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ABSTRACT: Background: Periodontopathic bacteria are detected at a high rate in specimens obtained from the aortic walls of patients with abdominal aortic aneurysm (AAA) and are involved in AAA development. The purpose of this study was to clarify the role of Toll-like receptors (TLRs), which are key receptors of virulence factors of many periodontal bacteria, on periodontopathic bacteria-accelerated AAA progression. Methods and Results: AAA was produced by peri-aortic application of 0.25mol/L CaCl(2), with NaCl used as a control. The mice were inoculated with live Porphyromonas (P.) gingivalis or vehicle once weekly. At 4 weeks after the application of CaCl(2), the aortic diameter of the P. gingivalis-infected wild-type mice showed a significant increase in comparison with vehicle control mice (P<0.05). The P. gingivalis-infected TLR-2 deficient mice showed no statistical increase in aortic diameter over the same period. The aortic diameter of the P. gingivalis-infected TLR-4 deficient mice statistically increased. Immunohistochemically, the levels of matrix metalloproteinase-2 and -9 in the aneurysmal samples from wild-type mice were higher than in TLR-2 deficient mice. Conclusions: P. gingivalis accelerated the progression of experimental AAA through TLR-2 signaling.
Circulation Journal 02/2013; · 3.77 Impact Factor
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Norihiko Ashigaki,
Jun-Ichi Suzuki, Masahito Ogawa,
Ryo Watanabe,
Norio Aoyama,
Naho Kobayashi,
Tomoya Hanatani,
Asuka Sekinishi,
Hirofumi Zempo,
Yuko Tada,
Chisato Takamura,
Kouji Wakayama,
Yasunobu Hirata,
Ryozo Nagai,
Yuichi Izumi,
Mitsuaki Isobe
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ABSTRACT: Periodontitis is one of the most common infections in humans. Recently, published reports assert that periodontitis is associated with cardiovascular disease. Although it is said that viral, bacterial infections and autoimmune diseases may be the cause of myocarditis, the pathogenesis of it remains unclear. The aim of this study was to investigate the influence of a periodontal pathogen on experimental autoimmune myocarditis (EAM). Porphyromonas gingivalis (P.g.), PBS as a control, were injected into the mice. Histopathological and immunohistochemical analyses were performed. We examined heart mRNA levels using quantitative RT-PCR. The anti-P.g. IgG antibody level in plasma samples of the P.g.-injected group significantly increased compared to the PBS injected group. Histopathological analysis detected that the myocarditis affected areas and the fibrotic area in the P.g.-injected EAM group significantly increased compared to the PBS injected EAM group (P < 0.05). Immunohistochemical analysis detected that more CD11b-positive cells were shown in the heart of the P.g.-injected EAM group compared to the PBS EAM injected group (P < 0.05). Hearts from the P.g.-injected EAM group showed significantly increased expression of MCP-1, IFN-γ and MMP-9 mRNA compared to the hearts from the PBS injected EAM group (P < 0.05). On a day 7, serum levels of IL-6 were significantly enhanced in the P.g. injected EAM group compared to the PBS injected EAM group (P < 0.05). These results showed that P.g. injection could deteriorate EAM in mice through CD11b-positive cells, cytokines and MMP-9 expression.
AJP Heart and Circulatory Physiology 12/2012; · 3.71 Impact Factor
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ABSTRACT: Background: Pressure-overload is known to be a cause of cardiac hypertrophy that often transits to heart failure. Although nuclear factor-kappaB (NF-kappaB) is a key factor in the progression of cardiac hypertrophy, its pathophisiology is yet to be elucidated. Thus, we aimed to show that inhibition of NF-kappaB activation improves pressure overload-induced cardiac dysfunction. Material and methods: To assess the effect of inhibition on NF-kappaB activation in pressure overload cardiac hypertrophy, we used IMD-1041 in a murine thoracic aortic constriction (TAC) model. IMD-1041 inhibits the phosphorylation of IkappaB via inhibition of IKK-beta. IMD-1041 (100mg/kg/day) or vehicle was administered orally into the mice once a day, and the mice were sacrificed on day 42 after TAC. Results: TAC resulted in LV wall thickening, cardiac dysfunction and the increase of heart and lung weight, while IMD-1041 significantly suppressed its development 6 weeks after TAC. Histologically, developed cardiac fibrosis and cardiomyocyte hypertrophy occurred in the vehicle group, while IMD-1041 significantly attenuated these changes. IMD-1041 suppressed the expression of p65 positive cells, and the nuclear translocation of p65 induced by TAC compared to the vehicle group. MMP-2 activity increased in the vehicle+TAC group, however, it was suppressed in the IMD-1041+TAC group. The IMD-1041 treatment from day 28 to day 42 after TAC significantly attenuated the decrease of %FS and cardiac fibrosis without anti-hypertrophic effect. Conclusion: IMD-1041 may be useful for preventing pressure overload-induced cardiac dysfunction and the transition of cardiac hypertrophy to contraction failure via suppression of NF-kappaB activation.
