Biological response

FIGURE 12.1 Mitogen-activated protein kinase (MAPK) signaling pathways and their responses. MLK = mixed lineage kinase (generic MEK). MEK = MAPK kinase. MEKK = MAPK kinase kinase.

erk1 and erk2 signaling, effects of ppar-y, and vascular remodeling

ERK1 and ERK2 are ubiquitous proteins highly expressed in different tissues of the cardiovascular system (blood vessels, kidneys, heart).28 Additionally, differential regulation occurs in different cell types. ERK2 expression was significantly higher than ERK1 expression in immune cells,26 but both enzymes are equally and highly expressed in endothelial cells and vascular smooth muscle cells (VSMCs).29-31 Ang II through binding to AT1 receptors activates signaling cascades such as the Src homology 2 domain (Shc), c-Src, growth factor receptor-bound protein 2 (Grb2), Son of sevenless (Sos), Ras-GTP, and MEK1, which then activate ERK1/2 through phosphorylation.32

Several studies using the MEK specific inhibitor PD98059 demonstrated an important role of ERK1/2 in the development and the maintenance of hypertension.33,34 For instance, in hypertensive vascular remodeling, ERK1/2 activation led to activation of phospholipase A2, cyclooxygenase (COX)-2, and p90 riboso-mal S6 kinase (p90Rsk), along with translocation of nuclear receptors and reorganization of cytoskeletal proteins implicated in cell growth and migration.26 More specifically, once ERK1/2 is phosphorylated, it will translocate to the nucleus and activate transcription of cell cycle genes.23,26

In VSMCs, ERK1/2 phosphorylation induced p90Rsk activation leading to ribosomal S6 protein phosphorylation and protein synthesis. In VSMCs derived from mesenteric arteries, we demonstrated the stimulatory effect of Ang II on cell hypertrophy, proliferation, and contractility.29 Ang Il-induced ERK1/2 activity was inhibited by PPAR-y activation in conduit vessels whereas no effect was observed in mesenteric resistance vessels.14 Unlike results of in vivo studies, in vitro acute stimulation of mesenteric VSMCs with Ang II-induced ERK1/2 activation was abrogated by PPAR-y pre-stimulation with rosiglitazone (Figure 12.2).14 Taken together, these results suggest that the extracellular environment and duration of stimulation (acute versus chronic) affect PPAR-y-modulated changes in Ang II-induced ERK1/2 activation.

ERK1/2 may on the other hand inhibit PPAR-y activity. In vivo, insulin, which constitutively activates MEKK1, induced in a ligand-independent manner PPAR-y phosphorylation which increased TZD-dependent PPAR-y trans-activation properties.35 In contrast, both epidermal growth factor (EGF) and platelet derived growth factor (PDGF) reduced PPAR-y transcriptional activity in a ligand-depen-dent manner in adipocytes contained in the vascular periadventitial fat that regulates vascular function in paracrine fashion and may play an important role in blood pressure regulation and vascular remodeling.36

Although mesenteric artery PPAR-y activity was reduced in Ang II-infused rats, albeit in the absence of changes in PPAR-y expression, treatment with rosiglitazone prevented these changes, suggesting a potent negative regulatory role of PPAR-y activators.14 Endogenous PPAR ligands such as linoleic and retinoic acid may stimulate ERK1/2 activity in adipocytes and aortic VSMCs, respectively,37,38 whereas prostaglandin J2 (PGJ2) activated ERK1/2 through PI3K

Resistance Artery SMC

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