NEW TREATMENT FOR DIASTOLIC DYSFUNCTION BY PREVENTING CARDIAC FIBROSIS -GENE THERAPY USING A MUTANT TGF-β, RECEPTOR-

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(1) By using PCR, a soluble mutant TGF-β receptor (TβRII : Fc) is being constructed by conjugating an extracellular domain of human TGF-β receptor with human IgG Fc segment.(2) To block the in vivo activity of TGF-β, we used an anti-TGF-β monoclonal TGF-β neutralizing antibody (NAb). Chronic daily treatment with NAb did not change blood pressure elevation and LV hypertrophy induced by aortic constriction (AC) in rats, but almost abolished the AC-induced fibroblast proliferation and myocardial fibrosis. Furthermore, NAb prevented of diastolic dysfunction in AC rats.(3) In the intramyocardial arteries of AC rats, ICAM-1 expression and MCP-1 expression were rapidly and transiently observed, associated with the perivascular macrophage accumulation. Anti-ICAM-1 monoclonal antibody not only reduced macrophage accumulation but also prevented myocardial fibrosis.(4) Chronic NAb treatment did not significantly affected the progression of cardiac fibrosis in Dahl salt-sensitive rats of OLETF rats, probably because the activity of NAb might not remain during the too long treatment (>6 weeks).