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Innate immunity is a new therapeutic target for heart failure
The 12th Annual Scientific Meeting
JHFS
S135
Symposium 2 S2-1 (Abstract not available)
S2-2 Innate immunity is a new therapeutic target for heart failure YASUCHIKA TAKEISHI First Department of Internal Medicine, Fukushima Medical University Toll-like receptor (TLR) is expressed in a variety of tissues and recognizes pathogens such as bacteria, fungus and virus. Ligand binding to TLR leads to the activation of NF-kB and causes inflammatory response. On the other hand, pentraxin 3 (PTX3) is a soluble pattern recognition receptor produced by endothelial cells, smooth muscle cells and macrophages in response to primary inflammatory signals. PTX3 recognizes microbes, activates compliment and facilitates pathogen recognition. Therefore, TLR and PTX3 are thought to be responsible for cellular and humoral innate immunity, respectively. In TLR2 knockout (KO) mice, ventricular remodeling after myocardial infarction was suppressed, and cardiac function was preserved compared to wild-type littermate (WT) mice. Survival rate after myocardial infarction was higher in TLR2 KO mice than in WT mice. After doxorubicin administration, cardiomyocyte apoptosis and cardiac dysfunction were blocked in TLR2 KO mice compared to WT mice. In PTX3 KO mice, pressure overload-induced cardiac dysfunction was attenuated compared to WT mice. In human heart failure, plasma PTX3 levels increased with advancing NYHA functional class. The multivariate Cox proportional hazard analysis demonstrated that PTX3 was an independent predictor of adverse clinical outcomes in patients with heart failure. These data suggest that innate immunity plays an important role in heart failure and may be a potential novel therapeutic target to prevent heart failure.
S2-3 Cardiac-specific autoantibodies as a new therapeutic target for patients with dilated cardiomyopathy TSUTOMU YOSHIKAWA1, AKIYASU BABA2 1 Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan, 2Cardiology, Kitasato Institute Hospital Autoimmune disorder is one of the pivotal causes of dilated cardiomyopathy (DCM), as well as genetic predisposition and virus infection. We found that cardiac-specific autoantibodies were detected in approximately 85% patients with DCM. Among them, autoantibody directed against beta1-adrenergic receptors exerts agonist-like action inducing receptor uncoupling and cardiac hypertrophy. Presence of the autoantibody was an independent predictor of sudden cardiac death in association with ventricular tachycardias in patients with DCM. Presence of autoantibody against muscarinic M2-acetylcholine receptors was associated with atrial fibrillation in such patients. We found previously undescribed autoantibody directed against NaK-ATPase in 26% patients with DCM. This autoantibody affects catalytic alpha-subunit of Na-K-ATPase, inducing reduction of the enzyme affinity. Presence of the autoantibody was also associated with ventricular tachycardias and was a powerful predictor of sudden death. We set out to remove such autoantibodies using immunoadsorption technique in patients with severe heart failure due to DCM. We observed plasma brain natriuretic peptide level was significantly decreased (p 5 0.007) after 3e5 consecutive sessions in 10 patients with DCM. We are attempting to characterize autoantibody profile to identify responders who benefit most from the therapy. Conclusions: Some autoantibodies play a pivotal role in mediating pathophysiology of patients with DCM. Immunoadsoprtion technique to remove such autoantibodies may become a promising therapeutic alternative in refractory heart failure due to DCM.
