The renin-angiotensin system (RAS) is known to be involved in the pathogenesis of the atherosclerosis and the regulation of the cardiac function. However, the administration of aldosterone in the development of the atherosclerosis in apolipoprotein E-deficient (ApoE KO) mice demonstrated conflicting results, and the role of angiotensin II type 2 receptor in the atherosclerosis and the cardiac function is incompletely understood. We investigated the pathophysiological effect of the deoxycorticosterone acetate (DOCA) salt on the cardiac function and the aorta in ApoE KO mice. ApoE KO and age-matched wild type (WT) mice were treated with DOCA (25 mg/kg) with 1% NaCl after receiving the right nephrectomy. Systolic blood pressure was noninvasively measured. After 12 weeks treatment, the extent of the aortic atherosclerotic lesion area and the myocardial fibrosis were evaluated, and expression of angiotensin II type 1 and type 2 receptors were studied by RT-PCR and immunohistochemistry. The expression of mRNA of type-1 plasminogen activator inhibitor (PAI-1), type IV collagen, macrophage chemoattractant protein-1 (MCP-1), and 11��-hydroxysteroid dehydrogenase (11��-HSD2) were also determined. DOCA-salt failed to elevate systolic blood pressure in ApoE KO and WT mice. However, the DOCA-salt treated groups in WT and ApoE KO mice developed prominent atherosclerosis (P < 0.05) and vascular remodeling (P < 0.05) in the ascending aorta, and showed the myocardial fibrosis. The simultaneous expression of both AT1 and AT2 receptors in the LV myocardium and the atherosclerotic plaque lesions were increased by the DOCA-salt treatment. The expression of mRNA of PAI-1, type IV collagen, MCP-1, and 11��-HSD2 were also increased in the DOCA groups. Despite the lack of systemic hypertension, chronic treatment with a low dose of DOCA-salt induced the cardiac fibrosis of the LV myocardium, and accelerated atherosclerosis in the ascending aorta. These results suggest that activation of local RAS via the increased expression of AT1 and AT2 receptors in response to chronic treatment with a low dose of DOCA-salt may work the mechanism of the cardiac fibrosis signaling and the aggravation of atherosclerosis in ApoE KO mice.