Abstract 14805: Sphingosine 1-Phosphate Receptor 1 Signaling in Cardiac Fibroblasts Regulates Cardiac Hypertrophy and Fibrosis Through Angiotensin II and Interleukin-6
Background: Cardiac fibroblasts, together with cardiomyocytes, occupy the majority of cells in the myocardium and are implicated in myocardial remodeling. The lysophospholipid mediator sphingosine-1-phosphate (S1P) regulates functions of cardiovascular cells including cardiomyocytes and cardiac fibroblasts through multiple S1P receptors including S1PR1 to S1PR3. The role of S1PR1 in cardiac remodeling is not well understood.
Methods and Results: Angiotensin II significantly induced expression of S1PR1 but not other S1P receptors in the mouse heart. Anti-S1PR1 immunohistochemical staining showed abundant S1PR1 expression in the vascular wall of coronary artery but not cardiomyocytes. Therefore, we investigated a role of S1PR1 during cardiac remodeling by employing transgenic mice which overexpressed S1PR1 under the control of α-smooth muscle actin promoter (Tg-S1PR1). Tg-S1PR1 developed bi-ventricular hypertrophy by 12-week-old and diffuse interstitial fibrosis by 24-week-old without hemodymanic stress. In Tg-S1PR1 mouse heart, fibroblasts and/or myofibroblasts were hyperplastic, and those cells as well as vascular smooth muscle cells overexpressed S1PR1. Cardiac remodeling in Tg-S1PR1 was associated with higher ERK phosphorylation, upregulation of fetal genes, and systolic dysfunction. Tg-S1PR1 mouse heart showed increased mRNA expression of angiotensin-converting enzyme and interleukin-6. Isolated fibroblasts from Tg-S1PR1 mouse heart exhibited enhanced generation of angiotensin II, which in turn stimulated interleukin-6 release. Either an AT1 blocker or angiotensin-converting enzyme inhibitor prevented development of cardiac hypertrophy and fibrosis, systolic dysfunction and increased interleukin-6 expression in Tg-S1PR1. Finally, administration of anti-interleukin-6 antibody prevented development of cardiac hypertrophy in Tg-S1PR1.
Conclusion: These results demonstrate the promoting role of S1PR1 in cardiac fibroblasts for cardiac remodeling, in which angiotensin II-AT1 and IL-6 are essential downstream pathways of S1PR1.
- © 2013 by American Heart Association, Inc.