S2-4 Clarithromycin Attenuates Ventricular Remodeling after Ischemia and Transplant Allograft Rejection JUN-ICHI SUZUKI1, MITSUAKI ISOBE2 1 Department of Advanced Clinical Science and Therapeutics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan, 2The Department of Cardiovascular Medicine, Tokyo Medical and Dental University Background: Matrix metalloproteinases (MMPs) are critical in the development of inflammation and tissue remodeling. Clarithromycin (CAM), a major macrolide
antibiotic, has many biological functions including MMP regulation. However, little is known about the effect of CAM in ventricular remodeling after myocardial ischemia and heart transplant rejection through the MMP alteration. Methods: To clarify the role of MMPs regulated by CAM in ischemia and rejection, we orally administered CAM into rat ischemia reperfusion injury and murine cardiac transplant models. Results: In the myocardial ischemia reperfusion model, CAM resulted in a significant reduction of the infarction area/area at risk ratio and preserved fractional shortening ratio. Less macrophages were detected in the ischemic area of the hearts following ischemia reperfusion in the CAM-treated group compared to the nontreated group. Although ischemia reperfusion resulted in ventricular fibrosis and increased MMP-9 activity, CAM significantly reduced these changes. In transplantation, CAM improved acute rejection judged by graft survival and the myocardial cell infiltrating area in a total allomismatch combination. CAM-treated allografts showed affected expression of T-cells, macrophages and MMP-9 in immunohistochemistry. Zymography indicated that enhanced MMP activities were observed in non-treated hearts, while CAM suppressed these levels. Conclusions: CAM is useful to suppress both ischemia reperfusion injury and allograft rejection because they are critically involved in their prevention through the suppression of MMP-9.
S2-5 Negative Regulation of JAK-STAT Signaling and Heart Failure HIDEO YASUKAWA, TOYOHARU OBA, YUSUKE SUGI, TSUTOMU IMAIZUMI Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan Cytokines including interferons and interleukins activate JAK-STAT pathway that is an evolutionary conserved essential signaling network involved in distinct cellular process including inflammation. Suppressor of cytokine signaling 3 (SOCS3) is cytokine-inducible inhibitor of JAK-STAT pathway. We recently reported that cardiac-restricted overexpression of SOCS3 markedly increases cardiac myocyte susceptibility to virus infection. This suggests that endogenous SOCS3 also has significant biological effect in the cardiomyocyte. To understand physiological role of SOCS3 in the cardiomyocyte, we generated cardiac-specific SOCS3 knockout mice (SOCS3-CKO). The mice developed cardiac dysfunction estimated by echocardiogram from 5 months of age and died with signs of dyspnea by 7 months of age. Postmortem analysis revealed significant pleural effusions and ascites, consistent with the presence of heart failure in SOCS3-CKO. Histological analysis showed that the heart has a thin left and right ventricular walls with chamber dilatation; however, inflammation and fibrosis were only rarely observed in SOCS3-CKO. Western blot showed that STAT3 phosphorylation was greater in SOCS3-CKO than wild-type mice. Also microarray analysis revealed that STAT3 target genes were upregulated in SOCS3CKO. These results suggest that cardiac SOCS3 would be important to prevent heart failure with aging.
S2-6 Role of myocardial lymphangiogenesis in heart failure RYOSUKE NISHIO1, HAJIME KUBO2, AKIRA MATSUMORI3 1 Division of Emergency Medicine, Kyoto University Hospital, Kyoto, Japan, 2 Department of Surgery, Graduate School of Medicine, Kyoto University, 3 Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine Background: Recent reports have emphasized the important role of inflammation in the pathophysiology of heart failure. Lymphatic system is important in immune responses. The vascular endothelial growth factor (VEGF)-C/VEGF-D/VEGF receptor (VEGFR)-3 signaling pathway is crucial for lymphangiogenesis. However, the roles of lymphatic vessels in myocardium remain unclear. This study was designed to examine the role of myocardial lymphangiogenesis in heart failure. Methods and Results: We