Sphingosine-1-phosphate (S1P) is a plasma lysophospholipid with diverse activities, and is released in a large amount from activated platelets. Our laboratory as well as others have identified the existence of the G protein-coupled S1P receptor family, which include ubiquitously expressed S1P1, AGR16/Edg5/S1P2 and S1P3. In an attempt to get more insight into roles of S1P in vivo, we have generated transgenic (TG) mice that overexpress a major S1P synthetic enzyme sphingosine kinase 1 (SPHK1) in diverse tissues, with up to several ten fold increases in the SPHK1 activity. Although previous reports suggested the involvement of SPHK1 in cell proliferation and transformation, the TG mice show normal growth and no obvious increase in spontaneous malignancy. Importantly, TG mice with a high but not a low level of SPHK1 expression in the heart show age-dependent, progressive cardiac fibrosis with development of dilated cardiomyopathy in a limited population. Transgenic heart tissues show elevated activities in both Rac1 and RhoA small molecular weight G proteins and enhanced superoxide generation in responses to phorbol ester. Treatment of TG mice with an HMG-CoA reductase inhibitor or an antioxidant N-2-mercaptopropyonylglycine, but not an angiotensin II type 1 receptor blocker, resulted in alleviation of cardiac fibrosis. These results provide evidence for a pathophysiological role of SPHK1 and probably S1P. [J Physiol Sci. 2006;56 Suppl:S68]