Physiological and pathophysiological roles of the S1P signaling system : an in vivo study

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The sphingosine-1-phosphate (S1P) signaling system plays crucial roles in diverse biological phenomena, which include embryonic vascular maturation and lymphocyte trafficking. It is also implicated in development of certain diseases such as cancer. In an attempt to elucidate pathophysiological role, if any, of the S1P signaling system, we have generated transgenic (TG) mice that overexpress SPHK1 in diverse tissues, with up to several ten fold increases in the enzymatic activity. Although TG x TG matings yielded a slightly reduced litter size, the TG mice grew normally without any obvious abnormality. Notably, TG mice with a high but not a low level of SPHK1 expression in the heart showed age-dependent, progressive cardiac fibrosis. Transgenic heart tissues showed embryonic gene upregulation, elevated Rac1 and RhoA activities and increased oxidative stress. 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. TG mice also developed modest renal glomerular dysfunction with age. Unexpectedly, the TG mice did not show a propensity for spontaneous malignancy or reduced lifespan as compared to the wild type littermates. These results provide evidence for a pathophysiological role of SPHK1 in cardiac remodeling and glomerular injury.