Oxidized phospholipids induce phenotypic switching of vascular smooth muscle cells in vivo and in vitro

Nataliya A. Pidkovka, Olga A. Cherepanova, Tadashi Yoshida, Matthew R. Alexander, Rebecca A. Deaton, James A. Thomas, Norbert Leitinger, Gary K. Owens

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

Atherosclerosis is a vascular disease characterized by lipid deposition and inflammation within the arterial wall. Oxidized phospholipids (oxPLs), such as 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) and its constituents 1-palmytoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) are concentrated within atherosclerotic lesions and are known to be potent proinflammatory mediators. Phenotypic switching of smooth muscle cells (SMCs) plays a critical role in the development, progression, and end-stage clinical consequences of atherosclerosis, yet little is known regarding the effects of specific oxPLs on SMC phenotype. The present studies were focused on determining whether oxPLs regulate expression of SMC differentiation marker genes and the molecular mechanisms involved. Results showed that POVPC and PGPC induced profound suppression of smooth muscle (SM) α-actin and SM myosin heavy chain expression while simultaneously increasing expression of MCP-1, MCP-3, and cytolysin. OxPLs also induced nuclear translocation of Krüppel-like transcription factor 4 (KLF4), a known repressor of SMC marker genes. siRNA targeting of KLF4 nearly blocked POVPC-induced suppression of SMC marker genes, and myocardin. POVPC-induced repression of SMC marker genes was also significantly attenuated in KLF4 knockout SMCs. Taken together, these results suggest a novel role for oxPLs in phenotypic modulation of SMCs and indicate that these effects are dependent on the transcription factor, KLF4. These results may have important novel implications for the mechanisms by which oxPLs contribute to the pathogenesis of atherosclerosis.

Original languageEnglish
Pages (from-to)792-801
Number of pages10
JournalCirculation Research
Volume101
Issue number8
DOIs
Publication statusPublished - 2007 Oct
Externally publishedYes

Fingerprint

Vascular Smooth Muscle
Smooth Muscle Myocytes
Phospholipids
Phosphorylcholine
Transcription Factors
Atherosclerosis
Genes
Smooth Muscle Myosins
Arteritis
Perforin
Myosin Heavy Chains
In Vitro Techniques
Differentiation Antigens
Vascular Diseases
Small Interfering RNA
Smooth Muscle
Actins
Cell Differentiation
Phenotype
Lipids

Keywords

  • Atherosclerosis
  • Oxidized phospholipids
  • Smooth muscle cell phenotypic switching

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Pidkovka, N. A., Cherepanova, O. A., Yoshida, T., Alexander, M. R., Deaton, R. A., Thomas, J. A., ... Owens, G. K. (2007). Oxidized phospholipids induce phenotypic switching of vascular smooth muscle cells in vivo and in vitro. Circulation Research, 101(8), 792-801. https://doi.org/10.1161/CIRCRESAHA.107.152736

Oxidized phospholipids induce phenotypic switching of vascular smooth muscle cells in vivo and in vitro. / Pidkovka, Nataliya A.; Cherepanova, Olga A.; Yoshida, Tadashi; Alexander, Matthew R.; Deaton, Rebecca A.; Thomas, James A.; Leitinger, Norbert; Owens, Gary K.

In: Circulation Research, Vol. 101, No. 8, 10.2007, p. 792-801.

Research output: Contribution to journalArticle

Pidkovka, NA, Cherepanova, OA, Yoshida, T, Alexander, MR, Deaton, RA, Thomas, JA, Leitinger, N & Owens, GK 2007, 'Oxidized phospholipids induce phenotypic switching of vascular smooth muscle cells in vivo and in vitro', Circulation Research, vol. 101, no. 8, pp. 792-801. https://doi.org/10.1161/CIRCRESAHA.107.152736
Pidkovka, Nataliya A. ; Cherepanova, Olga A. ; Yoshida, Tadashi ; Alexander, Matthew R. ; Deaton, Rebecca A. ; Thomas, James A. ; Leitinger, Norbert ; Owens, Gary K. / Oxidized phospholipids induce phenotypic switching of vascular smooth muscle cells in vivo and in vitro. In: Circulation Research. 2007 ; Vol. 101, No. 8. pp. 792-801.
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AU - Owens, Gary K.

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AB - Atherosclerosis is a vascular disease characterized by lipid deposition and inflammation within the arterial wall. Oxidized phospholipids (oxPLs), such as 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) and its constituents 1-palmytoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) are concentrated within atherosclerotic lesions and are known to be potent proinflammatory mediators. Phenotypic switching of smooth muscle cells (SMCs) plays a critical role in the development, progression, and end-stage clinical consequences of atherosclerosis, yet little is known regarding the effects of specific oxPLs on SMC phenotype. The present studies were focused on determining whether oxPLs regulate expression of SMC differentiation marker genes and the molecular mechanisms involved. Results showed that POVPC and PGPC induced profound suppression of smooth muscle (SM) α-actin and SM myosin heavy chain expression while simultaneously increasing expression of MCP-1, MCP-3, and cytolysin. OxPLs also induced nuclear translocation of Krüppel-like transcription factor 4 (KLF4), a known repressor of SMC marker genes. siRNA targeting of KLF4 nearly blocked POVPC-induced suppression of SMC marker genes, and myocardin. POVPC-induced repression of SMC marker genes was also significantly attenuated in KLF4 knockout SMCs. Taken together, these results suggest a novel role for oxPLs in phenotypic modulation of SMCs and indicate that these effects are dependent on the transcription factor, KLF4. These results may have important novel implications for the mechanisms by which oxPLs contribute to the pathogenesis of atherosclerosis.

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