Abstract
Hyperhomocysteinemia (HHcy) is a highly-related risk factor in vascular smooth muscle cell (VSMC) phenotypic modulation and atherosclerosis. Growing evidence indicated that autophagy is involved in pathological arterial changes. However, the risk mechanisms by which homocysteine and VSMC autophagy interact with cardiovascular disease are poorly understood. This study verified the homocysteine-responsive endoplasmic reticulum protein promotion of VSMC phenotypic switching, and the formation of atherosclerotic plaque in vitro. We found that impaired autophagy, as evidenced by decreased levels of MAP1LC3B II/MAP1LC3B I, has a vital role in HHcy-induced human aortic (HA)-VSMC phenotypic switching, with a decrease in contractile proteins (SM α-actin and calponin) and an increase in osteopontin. Knockdown of the essential autophagy gene Atg7 by small interfering RNA promoted HA-VSMC phenotypic switching, indicating that impaired autophagy induces phenotypic switching in these cells. HHcy co-treatment with rapamycin triggered autophagy, which alleviated HA-VSMC phenotypic switching. Finally, we found that Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor for maintaining genomic stability by resisting oxidative stress and restoring autophagy, is closely involved in this process. HHcy clearly decreased KLF4 expression. KLF4-specific siRNA aggravated defective autophagy and phenotypic switching. Mechanistically, KLF4 regulated the HHcy-induced decrease in HA-VSMC autophagy via the m-TOR signaling pathway. In conclusion, these results demonstrated that the KLF4-dependent rapamycin signaling pathway is a novel mechanism underlying HA-VSMC phenotypic switching and is crucial for HHcy-induced HA-VSMCs with defective autophagy to accelerate early atherosclerosis.
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Abbreviations
- HHcy:
-
Hyperhomocysteinemia
- Hcy:
-
Homocysteine
- VSMC:
-
Vascular smooth muscle cell
- HA-VSMC:
-
Primary human aortic vascular smooth muscle cells
- m-TOR:
-
Mammalian target of rapamycin
- KLF4:
-
Krüppel-like factor 4
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Acknowledgements
This research was sponsored by grants from the National Natural Science Foundation of China (Grant No. 81873120), the 325 Talent Plan of Zhejiang Province (Grant No. 2017.10), and the Provincial Ministry of Construction Project of Zhejiang Province (Grant No. WKJ-ZJ-1729).
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Ni, T., Gao, F., Zhang, J. et al. Impaired autophagy mediates hyperhomocysteinemia-induced HA-VSMC phenotypic switching. J Mol Hist 50, 305–314 (2019). https://doi.org/10.1007/s10735-019-09827-x
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DOI: https://doi.org/10.1007/s10735-019-09827-x