Augmented sphingosine 1 phosphate receptor-1 signaling in cardiac fibroblasts induces cardiac hypertrophy and fibrosis through angiotensin II and interleukin-6.

Abstract

BACKGROUND:

Cardiac fibroblasts, together with cardiomyocytes, occupy the majority of cells in the myocardium and are involved in myocardial remodeling. The lysophospholipid mediator sphigosine-1-phosphate (S1P) regulates functions of cardiovascular cells through multiple receptors including S1PR1-S1PR3. S1PR1 but not other S1P receptors was upregulated in angiotensin II-induced hypertrophic hearts. Therefore, we investigated a role of S1PR1 in fibroblasts for cardiac remodeling by employing transgenic mice that overexpressed S1PR1 under the control of α-smooth muscle actin promoter. In S1PR1-transgenic mouse heart, fibroblasts and/or myofibroblasts were hyperplastic, and those cells as well as vascular smooth muscle cells overexpressed S1PR1. Transgenic mice developed bi-ventricular hypertrophy by 12-week-old and diffuse interstitial fibrosis by 24-week-old without hemodynamic stress. Cardiac remodeling in transgenic mice was associated with greater ERK phosphorylation, upregulation of fetal genes, and systolic dysfunction. Transgenic mouse heart showed increased mRNA expression of angiotensin-converting enzyme and interleukin-6 (IL-6). Isolated fibroblasts from transgenic mice exhibited enhanced generation of angiotensin II, which in turn stimulated IL-6 release. Either an AT1 blocker or angiotensin-converting enzyme inhibitor prevented development of cardiac hypertrophy and fibrosis, systolic dysfunction and increased IL-6 expression in transgenic mice. Finally, administration of anti-IL-6 antibody abolished an increase in tyrosine phosphorylation of STAT3, a major signaling molecule downstream of IL-6, in the transgenic mouse heart and prevented development of cardiac hypertrophy in transgenic mice. These results demonstrate a promoting role of S1PR1 in cardiac fibroblasts for cardiac remodeling, in which angiotensin II-AT1 and IL-6 are involved.

• Authors: Sei-Ichiro Ohkura, Soichiro Usui, Shin-Ichiro Takashima, Noriko Takuwa, Kazuaki Yoshioka, Yasuo Okamoto, Yutaka Inagaki, Naotoshi Sugimoto, Teppei Kitano, Masayuki Takamura, Takashi Wada, Shuichi Kaneko, Yoh Takuwa
• Journal: PloS one (PLoS One) Vol. 12 Issue 8 Pg. e0182329 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 28771545 (Publication Type: Journal Article)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Benzimidazoles
• Biphenyl Compounds
• Interleukin-6
• Receptors, Lysosphingolipid
• Tetrazoles
• Angiotensin II
• Peptidyl-Dipeptidase A
• candesartan

Topics

• Angiotensin II (analysis, metabolism)
• Angiotensin-Converting Enzyme Inhibitors (pharmacology, therapeutic use)
• Animals
• Benzimidazoles (pharmacology, therapeutic use)
• Biphenyl Compounds
• Cardiomegaly (diagnostic imaging, pathology, prevention & control)
• Cells, Cultured
• Fibroblasts (cytology, drug effects, metabolism)
• Heart Ventricles (diagnostic imaging)
• Humans
• Interleukin-6 (analysis, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (cytology, metabolism)
• Peptidyl-Dipeptidase A (genetics, metabolism)
• Phosphorylation (drug effects)
• Plasmids (genetics, metabolism)
• Receptors, Lysosphingolipid (genetics, metabolism)
• Signal Transduction (drug effects)
• Tetrazoles (pharmacology, therapeutic use)