AJP Heart and Circulatory Physiology 10/2012; · 3.71 Impact Factor
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ABSTRACT: The complex pathophysiological interactions between heart and kidney diseases are collectively known as cardiorenal syndrome. The renin-angiotensin system (RAS) may have a pivotal role in the development of cardiorenal syndrome. The aim of this study was to elucidate the RAS activity responsible for adverse post-infarction remodeling and prognosis in mice with renal failure. To establish the type IV cardiorenal syndrome model, 5/6 nephrectomy (NTX) was performed in a surgical procedure, followed by the induction of myocardial ischemia (MI) by a coronary artery ligation 4 weeks later. NTX and MI resulted in deteriorated left ventricular remodeling and RAS activation, which was improved by an aliskiren that appeared to be independent of renal function and blood pressure (BP). Moreover, MI induced in renin and angiotensinogen double-transgenic (Tg) mice showed comparable effects to MI plus NTX mice, including advanced ventricular remodeling and enhancement of RAS, oxidative stress, and monocytes chemoattractant protein (MCP)-1. Aliskiren suppressed these changes in the MI-induced Tg mice. In in vitro study, Nox2 expression was elevated by the stimulation of plasma from NTX mice in isolated neonatal cardiomyocytes. However, Nox2 upregulation was negated when we administered plasma from aliskiren-treated-NTX mice or isolated cardiomyocytes from AT1-deficient mice. Primary mononuclear cells also showed an upregulation in the expression of Nox2 and MCP-1 by stimulation with plasma from NTX mice. Our data suggest that renal disorder results in ventricular dysfunction and deteriorates remodeling after MI through excessive RAS activation. Moreover, renin inhibition improved the changes caused by cardiorenal syndrome.Laboratory Investigation advance online publication, 17 September 2012; doi:10.1038/labinvest.2012.136.
Laboratory Investigation 09/2012; · 3.64 Impact Factor
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ABSTRACT: INTRODUCTION: Although 100,000 cardiac transplants have been performed, coronary allograft vasculopathy (CAV), which is a phenomenon of chronic rejection, is still a serious problem. AREAS COVERED: Several adhesion molecules, cytokines, and chemokines play a critical role in the process. Recent investigations have proved some promising methodologies for preventing or treating rejection. Although immunoglobulins are known to be an effective treatment in many diseases, their effect on cardiac transplantation or CAV is to be elucidated. EXPERT OPINION: In this review article, we described some promising methodologies that use immunoglobulins to prevent CAV. Immunoglobulins may be used to prevent CAV.
Expert opinion on therapeutic targets 07/2012; 16(8):783-9. · 3.72 Impact Factor
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ABSTRACT: Inflammation plays a key role in neointimal hyperplasia after an arterial injury. Chronic infectious disorders, such as periodontitis, are associated with an increased risk of cardiovascular diseases. However, the effects of a periodontal infection on vascular remodeling have not been examined. We assess the hypothesis that periodontal infection could promote neointimal formation after an arterial injury.
Mice were implanted with subcutaneous chambers (n = 41). Two weeks after implantation, the femoral arteries were injured, and Porphyromonas gingivalis (n = 21) or phosphate-buffered saline (n = 20) was injected into the chamber. The murine femoral arteries were obtained for the histopathological analysis. The expression level of mRNA in the femoral arteries was analyzed using quantitative reverse transcriptase polymerase chain reaction (n = 19-20).
