Sphingomyelin phosphodiesterase 1 (SMPD1) mediates the attenuation of myocardial infarction-induced cardiac fibrosis by astaxanthin
- Department of Cardiology, Yantai Yuhuangding Hospital, Yantai, Shandong Province, 264001 (China)
- Department of Critical Care Medicine, Yantai Yuhuangding Hospital, Yantai, Shandong Province, 264001 (China)
- Department of Cardiac Surgery ICU, Yantai Yuhuangding Hospital, Yantai, Shandong Province, 264001 (China)
- School of Medicine, University of California, San Diego, San Diego, CA, 92103 (United States)
Highlights: • Astaxanthin (ASX) attenuated cardiac fibrosis following myocardial infarction (MI). • MI-induced overaccumulation of myocardial ceramides was normalized by ASX. • Sphingomyelin phosphodiesterase 1 (SMPD1) mediates the anti-fibrotic effect of ASX. • SMPD1 knockout abrogated the cardioprotective functions of ASX. Uncontrolled cardiac fibrosis following myocardial infarction (MI) is a critical pathological change leading to heart failure. Current pharmacotherapies are limited by unsatisfactory efficacy and undesired systemic side effects. Astaxanthin (ASX) is a natural carotenoid with strong antioxidant and anti-inflammatory activities. The effects of ASX on MI-induced cardiac fibrosis and the underlying mechanisms remain largely unknown. In this study, after the establishment of MI model, mice were administrated with ASX (200 mg/kg⋅d) for 4 weeks. We found that ASX treatment attenuated cardiac fibrosis and improved heart function following MI, as evidenced by reduced collagen I/III ratio, hydroxyproline content and left ventricular end diastolic pressure (LVEDP). Lipidomic analysis revealed the overaccumulation of myocardial ceramides in mice with cardiac fibrosis, which was normalized by ASX treatment. Molecular docking analysis showed that ASX produced a tight fit in the pocket of sphingomyelin phosphodiesterase 1 (SMPD1), a key enzyme in the production of ceramides. Western blot analysis confirmed the significant inhibition of SMPD1 expression by ASX. Furthermore, MI-induced overexpression of transforming growth factor β1 (TGF-β1) and phosphorylated SMAD2/3 were attenuated by ASX administration. SMPD1 knockout (KO) abrogated the beneficial effect of ASX. Taken together, our results suggest that the cardioprotective effects of ASX are mediated by SMPD1 through the indirection inhibition of TGF- β1/SMAD signaling cascade.
- OSTI ID:
- 23136934
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 503, Issue 2; Other Information: Copyright (c) 2018 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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