examined the role of myocardial lymphangiogenesis in murine models of viral myocarditis, myocardial infarction, and hypertensive heart failure. We studied the lymphatic morphology by immunohistochemistry, using monoclonal antibodies against podoplanin, specifically expressed in lymphatic vessels. In addition, we examined the effects of VEGF-C156S, lymphangiogenesis inducer, or VEGFR3-Fc, lymphangiogenesis blocker, on survival, myocardial injuries, and hemodynamics in these three models. Immunohistochemical staining for podoplanin resulted in successful labeling of lymphatic capillaries in myocardium. VEGF-C156S and VEGFR3-Fc proteins were successfully expressed in myocardium. Modulating lymphangiogenesis attenuated myocardial injuries, and
JHFS
S135
Symposium 2 S2-1 (Abstract not available)
S2-2 Innate immunity is a new therapeutic target for heart failure YASUCHIKA TAKEISHI First Department of Internal Medicine, Fukushima Medical University Toll-like receptor (TLR) is expressed in a variety of tissues and recognizes pathogens such as bacteria, fungus and virus. Ligand binding to TLR leads to the activation of NF-kB and causes inflammatory response. On the other hand, pentraxin 3 (PTX3) is a soluble pattern recognition receptor produced by endothelial cells, smooth muscle cells and macrophages in response to primary inflammatory signals. PTX3 recognizes microbes, activates compliment and facilitates pathogen recognition. Therefore, TLR and PTX3 are thought to be responsible for cellular and humoral innate immunity, respectively. In TLR2 knockout (KO) mice, ventricular remodeling after myocardial infarction was suppressed, and cardiac function was preserved compared to wild-type littermate (WT) mice. Survival rate after myocardial infarction was higher in TLR2 KO mice than in WT mice. After doxorubicin administration, cardiomyocyte apoptosis and cardiac dysfunction were blocked in TLR2 KO mice compared to WT mice. In PTX3 KO mice, pressure overload-induced cardiac dysfunction was attenuated compared to WT mice. In human heart failure, plasma PTX3 levels increased with advancing NYHA functional class. The multivariate Cox proportional hazard analysis demonstrated that PTX3 was an independent predictor of adverse clinical outcomes in patients with heart failure. These data suggest that innate immunity plays an important role in heart failure and may be a potential novel therapeutic target to prevent heart failure.
S2-3 Cardiac-specific autoantibodies as a new therapeutic target for patients with dilated cardiomyopathy TSUTOMU YOSHIKAWA1, AKIYASU BABA2 1 Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan, 2Cardiology, Kitasato Institute Hospital Autoimmune disorder is one of the pivotal causes of dilated cardiomyopathy (DCM), as well as genetic predisposition and virus infection. We found that cardiac-specific autoantibodies were detected in approximately 85% patients with DCM. Among them, autoantibody directed against beta1-adrenergic receptors exerts agonist-like action inducing receptor uncoupling and cardiac hypertrophy. Presence of the autoantibody was an independent predictor of sudden cardiac death in association with ventricular tachycardias in patients with DCM. Presence of autoantibody against muscarinic M2-acetylcholine receptors was associated with atrial fibrillation in such patients. We found previously undescribed autoantibody directed against NaK-ATPase in 26% patients with DCM. This autoantibody affects catalytic alpha-subunit of Na-K-ATPase, inducing reduction of the enzyme affinity. Presence of the autoantibody was also associated with ventricular tachycardias and was a powerful predictor of sudden death. We set out to remove such autoantibodies using immunoadsorption technique in patients with severe heart failure due to DCM. We observed plasma brain natriuretic peptide level was significantly decreased (p 5 0.007) after 3e5 consecutive sessions in 10 patients with DCM. We are attempting to characterize autoantibody profile to identify responders who benefit most from the therapy. Conclusions: Some autoantibodies play a pivotal role in mediating pathophysiology of patients with DCM. Immunoadsoprtion technique to remove such autoantibodies may become a promising therapeutic alternative in refractory heart failure due to DCM.
