MYOCARDITIS INDUCED BY TARGETED EXPRESSION OF THE MCP-1 GENE IN MURINE CARDIAC-MUSCLE

To explore the possible role of monocyte chemotactic protein (MCP-1) i n inflammatory diseases of the heart, we expressed the murine MCP-1(JE ) gene under the control of the alpha-cardiac myosin heavy chain promo ter to attempt to target MCP-1 expression to the adult heart muscle, T he five lines of transgenic mice thus produced showed targeted express ion of MCP-1 transcripts and protein in the adult heart muscle and pul monary vein but not in skeletal muscle, MCP-1 level in the transgenic hearts increased up to 30 to 45 days of age, and leukocyte infiltratio n into interstitium between cardiomyocytes increased up to 60 to 75 da ys, The infiltrate was mainly macrophages but not T cells, The presenc e of MCP-1 in the transgenic hearts did not induce cytokine production indicative of leukocyte activation. Echocardiographic analysis of 1-y ear-old mice that express MCP-1 in the myocardium and of age-matched c ontrols revealed cardiac hypertrophy and dilation, increases in left v entricular (LV) mass, and systolic and diastolic left ventricular inte rnal diameters, A significant decline in M-mode shortening fraction sh owed depressed contractile function. Transgenic hearts were 65% heavie r, and histological analysis showed moderate myocarditis, edema, and s ome fibrosis, Thus, MCP-1 expression in the heart muscle may provide a model to investigate myocarditis and cardiomyopathy.