Abstract
Previously, we demonstrated that progesterone (P4) at physiologic levels (5-500 nM) inhibited proliferation in cultured rat aortic smooth muscle cells (RASMCs) through a P4 receptor (PR)-dependent pathway. We also showed that P4-induced cell cycle arrest in RASMCs occurs when the cyclin-CDK2 system is inhibited just as p21cip1 and p27kip1 protein levels are augmented. In the present study, we further investigated the molecular mechanism underlying P4-induced up-regulations of p21cip1 and p27kip1 in RASMCs. We used pharmacological inhibitors as well as dominant negative constructs and conducted Western blot analyses to delineate the signaling pathway involved. Our data suggest that P4 up-regulated the expression of p21cip1 and p27kip1 in RASMCs through increasing the level of p53 protein mediated by activating the cSrc/Kras/Raf-1/AKT/ERK/p38/IκBα/NFκB pathway. The findings of the present study highlight the molecular mechanism underlying P4-induced up-regulations in p21cip1 and p27kip1 in RASMCs.
Highlights
Atherogenesis, a degenerative process involving a variety of lesions of the arterial wall, is a response of vascular endothelial cells and smooth muscle cells to injury [1,2,3,4]
To delineate the signaling pathway involved in the P4-induced up-regulations of p21cip1 and p27kip1 in rat aortic smooth muscle cells (RASMCs), we initially examined the activity changes of several candidate molecules, which have been indicated to be involved in regulating cell proliferation, in P4-treated RASMCs
Our results showed that treatment with P4 (50 nM) for 5 min increased the levels of p-cSrc, p-Raf-1, p-ERK1/2, p-AKT, and p-p38 protein (Fig 1A) and membrane translocation of Kras (Fig 1B) in RASMCs
Summary
Atherogenesis, a degenerative process involving a variety of lesions of the arterial wall, is a response of vascular endothelial cells and smooth muscle cells to injury [1,2,3,4]. Vascular smooth muscle cells reside in the media of blood vessels and compose the majority of the vessel wall. Vascular smooth muscle cells have a very low proliferative activity. In response to injury or to various stimuli, vascular endothelial cells are activated and produce cytokines as well as growth factors to promote proliferation and migration of vascular smooth muscle cells [3]. Damage to the endothelium might induce inflammatory responses involved in the development of atherosclerosis. Atherosclerosis is initiated by inflammatory processes of the endothelium that retain low-density lipoprotein particles and circulating monocytes. The attached monocytes migrate to the subendothelial space, PLOS ONE | DOI:10.1371/journal.pone.0125903 May 1, 2015
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