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1、New Strategies for Immune-mediated Heart Diseases,Mitsuaki IsobeDepartment of Cardiovascular Medicine Tokyo Medical and Dental University,China-Japan Cardiovascular Forum 2008,Immune-mediated heart diseases,Ischemia-reperfusion injury Atherosclerosis Restenosis Cardiac allograft rejection Cardiac al
2、lograft vasculopathy Myocarditis Congestive heart failure Arrhythmia,Immune-mediated heart diseases,Ischemia-reperfusion injury Atherosclerosis Restenosis Cardiac allograft rejection Cardiac allograft vasculopathy Myocarditis Congestive heart failure Arrhythmia,Inflammation in coronary arteriosclero
3、sis and atherogenesisPPAR(Peroxisome proliferator-activated receptor-)NFB,Acute cardiac allograft rejection,Ectopic heart transplantion recipients : C3H/He donors : BALB/c full mismatch,Administration of pioglitazone (3mg/kg/day) to the recipient mice.,Murine heart transplantation,Survival Rate,Post
4、operative Days,Pioglitazone (3mg/kg/day),Control chow,Prolongation of heart graft by pioglitazone,1,0.8,0.6,0.4,0.2,0,10,20,30,40,50,60,70,*,*p0.05,Kosuge, Suzuki, Isobe: Circulation 113: 2613-2622、 2006,0.8,0.6,0.4,0.2,0,Optical Density,R,R + Pio10-6M,R + S,R + S + Pio10-6M,R + S + Pio10-7M,R + S +
5、 Pio10-5M,R: responder(recipient),S: stimulator(donor),Pio: pioglitazone,*,*,*p0.05,Suppression of T cell Proliferation by Pioglitazone in Mixed Lymphocyte Reaction,*,Chronic cardiac rejection Graft arterial disease (GAD),RCA,LAD,LCX,8-y-o boy,Small arteries,Myocardium,Accelerated coronary sclerosis
6、 Graft vasculopathy Cardiac allograft vasculopathy,Pathology:,Diffuse intimal,thickening of small to large,coronary arteries,Pathology:,Diffuse intimal,thickening of small to large,coronary arteries,Risk factors:,CMV infection,episodes of acute rejection,Risk factors:,CMV infection,episodes of acute
7、 rejection,Therapy:,?,Therapy:,?,Progression:,months to years,Progression:,months to years,Chronic cardiac allograft rejection Cardiac allograft vasculopathy,recipients : C57BL/6 donors : Bm12 classII mismatch,-1 0 7 14 21 28 35 42 49 56 days,sacrifice,Control chow Pioglitazone (3mg/kg/day) Telmisar
8、tan (10mg/kg/day),8 Weeks after Transplantation,Luminal occlusion (%),p0.05,Control,Pioglitazone,Attenuation of Graft Arteriosclerosis by Treatment with Pioglitazone or Telmisartan,Telmisartan,p0.05,Control,Telmisartan,Kosuge, Suzuki, Isobe: Circulation 2006,Aorta,SMCs,activated splenocytes,Prolifer
9、ation,SMC Proliferation Assay,Pioglitazone telmisartan,Suppression of SMC proliferation ?,Suppression of SMC Proliferation after Interaction with Splenocytes by Pioglitazone or Telmisartan,SMCs+Pio10-6M,Sp+SMCs+Pio10-7M,Sp+SMCs+Pio10-6M,Sp+SMCs+Pio10-5M,0,5.0,4.0,3.0,2.0,1.0,Optical Density,SMCs,Sp+
10、SMCs,*,*,*,0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,SMCs,SMCs+Tel 10-6M,FBS+SMCs,*,*,*,FBS+SMCs+Tel 10-7M,FBS+SMCs+Tel10-6M,FBS+SMCs+Tel 10-5M,FBS+SMCs+Tel 10-5M+GW,Summary 1,PPAR is associated with pathophysiology of immune-mediated heart diseases. PPAR- agonists (pioglitazone and telmisartan) are effective i
11、n suppressing experimental cardiac allograft rejection (acute rejection and allograft vasculopathy).,References Kosuge, Suzuki, Isobe: Circulation 113: 2613-2622, 2006 Isobe, Kosuge, Suzuki: ATVB, 26: 1447-1456, 2006 Kosuge, Suzuki, Isobe: ATVB, 26: 2660-2665, 2006 Onai, Suzuki, Maejima: Am J Physio
12、l, 292, H530-538, 2007 Kosuge, Suzuki, Isobe, Transplanation, in press Maejima, Suzuki, Okada, Isobe: in submission,Inflammation in coronary arteriosclerosis and atherogenesisPPAR(Peroxisome proliferator-activated receptor-)NFB,LPS,TNF,NFB,StimuliAnoxiaReactive oxygen speciesLPSCytokines (IL-1, TNF)
13、Re-oxygenationLipoproteinThrombin,Gene ExpressionCytokines (IL-1, TNF)iNOS, COX-2Adhesion molecules (ICAM-1, VCAM-1)Immunoreceptors (MHC class I, II)IL-6, M-CSF, GM-CSFChemokines (MCP-1, )Acute phase protein (CRP,),Role of NF-kB in Cardiovascular Diseases,Heart failure Vascular remodeling Allograft
14、rejection Myocarditis Reperfusion injury Ventricular remodeling,NF-B Activation,NF-B decoy - Mechanism of Action -,Cell Membrane,Nucleus,Cis-Element,Inflammatory genes,Decoy,Decoy,Acute Myocarditis Experimental Allergic Myocarditis in Rats,ImmunizationLewis rats were immunized with porcine cardiac myosin.In vivo gene transferInjection of HVJ-liposome- NFB decoy at coronary cuspDay 0, 7 or 14,