The intima/media thickness ratio in the P. gingivalis infected group was found to be significantly increased in comparison to the non-infected group. The expression of matrix metalloproteinase-2 mRNA was significantly increased in the P. gingivalis infected group compared to the non-infected group.
These findings demonstrate that P. gingivalis injection can promote neointimal formation after an arterial injury. Periodontitis may be a critical factor in the development of restenosis after arterial intervention.
Journal of Vascular Research 06/2012; 49(5):417-24. · 2.65 Impact Factor
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Ayako Nagashima,
Ryo Watanabe, Masahito Ogawa,
Jun-Ichi Suzuki,
Mayumi Masumura,
Keiichi Hishikari,
Tomoko Shimizu,
Kiyoshi Takayama,
Yasunobu Hirata,
Ryozo Nagai,
Mitsuaki Isobe
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ABSTRACT: Telmisartan is an angiotensin II receptor blocker, which acts as a partial agonist of peroxisome proliferator activator receptor-γ (PPAR-γ). Because PPAR-γ initiates a variety of antiinflammatory responses, the effect on myocardial ischemia is to be elucidated.
The left anterior descending arteries were ligated to induce myocardial infarction in rats. The animals were assigned to 4 groups: (1) control (saline, n = 6), (2) telmisartan (10 mg·kg·d, n = 6), (3) telmisartan + GW9662 (PPAR-γ-antagonist) (10 mg·kg·d of telmisartan and 1 mg·kg·d of GW9662, n = 6), and (4) amlodipine (10 mg·kg·d, n = 8) groups. Telmisartan reduced mean blood pressure compared with that in the control group. There was no statistical difference among the telmisartan, telmisartan + GW9662 and amlodipine groups. The end-diastolic left ventricular diameter was smaller in telmisartan group compared with that in the control group; GW9662 negated the effect of telmisartan. The thickness of the ventricular septum was kept in the telmisartan group compared with that in the control group; GW9662 negated the effect. Histopathologic analyses showed that telmisartan suppressed myocardial fibrosis compared with that of the control, whereas GW9662 negated the telmisartan effect.
Telmisartan suppresses pathological remodeling by PPAR-γ agonistic activities independent of its antihypertensive effects.
Journal of cardiovascular pharmacology 05/2012; 60(2):158-64. · 2.83 Impact Factor
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ABSTRACT: Restenosis after percutaneous coronary intervention (PCI) is still a clinically serious problem. We examined the treatment efficacy of IMD-0354, a novel IKK inhibitor, on arteriopathy. Using C57BL/6J mice, a wire-injury model was prepared and the mice were intraperitoneally injected with IMD-0354 or vehicle twice a day. The vehicle-treated injured arteries showed significantly thickened intima (3.77 ± 0.59, n = 8), however, IMD-0354 suppressed its progression (1.62 ± 0.22, n = 10, P < 0.05) on day 28. While enhanced expression of PCNA and NF-κB was observed in the untreated injured arteries, IMD-0354 significantly suppressed their expressions. Quantitative RT-PCR revealed that the expression of several inflammatory factors was reduced in the arteries from mice which received IMD-0354 treatment compared with the control animals. Thus, this drug may effectively prevent restenosis after coronary intervention and other cardiovascular diseases.
International Heart Journal 01/2012; 53(2):133-8. · 1.16 Impact Factor
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ABSTRACT: ONO-1301MS is a compound that acts as a prostacyclin agonist with thromboxane A2 synthase inhibitory activity. We investigated the effect of ONO-1301MS on myocardial remodeling in murine cardiac allografts. The hearts of Balb/c mice were transplanted into C3H/He mice (a full allomismatch combination) to assess acute rejection or C57BL/6 hearts into B6.C-H2(‹bm12›) KhEg (a class II mismatch combination) to examine chronic rejection. ONO-1301MS did not prolong full allomismatch cardiac graft survival. Severe myocardial fibrosis with high collagen concentration was observed in untreated class II mismatch allografts on day 60. However, significantly suppressed myocardial fibrosis with less collagen synthesis was observed in the ONO-1301MS-treated group compared to the control group. ONO-1301MS could be an effective strategy to suppress chronic myocardial remodeling in cardiac transplantation.
