periaortic application of CaCl(2). NaCl (0.9%)-applied mice were used as a sham group. Mice were treated with intraperitoneal injection of PBS (Sham/CON, AAA/CON, n=30 for each) or resveratrol (100 mg/kg/day) (AAA/RSVT, n=30). Six weeks after the operation, aortic tissue was excised for further examinations. Aortic diameter was enlarged in AAA/CON compared with Sham/CON. Resveratrol treatment reduced the aneurysm size and inflammatory cell infiltration in the aortic wall compared with AAA/CON. Elastica Van Gieson staining showed destruction of the wavy morphology of the elastic lamellae in AAA/CON, while it was preserved in AAA/RSVT. The increased mRNA expression of monocyte chemotactic protein-1, tumor necrosis factor-α, intercellular adhesion molecule-1, CD68, vascular endothelial growth factor-A, p47, glutathione peroxidase (GPX)1 and GPX3 were attenuated by resveratrol treatment (all p<0.05). Administration of resveratrol decreased protein expression of phospho-p65 in AAA. The increased 8-hydroxy-2'-deoxyguanosine-positive cell count and 4-hydroxy-2-nonenal-positive cell count in AAA were also reduced by resveratrol treatment. Zymographic activity of matrix metalloproteinase (MMP)-9 and MMP-2 was lower in AAA/RSVT compared with AAA/CON (both p<0.05). Compared with AAA/CON, Mac-2(+) macrophages and CD31(+) vessels in the aortic wall were decreased in AAA/RSVT (both p<0.05). Treatment with resveratrol in mice prevented the development of CaCl(2)-induced AAA, in association with reduced inflammation, oxidative stress, neoangiogenesis, and extracellular matrix disruption. These findings suggest therapeutic potential of resveratrol for AAA.
    Atherosclerosis 04/2011; 217(2):350-7. · 3.71 Impact Factor
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    ABSTRACT: Increased angiogenesis, chronic inflammation, and extracellular matrix degradation are the major pathological features of abdominal aortic aneurysm (AAA). We sought to elucidate the role of vascular endothelial growth factor (VEGF)-A, a potent angiogenic and proinflammatory factor, in the development of AAA. Human AAA samples showed increased VEGF-A expression, neovascularization, and macrophage infiltration compared with normal aortic walls. AAA was induced in mice by periaortic application of CaCl(2). AAA mice were treated with soluble VEGF-A receptor (sFlt)-1 or phosphate-buffered saline and sacrificed 6 weeks after the operation. Treatment with sFlt-1 resulted in reduced aneurysm size, restored wavy structure of the elastic lamellae, reduced Mac-2(+) monocytes/macrophages, CD3(+) T-lymphocytes, and CD31(+) vessels, and attenuated matrix metalloproteinase (MMP)-2 and 9 activity in periaortic tissue of AAA. Increased aortic mRNA expression of monocyte chemotactic protein-1, tumour necrosis factor-α, and intercellular adhesion molecule-1 in AAA was attenuated by sFlt-1 treatment. VEGF-A was overexpressed in the aortic wall of human and experimental AAA. Treatment with sFlt-1 inhibited AAA development in mice, in association with reduced neoangiogenesis, infiltration of inflammatory cells, MMP activity, and extracellular matrix degradation. These findings suggest a crucial role of VEGF-A in the development of AAA.
    Cardiovascular Research 03/2011; 91(2):358-67. · 5.81 Impact Factor
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    ABSTRACT: Objective: To verify the diagnostic efficiency of venous duplex ultrasound and lymphangioscintigraphy (LAS) in establishing the cause of leg edema and to clarify the pathology of these leg edemas. Materials and Methods: Between April 2009, and March 2010, 62 patients with leg edema of unknown origin were referred to the Edema Clinic of the Yamaguchi University Graduate School of Medicine. All patients underwent a venous duplex ultrasound scan and LAS. Results: Of 62 patients, lymphatic insufficiency, venous insufficiency or both was diagnosed in 42 (68%), and lymphedema, in 29 (47%). Venous duplex ultrasound detected obvious venous disorders in only 13 (21%), and for 20 patients, the ultrasound and LAS did not reveal any abnormalities; however, for 15 of the 20 (24% of all patients), venous edema was attributed to functional causes. Conclusion: Venous duplex ultrasound and LAS assisted in the diagnosis of leg edema of unknown origin and also proved useful in establishing treatment strategies.
    Annals of Vascular Diseases 01/2010; 3(3):222-7.
  • Journal of Cardiac Failure - J CARD FAIL. 01/2010; 16(9).
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    ABSTRACT: Lysyl oxidase (LOX) is an enzyme critical for the stability of extracellular matrix and also known to have diverse biological functions. Little is known, however, about the role of LOX in regulating inflammation. Here we demonstrate that LOX suppresses secretion of monocyte chemoattractant protein-1 (MCP-1) in cultured vascular smooth muscle cells. Furthermore, enhancement of LOX activity reduces MCP-1 in a mouse model of abdominal aortic aneurysm (AAA), thereby preventing macrophage infiltration and AAA progression. These findings suggest that LOX has a novel function in resolving inflammation by reducing MCP-1 in AAA.
    Atherosclerosis 08/2009; 208(2):366-9. · 3.71 Impact Factor
