Abstract 15402: Sphingosine 1-phosphate Signaling is Involved in the Pathogenesis of Cardiac Hypertrophy in Response to Pressure Overload and Angiotensin II
Molecular mechanisms underlying cardiac remodeling and heart failure are insufficiently understood. Sphingosine 1-phosphate (S1P), a biologically active lysophopholipid, is involved in many critical cellular processes. However, its role in cardiac pathologies is unclear. In the present study, we investigated the involvement of S1P signaling in cardiac hypertrophy in response to pressure overload and angiotensin II. Transverse aortic constriction (TAC) and angiotensin II infusion significantly increased cardiac expression levels of S1P1, the major cardiac receptor subtype for S1P, and sphingosine kinase 1 (SphK1), the key enzyme catalyzing the formation of S1P. Expression levels of S1P1 and SphK1 were increased by angiotensin II in cultured cardiomyocytes and were much higher than those in cardiac fibroblasts, suggesting S1P signaling is primarily activated in cardiomyocytes. S1P and S1P1-selective agonist induced ERK1/2 phosphorylation and cellular hypertrophy in cultured cardiomyocytes. Pharmacological inhibition of the ERK pathway using U0126 reduced S1P-induced cardiomyocyte hypertrophy, and knocking down S1P1 inhibited S1P-induced phosphorylation of ERK1/2, indicating S1P induces hypertrophic responses in cardiomyocytes via S1P1-mediated activation of ERK pathway. Moreover, knocking down S1P1 and SphK1 reduced cardiomyocyte hypertrophy and atrial natriuretic peptide upregulation in response to angiotensin II, suggesting S1P1 pathway is essential for angiotensin II-induced cardiomyocyte hypertrophy. Next we searched for small molecular weight compounds that can potentially inhibit S1P signaling for therapeutic intervention and found LE135, a synthetic retinoid, inhibited angiotensin II-induced S1P1 upregulation and S1P-mediated phosphorylation of ERK1/2. Oral LE135 inhibited TAC-induced S1P1 upregulation in the heart and reduced cardiac hypertrophy and fibrosis in response to pressure overload. LE135 also ameliorated cardiac hypertrophy and fibrosis induced by angiotensin II infusion. These results demonstrate that S1P/S1P1 signaling is an attractive therapeutic target for cardiac hypertrophy and remodeling.
- © 2010 by American Heart Association, Inc.