S2-4 Clarithromycin Attenuates Ventricular Remodeling after Ischemia and Transplant Allograft Rejection JUN-ICHI SUZUKI1, MITSUAKI ISOBE2 1 Department of Advanced Clinical Science and Therapeutics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan, 2The Department of Cardiovascular Medicine, Tokyo Medical and Dental University Background: Matrix metalloproteinases (MMPs) are critical in the development of inflammation and tissue remodeling. Clarithromycin (CAM), a major macrolide
antibiotic, has many biological functions including MMP regulation. However, little is known about the effect of CAM in ventricular remodeling after myocardial ischemia and heart transplant rejection through the MMP alteration. Methods: To clarify the role of MMPs regulated by CAM in ischemia and rejection, we orally administered CAM into rat ischemia reperfusion injury and murine cardiac transplant models. Results: In the myocardial ischemia reperfusion model, CAM resulted in a significant reduction of the infarction area/area at risk ratio and preserved fractional shortening ratio. Less macrophages were detected in the ischemic area of the hearts following ischemia reperfusion in the CAM-treated group compared to the nontreated group. Although ischemia reperfusion resulted in ventricular fibrosis and increased MMP-9 activity, CAM significantly reduced these changes. In transplantation, CAM improved acute rejection judged by graft survival and the myocardial cell infiltrating area in a total allomismatch combination. CAM-treated allografts showed affected expression of T-cells, macrophages and MMP-9 in immunohistochemistry. Zymography indicated that enhanced MMP activities were observed in non-treated hearts, while CAM suppressed these levels. Conclusions: CAM is useful to suppress both ischemia reperfusion injury and allograft rejection because they are critically involved in their prevention through the suppression of MMP-9.
S2-5 Negative Regulation of JAK-STAT Signaling and Heart Failure HIDEO YASUKAWA, TOYOHARU OBA, YUSUKE SUGI, TSUTOMU IMAIZUMI Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan Cytokines including interferons and interleukins activate JAK-STAT pathway that is an evolutionary conserved essential signaling network involved in distinct cellular process including inflammation. Suppressor of cytokine signaling 3 (SOCS3) is cytokine-inducible inhibitor of JAK-STAT pathway. We recently reported that cardiac-restricted overexpression of SOCS3 markedly increases cardiac myocyte susceptibility to virus infection. This suggests that endogenous SOCS3 also has significant biological effect in the cardiomyocyte. To understand physiological role of SOCS3 in the cardiomyocyte, we generated cardiac-specific SOCS3 knockout mice (SOCS3-CKO). The mice developed cardiac dysfunction estimated by echocardiogram from 5 months of age and died with signs of dyspnea by 7 months of age. Postmortem analysis revealed significant pleural effusions and ascites, consistent with the presence of heart failure in SOCS3-CKO. Histological analysis showed that the heart has a thin left and right ventricular walls with chamber dilatation; however, inflammation and fibrosis were only rarely observed in SOCS3-CKO. Western blot showed that STAT3 phosphorylation was greater in SOCS3-CKO than wild-type mice. Also microarray analysis revealed that STAT3 target genes were upregulated in SOCS3CKO. These results suggest that cardiac SOCS3 would be important to prevent heart failure with aging.
S2-6 Role of myocardial lymphangiogenesis in heart failure RYOSUKE NISHIO1, HAJIME KUBO2, AKIRA MATSUMORI3 1 Division of Emergency Medicine, Kyoto University Hospital, Kyoto, Japan, 2 Department of Surgery, Graduate School of Medicine, Kyoto University, 3 Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine Background: Recent reports have emphasized the important role of inflammation in the pathophysiology of heart failure. Lymphatic system is important in immune responses. The vascular endothelial growth factor (VEGF)-C/VEGF-D/VEGF receptor (VEGFR)-3 signaling pathway is crucial for lymphangiogenesis. However, the roles of lymphatic vessels in myocardium remain unclear. This study was designed to examine the role of myocardial lymphangiogenesis in heart failure. Methods and Results: We examined the role of myocardial lymphangiogenesis in murine models of viral myocarditis, myocardial infarction, and hypertensive heart failure. We studied the lymphatic morphology by immunohistochemistry, using monoclonal antibodies against podoplanin, specifically expressed in lymphatic vessels. In addition, we examined the effects of VEGF-C156S, lymphangiogenesis inducer, or VEGFR3-Fc, lymphangiogenesis blocker, on survival, myocardial injuries, and hemodynamics in these three models. Immunohistochemical staining for podoplanin resulted in successful labeling of lymphatic capillaries in myocardium. VEGF-C156S and VEGFR3-Fc proteins were successfully expressed in myocardium. Modulating lymphangiogenesis attenuated myocardial injuries, and