International Heart Journal 01/2012; 53(1):64-7. · 1.16 Impact Factor
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ABSTRACT: Chronic inflammation plays a fundamental role in coronary heart disease (CHD). Periodontal disease is a common infectious disease and is a potential source of systemic inflammation. However, the effect of periodontal infection on CHD has not yet been proven. The purpose of this study was to determine the effect of periodontopathic bacteria on experimental myocardial infarction (MI). We implanted a chamber into the subcutaneous tissue of each male mouse. Aggregatibacter actinomycetemcomitans (A.a. n = 8), which is a major periodontal pathogen, or PBS (n = 6) was injected into the chamber. Then, MI was induced by permanent ligation of the left anterior descending coronary artery. To exclude the nonspecific effect of the pathogen, we injected A.a. into the mice without MI (n = 4). The plasma level of anti-A.a. antibody was statistically higher in A.a.-infected mice than in vehicle control mice. Seven days after the myocardial ischemia, the A.a.-positive MI hearts showed a larger infarct size and length than the A.a.-negative MI mice. The A.a.-positive MI hearts showed more MOMA-2 positive myocardial infiltrating cells compared to the A.a.-negative MI mice. The injection of A.a. into the mice without MI did not affect their hearts. We concluded that a periodontal pathogen infection might deteriorate ventricular remodeling after MI through inflammatory cell infiltration.
International Heart Journal 01/2012; 53(4):253-6. · 1.16 Impact Factor
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Asuka Sekinishi,
Jun-Ichi Suzuki,
Norio Aoyama, Masahito Ogawa,
Ryo Watanabe,
Naho Kobayashi,
Tomoya Hanatani,
Norihiko Ashigaki,
Yasunobu Hirata,
Ryozo Nagai,
Yuichi Izumi,
Mitsuaki Isobe
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ABSTRACT: Although a relationship between periodontitis and myocardial hypertrophy has been reported, the precise mechanism has not been clarified. The purpose of this study was to investigate the association between periodontal infection and myocardial hypertrophy. Transverse aortic constriction (TAC) was performed. Mice were injected with Aggregatibacter actinomycetemcomitans (A.a.) (0.1 mL of 10(8) CFU/mL) in the infected group and PBS in the control group. Echocardiography, histopathology, and immunohistochemistry were performed. Echocardiography indicated that left ventricular fractional shortening had decreased in the infected group compared to the control group on day 28. Heart to body weight ratio increased in the infected group compared to the control group. Histopathologically, A.a.-infected mice showed markedly enhanced cardiac hypertrophy, fibrosis and arteriosclerosis 4 weeks after TAC operation. Immunohistochemistry revealed that expression of MMP-2 in the interstitial tissue was enhanced in the infected group. These results suggested that the periodontal pathogen caused a deterioration of pressure overload-induced myocardial hypertrophy through MMP activation.
International Heart Journal 01/2012; 53(5):324-30. · 1.16 Impact Factor
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ABSTRACT: Macrolide antibiotics are broadly used for the treatment of various microbial infections. However, they are also known to have multiple biologic effects, such as alteration of inflammatory factors and matrix metalloproteinases (MMPs). Because of controversial results in clinical trials, the effects of macrolides on cardiovascular diseases are still to be elucidated. It has been reported that MMP activity is upregulated in various cardiovascular diseases, such as myocarditis, cardiac transplant rejection and myocardial infarction. However, little is known about the effects of macrolides on cardiovascular diseases. We have reported that clarithromycin suppressed the development of myocarditis, cardiac rejection and myocardial ischemia using animal models. In this article, we reviewed the roles of MMPs in cardiovascular diseases and the effects of macrolides on the prevention of adverse tissue remodeling.
Cardiovascular Therapeutics 12/2011; · 2.35 Impact Factor
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ABSTRACT: Angiotensin converting enzyme inhibitors have been used clinically to prevent myocardial infarction (MI). The angiotensin converting enzyme inhibitors attenuated ventricular remodeling and improved cardiac function by inhibition of matrix metalloproteinases after MI. Although the effect is thought to be a class effect, there are significant differences among the drugs. The aim of this study was to compare the effects of imidapril and ramipril on ventricular remodeling after MI.