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    ABSTRACT: Lymphedema is a chronic problem causing distress and loss of functions throughout the lifespan. Complex decongestive physiotherapy (CDP) is in common use in developed countries but has only recently been used in Japan for people in outpatient settings. CDP is a representative conservative treatment for lymphedema, conducted by combining four kinds of physical therapies: skin care, manual lymph drainage (MLD), bandage and exercise. This research project lead by a nurse is underway using CDP in an outpatient department. We report a case of secondary lymphedema caused by infection successfully treated by CDP. A 22-year-old man suffered from cellulitis of unknown origin when he was a high school student. After this event, he had been repeatedly admitted to hospital with infections as a result of the lymphedema. He underwent MLD once or twice monthly and received health education for skin care, self-massage and exercise, and was advised to wear compression stockings. Within 7 months the leg swelling had significantly reduced and his feelings of malaise and pain disappeared. Fourteen months later the circumferences of his knee and ankle had kept the sizes, and he has not re-entered hospital for infections. For this man, CDP had a positive outcome, as it has for many others around the world. Our experience has found it very important to establish adequate support systems for such people in outpatient and community settings. However, more research and knowledge sharing are required to understand the usefulness and effectiveness about this program as a primary treatment combined with health education in community settings in Japan.
    Fukuoka igaku zasshi = Hukuoka acta medica 07/2009; 100(6):235-41.
  • Journal of Cardiac Failure - J CARD FAIL. 01/2009; 15(7).
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    ABSTRACT: Abdominal aortic aneurysm (AAA) is a common disease that eventually results in aortic rupture with high mortality. Although a pharmacologic therapy for AAA is eagerly awaited, the destruction of the aortic walls in AAA has been considered an irreversible process. Recently, we identified c-Jun N-terminal kinase (JNK) as a key molecule in the pathogenesis of AAA. JNK was highly activated in the aortic walls of AAA patients. In in vitro studies, JNK not only enhanced expression of matrix metalloproteinases (MMPs), but also reduced expression of biosynthetic enzymes for extracellular matrix (ECM). An AAA model induced by CaCl2 in mice was accompanied by activation of JNK and MMP-9. Treatment with a specific JNK inhibitor, SP600125, completely prevented AAA formation. SP600125 also caused a significant reduction in aneurysmal diameter in established AAA. Surprisingly, SP600125 was effective in normalizing tissue architecture. Furthermore, treatment with SP600125 caused significant regression of angiotensin II-induced AAA in ApoE-null mice after its establishment. These data indicated that pharmacologic inhibition of JNK caused healing of aneurysmal tissue and regression of established AAA, providing a novel therapeutic option for treatment of AAA.
    12/2008: pages 43-49;
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    ABSTRACT: Inflammation is a key process in cardiovascular diseases. The extracellular matrix (ECM) of the vasculature is a major target of inflammatory cytokines, and TNFalpha regulates ECM metabolism by affecting collagen production. In this study, we have examined the pathways mediating TNFalpha-induced suppression of prolyl-4 hydroxylase alpha1 (P4Halpha1), the rate-limiting isoform of P4H responsible for procollagen hydroxylation, maturation, and organization. Using human aortic smooth muscle cells, we found that TNFalpha activated the MKK4-JNK1 pathway, which induced histone (H) 4 lysine 12 acetylation within the TNFalpha response element in the P4Halpha1 promoter. The acetylated-H4 then recruited a transcription factor, NonO, which, in turn, recruited HDACs and induced H3 lysine 9 deacetylation, thereby inhibiting transcription of the P4Halpha1 promoter. Furthermore, we found that TNFalpha oxidized DJ-1, which may be essential for the NonO-P4Halpha1 interaction because treatment with gene specific siRNA to knockout DJ-1 eliminated the TNFalpha-induced NonO-P4Halpha1 interaction and its suppression. Our findings may be relevant to aortic aneurysm and dissection and the stability of the fibrous cap of atherosclerotic plaque in which collagen metabolism is important in arterial remodeling. Defining this cytokine-mediated regulatory pathway may provide novel molecular targets for therapeutic intervention in preventing plaque rupture and acute coronary occlusion.
    Biochimica et Biophysica Acta 09/2008; 1783(8):1517-28. · 4.66 Impact Factor

Publication Stats

605 Citations
110.63 Total Impact Points

Institutions

  • 2006–2014
    • Yamaguchi University
      Yamaguti, Yamaguchi, Japan
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 2012
    • Yamaguchi Prefectural University
      Yamaguti, Yamaguchi, Japan
  • 2007–2008
    • Baylor College of Medicine
      • Division of Cardiothoracic Surgery
      Houston, TX, United States