Abstract 792: Reduced Myocardial S1P Signaling Post-MI: Novel Target for Molecular Intervention
Pathologic post-MI remodeling likely involves progressive apoptosis of cardiac myocytes (CM). Sphingosine 1 phosphate (S1P) has recently been identified as part of a critical signaling pathway with anti-apoptotic effects in a number of cell types. Although in vitro data have begun to suggest anti-apoptotic properties of S1P in CM, its role in CM survival in vivo has not yet been explored. We hypothesized that the progression of post-MI cardiomyopathy is associated with a decrease in S1P signaling, and that therapeutic stimulation of the S1P pathway would improve ventricular function. Male C57/B6 mice underwent mid-LAD ligation via a median sternotomy. The resulting infarctions were found to involve 30 – 40% of the ventricular wall, and led to a steady decline between weeks 2 and 12 both in fractional shortening (serial echocardiography) and in maximum developed pressure (ex vivo Langendorff preparation). Sphingosine kinase (SK) activity, responsible for generation of S1P, was measured in cytosolic extracts from mouse myocardium via differential solvent extraction isolation of tritiated product (3H-S1P). SK activity in remote myocardium declined between weeks 1 and 12 post-MI from 3.28 ± 0.76pmol/min/mg protein in sham-operated hearts to 1.42 ± 0.06 at week 12 (P = 0.035), and the apoptotic index increased from 1.1 ± 0.39% to 2.27 ± 0.4% over the same time period. SK-1 is believed to be the SK isoform responsible for survival signaling, and LAD ligation was therefore performed in SK1-knockout mice. In these mice there was a 3-fold increase in apoptotic index in the infarcted region at 1 week post-MI vs. litter-mate controls (0.97 ± 0.23% vs. 0.28 ± 0.13%), with a worsening of wall thinning from 0.45 ± 0.03 mm to 0.25 ± 0.03 mm. Systemic administration of the S1P-1 receptor agonist SEW2871 during the first 2 weeks post-MI was associated with a 22% increase in fractional shortening compared to vehicle-treated controls (P < 0.0001, n=7– 8). These data suggest a potential role for modulating the SK-1/S1P pathway in limiting the progression of post-MI heart failure.