The middle portion of left anterior descending artery was ligated to induce a moderate size MI in rats (moderate MI group). The proximal portion of the artery was ligated to induce a large size MI (large MI group). The animals were assigned to subgroups in moderate MI group and large MI group: (1) nontreated group, (2) ramipril group (1 mg/kg daily), and (3) imidapril group (1 mg/kg daily). All rats were killed on day 28 after the MI operation.
Although the nontreated MI group showed impaired ventricular contraction and severe fibrosis, imidapril significantly negated ischemia-induced changes. Imidapril had a superior effect for preventing ventricular remodeling characterized by fibrosis and collagen accumulation in left ventricle compared with ramipril in the moderate and large MI groups, even though the dosage used in this study was too small to reduce systemic blood pressure.
Imidapril can be used as a substitute for ramipril to prevent ventricular remodeling after MI.
Journal of cardiovascular pharmacology 11/2011; 59(4):323-30. · 2.83 Impact Factor
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ABSTRACT: INTRODUCTION: Although prognosis in acute myocarditis is generally moderate, giant cell myocarditis shows poor prognosis. Giant cell myocarditis is considered to be an autoimmune disease, however, its pathophysiology and specific treatment is yet to be elucidated. AREAS COVERED: This article reviews the clinical characteristics of autoimmune myocarditis and its possible future treatments. An animal model of experimental autoimmune myocarditis (EAM) is characterized by severe myocardial damage and multinucleated giant cell infiltration, and this has been used as a disease model for human acute giant cell myocarditis. Using experimental models, we reported that NF-κB, cytokines, adhesion molecules and other factors play a critical role in the development of autoimmune myocarditis. EXPERT OPINION: Giant cell myocarditis, an autoimmune form of myocarditis, has a high mortality rate unless mechanical support or cardiac transplantation is performed. Therefore, further therapeutic applications of novel methodologies are needed to expand the number of alternative choices for treating autoimmune myocarditis.
Expert opinion on therapeutic targets 07/2011; 15(10):1163-72. · 3.72 Impact Factor
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ABSTRACT: Prostaglandins (PG) and their specific receptors for E type PG (EP) play an important role in inflammatory diseases. Although myocarditis results in inflammation of the heart, roles of PG and EP in its pathophysiology is still controversial. To clarify the role of PG and EP on the progression of myocarditis, we used an experimental autoimmune myocarditis model. A selective EP4 (EP4RAG) agonist was administered into both early (Day 0 to 21) and late (Day 14 to 21) -treated groups and the animals were killed on Day 21. We found that improved cardiac function was detected in the EP4RAG-treated groups in comparison to the untreated group. The infiltration area ratio in the early-treated (16.6% ± 4.6%) group was lower than those in the untreated group (32.1% ± 3.5%) (P < 0.05). The fibrosis area ratios in the early-treated (19.2% ± 6.3%) and the late-treated groups (24.4% ± 5.1%) were lower than those in the untreated group (37.4% ± 2.6%), respectively (P < 0.05). Moreover, we found that EP4RAG decreased T-cell proliferation and monocyte chemoattractant protein-1 production in vitro. We concluded that a selective EP4 agonist inactivates T-cells, which turns out to moderate the progression of experimental autoimmune myocarditis. Therefore, EP4 can be an effective target for myocarditis treatment.
Journal of cardiovascular pharmacology 03/2011; 57(3):365-72. · 2.83 Impact Factor
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ABSTRACT: Introduction: NF-κκB is a key regulator of inflammation and immunity in cancer development. The IκκB kinase (IKK) is a multisubunit complex containing catalytic subunits termed IKK-αα, -ββ and -γγ. It is well known that many pro-inflammatory stimuli require the IKK-ββ subunit for NF-κκB activation. Areas covered: NF-κκB affects the progression of inflammation-related diseases, such as myocardial ischemia, bronchial asthma, arthritis, cancer and other diseases. We review the characteristics and effects of these inhibitors on inflammatory and other diseases. Expert opinion: Various synthesized IKK inhibitors have been developed and they will be used clinically in the near future.
