15-Deoxy-Δ-^12,14-prostaglandin J2 effects in vascular smooth muscle cells: Implications in vascular smooth muscle cell proliferation and contractility

Highlights

• 15d-PGJ2 has antioxidative and antiproliferative effects in VSMCs.

• 15d-PGJ2 inhibits the expression of inflammatory mediators.

• 15d-PGJ2 forms covalent adducts with many intracellular proteins.

• Many 15d-PGJ2 effects are not mediated by PPAR-y.

• 15d-PGJ2 may have multiple targets within a signaling pathway.

Abstract

15-Deoxy-Δ-^12,14-prostaglandin J2 (15d-PGJ2) is an endogenous agonist of the ligand dependent transcriptional factor, peroxisome proliferator-activated receptor –gamma (PPAR-γ). Although PPAR-γ mediates some actions of 15d-PGJ2, many actions of 15d-PGJ2 are independent of PPAR-γ. The PPAR-γ signaling pathway has beneficial effects on tumor progression, inflammation, oxidative stress, and angiogenesis in numerous studies. In this review, various studies were analyzed to understand the effects of 15d-PGJ2 in vascular smooth muscle cells (VSMC)s. 15d-PGJ2 inhibits proliferation of VSMCs during vascular remodeling and it alters the expression of contractile proteins and inflammatory components within these cells as well. However, the effects of 15d-PGJ2 as well as its ability to induce PPAR-γ activation remains controversial as contradictory effects of this prostaglandin in VSMCs exist. Understanding the mechanisms by which 15d-PGJ2 elicit beneficial actions whether by PPAR-γ activation or independently, will aid in developing new therapeutic strategies for diseases such as hypertension with an inflammatory component. Although great advances are being made, more research is needed to reach definitive conclusions.

Introduction

Most prostaglandins are known to stimulate inflammation. However, 15-Deoxy-Δ-^12,14-prostaglandin J2 (15d-PGJ2) has demonstrated anti-inflammatory effects in numerous studies [1,2]. 15d-PGJ2, a product of the arachidonic acid, cyclooxygenase pathway is an endogenous ligand of the peroxisome proliferator-activated receptor-gamma (PPAR-γ). 15d-PGJ2 may also activate other PPAR subtypes including PPARα and PPARδ [3], and the prostaglandin D2 receptor (DP2) [4]. Moreover, 15d-PGJ2 can covalently interact with many intracellular proteins including H-Ras, nuclear factor kappa B (NF-κB), I kappa B kinase (IκB), Activator protein 1 (AP-1) and biological molecules such as glutathione (GSH) [5,6]. This covalent interaction occurs by Michael addition [5,6] and may inhibit or enhance the activity of the protein or biomolecule [7]. Physiological levels of 15d-PGJ2 are in the nanomolar range but it is believed that its levels may increase considerably in pathological conditions, similar to other prostaglandins [8]. This increase has been disputed by some authors [9]. Compared to other prostaglandins, 15d-PGJ2 mainly acts intracellularly and may have autocrine or paracrine actions [10]. It is reported that at physiological levels 15d-PGJ2 can activate DP2 receptors on the cell surface whereas pharmacological levels are required for nuclear activation of PPAR-γ [8].

DP2 receptors are coupled to G-protein alpha I (G_αi) and actions of 15d-PGJ2 mediated by the DP2 receptor are pro-inflammatory [8,10]. In addition to the actions of 15d-PGJ2 mediated by the DP2 or PPAR-γ, 15d-PGJ2 has many intracellular protein targets. 15d-PGJ2 may activate ERK-MAPKs and PI3K independently by binding H-Ras 10]. Moreover, 15d-PGJ2 inhibits transcription factors such as NF-κB by multiple mechanisms. 15d-PGJ2 covalently modifies NF-κB binding sites preventing DNA binding and also prevents NF-κB translocation by covalently interacting with IkB kinase 10]. 15d-PGJ2 activation of PPAR-γ may also directly inhibit NF-κB 10]. Similarly, 15d-PGJ2 covalent modifications of cJun inhibits DNA binding activity of AP-1 [11]. These covalent interactions mediate many 15d-PGJ2 effects that are PPAR-γ-independent.

15d-PGJ2-PPAR-γ signaling stimulates anti-tumor, anti-inflammatory, antioxidative, antifibrotic and anti-angiogenesis actions [1]. However, 15d-PGJ2 can also stimulate some of these effects independent of PPAR-γ [12]. 15d-PGJ2 exerts anti-tumor effects in various types of cancers by several PPAR-γ-dependent and independent mechanisms. 15d-PGJ2 enhances apoptosis, stimulates cell cycle arrest, inhibits neovascularization and cell migration, and reduces expression of matrix metalloproteinases (MMP)s [1]. 15d-PGJ2 elicits anti-inflammatory and antioxidative effects by regulating the expression and or activity of numerous inflammatory mediators, including interleukins, NF-κB, cyclooxygenase 2, reactive oxygen species, and cell adhesion molecules [1]. Its antiproliferative and antifibrotic effects include inhibition of growth factor induced mitogen activated protein kinases (MAPKs) activation [1]. Opposing actions may be observed in different cell types, it is important to note that 15d-PGJ2 effects are highly cell and context specific. It was also observed that its anti-inflammatory actions may be concentration- and time-dependent [4].

In this review, we summarize the current understanding of the main effects of 15d-PGJ2 in VSMCs and infer 15d-PGJ2 potential benefits in inflammatory conditions such as hypertension and other cardiovascular diseases. The available literature is presented in tabular format in Table 1. We present the effects of 15d-PGJ2 on VSMC proliferation, contraction, migration, angiogenesis and inflammatory mediators. These effects can be PPAR-γ dependent or independent. Where possible we highlight whether PPAR-γ mediates any of these actions of 15d-PGJ2. Comparison is also made to other PPAR-γ ligands to distinguish 15d-PGJ2 effects that are not mediated through PPAR-γ. In Fig. 1, we propose possible molecular mechanisms for these 15d-PGJ2 effects in VSMCs. These mechanisms have been confirmed for 15d-PGJ2 in other cell types.