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A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
Published on: June 8, 2022
Sphingosine-1-Phosphate Protects Against the Development of Cardiac Remodeling via Sphingosine Kinase 2 and the
Hui Yan1, Hu Zhao2, Shao-Wei Yi2
1Wuhan No. 4 Hospital, Wuhan Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Objective:
Cardiac remodeling is a common pathological change in various cardiovascular diseases and can ultimately result in heart failure. Thus, there is an urgent need for more effective strategies to aid in cardiac protection. Our previous work found that sphingosine-1-phosphate (S1P) could ameliorate cardiac hypertrophy. In this study, we aimed to investigate whether S1P could prevent cardiac fibrosis and the associated mechanisms in cardiac remodeling.
Methods:
Eight-week-old male C57BL/6 mice were randomly divided into a sham, transverse aortic constriction (TAC) or a TAC+S1P treatment group.
Results:
We found that S1P treatment improved cardiac function in TAC mice and that the cardiac fibrosis ratio in the TAC+S1P group was significantly lower and was accompanied by a decrease in α-smooth muscle actin (α-SMA) and collagen type I (COL I) expression compared with the TAC group. We also found that one of the key S1P enzymes, sphingosine kinase 2 (SphK2), which was mainly distributed in cytoblasts, was downregulated in the cardiac remodeling case and recovered after S1P treatment in vivo and in vitro. In addition, our in vitro results showed that S1P treatment activated extracellular regulated protein kinases (ERK) phosphorylation mainly through the S1P receptor 2 (S1PR2) and spurred p-ERK transposition from the cytoplasm to cytoblast in H9c2 cells exposed to phenylephrine.
Conclusion:
These findings suggest that SphK2 and the S1PR2/ERK pathway may participate in the anti-remodeling effect of S1P on the heart. This work therefore uncovers a novel potential therapy for the prevention of cardiac remodeling.
Insights
Sphingosine-1-phosphate (S1P) prevents cardiac fibrosis and improves heart function in mice with cardiac remodeling. This protective effect involves the sphingosine kinase 2 (SphK2) and S1P receptor 2 (S1PR2)/extracellular regulated protein kinases (ERK) pathway.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Pharmacology
Background:
- Cardiac remodeling, a precursor to heart failure, necessitates novel cardioprotective strategies.
- Previous research indicated sphingosine-1-phosphate (S1P) mitigates cardiac hypertrophy.
Purpose of the Study:
- To investigate S1P's efficacy in preventing cardiac fibrosis during remodeling.
- To elucidate the underlying molecular mechanisms of S1P's cardioprotective effects.
Main Methods:
- Utilized a mouse model of transverse aortic constriction (TAC) to induce cardiac remodeling.
- Administered S1P to TAC mice and assessed cardiac function, fibrosis, and molecular markers.
- Employed in vitro cell models (H9c2 cells) to explore signaling pathways.
Main Results:
- S1P treatment significantly reduced cardiac fibrosis and improved cardiac function in TAC mice.
- S1P administration decreased expression of α-smooth muscle actin (α-SMA) and collagen type I (COL I).
- Sphingosine kinase 2 (SphK2) was downregulated in cardiac remodeling and restored by S1P; S1P activated the S1PR2/ERK pathway in vitro.
Conclusions:
- SphK2 and the S1PR2/ERK pathway are implicated in S1P's anti-fibrotic effects on the heart.
- S1P presents a potential novel therapeutic avenue for preventing cardiac remodeling and heart failure.
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