Expert Opinion on Investigational Drugs 02/2011; 20(3):395-405. · 5.27 Impact Factor
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ABSTRACT: INTRODUCTION: plasminogen activator inhibitor-1 (PAI-1) is critical in thrombus formation and inflammation. Although these are essential pathological features of cardiovascular diseases, the effects of PAI-1 inhibition against the development of cardiovascular remodeling have not been well studied. AREAS COVERED: the review explores the therapeutic value of PAI-1 in the progression of various cardiovascular diseases. To date, the authors have reported that a novel PAI-1 inhibitor suppressed the development of experimental autoimmune myocarditis, vascular remodeling after arterial injury, and heart transplant rejection using rodent models. Pathologically, the PAI-1 inhibitor improved histological remodeling of myocardium and arteries with suppression of inflammation and thrombus formation. EXPERT OPINION: PAI-1 inhibitors appear to exhibit potent effects on the prevention of adverse tissue remodeling. However, PAI-1 is a multifunctional protein and more research is needed to further elucidate the association between PAI-1 expression and cardiovascular disease.
Expert Opinion on Investigational Drugs 02/2011; 20(2):255-64. · 5.27 Impact Factor
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ABSTRACT: INTRODUCTION: NF-kB is a key regulator of inflammation and immunity in cancer development. The IkB kinase (IKK) is a multisubunit complex containing catalytic subunits termed IKK-α, -β and -γ. It is well known that many pro-inflammatory stimuli require the IKK-β subunit for NF-kB activation. AREAS COVERED: NF-kB affects the progression of inflammation-related diseases,such as myocardial ischemia, bronchial asthma, arthritis, cancer and other diseases. We review the characteristics and effects of these inhibitors on inflammatory and other diseases. EXPERT OPINION: Various synthesized IKK inhibitors have been developed and they will be used clinically in the near future.
Expert Opinion on Investigational Drugs 02/2011; 20(3):395-405. · 5.27 Impact Factor
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ABSTRACT: Background. Acute rejection and graft arterial disease (GAD) in cardiac transplantation limit the long-term survival of recipients; these processes are enhanced by inflammation and thrombus formation. Plasminogen activator inhibitor (PAI)-1 is critical in the inflammation and thrombus formation. However, little is known about the effect of PAI-1 in heart transplantation. Thus, the objective was to clarify the role of PAI-1 in the progression of cardiac rejection.
Methods. Murine hearts were heterotopically transplanted using major mismatch combinations for evaluation of acute rejection and class II mismatch combinations for the GAD. We administered the specific PAI-1 inhibitor (IMD-1622) into murine recipients after cardiac allografts.
Results. Nontreated allografts of the major mismatch group were acutely rejected, whereas the PAI-1 inhibitor prolonged their survival. Although severe cell infiltration and intimal thickening with enhancement of inflammatory factors were observed in untreated allografts of class II mismatch group on day 60, the PAI-1 inhibitor attenuated these changes.
Conclusion. The PAI-1 inhibitor is potent for the suppression of both acute rejection and GAD.
Transplantation 01/2011; 91(1):21-26. · 4.00 Impact Factor
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ABSTRACT: Plasminogen activator inhibitor-1 (PAI-1) contributes to cardiac ventricular remodeling because migration of inflammatory cells and attenuation of extracellular matrix degradation are caused by plasmin and matrix metalloproteinase. However, the roles of PAI-1 in myocardial ischemia reperfusion (I/R) injury and the following inflammatory response have not yet been well elucidated. To clarify the role of PAI-1 in myocardial I/R injury, we used a specific PAI-1 inhibitor (IMD-1622) in a rat model. The left anterior descending coronary artery was ligated and reperfusion was performed by loosening the suture after 30 minutes of arterial occlusion. A single administration of IMD-1622 (20 mg/kg) or vehicle was given intraperitoneally and then the rats were sacrificed on day 1 or day 14 after I/R. Blood pressure, echocardiograms, histopathology, and molecular examination were performed. The examinations revealed that PAI-1 inhibitor showed limited effects on cardiac dysfunction and ventricular remodeling after I/R. We conclude that the pharmacological inhibition of PAI-1 may not affect ventricular remodeling after myocardial I/R injury.
International Heart Journal 01/2011; 52(6):388-92. · 1.16 Impact Factor
