Novel mechanisms of endothelial mechanotransduction - PubMed (original) (raw)

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Novel mechanisms of endothelial mechanotransduction

Jun-ichi Abe et al. Arterioscler Thromb Vasc Biol. 2014 Nov.

Abstract

Atherosclerosis is a focal disease that develops preferentially where nonlaminar, disturbed blood flow occurs, such as branches, bifurcations, and curvatures of large arteries. Endothelial cells sense and respond differently to disturbed flow compared with steady laminar flow. Disturbed flow that occurs in so-called atheroprone areas activates proinflammatory and apoptotic signaling, and this results in endothelial dysfunction and leads to subsequent development of atherosclerosis. In contrast, steady laminar flow as atheroprotective flow promotes expression of many anti-inflammatory genes, such as Kruppel-like factor 2 and endothelial nitric oxide synthase and inhibits endothelial inflammation and athrogenesis. Here we will discuss that disturbed flow and steady laminar flow induce pro- and antiatherogenic events via flow type-specific mechanotransduction pathways. We will focus on 5 mechanosensitive pathways: mitogen-activated protein kinases/extracellular signal-regulated kinase 5/Kruppel-like factor 2 signaling, extracellular signal-regulated kinase/peroxisome proliferator-activated receptor signaling, and mechanosignaling pathways involving SUMOylation, protein kinase C-ζ, and p90 ribosomal S6 kinase. We think that clarifying regulation mechanisms between these 2 flow types will provide new insights into therapeutic approaches for the prevention and treatment of atherosclerosis.

Keywords: ERK5; PKCζ; SUMOylation; flow.

© 2014 American Heart Association, Inc.

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Figures

Figure 1

Figure 1. Primary structure of ERK5 and its regulation

The N-terminus region with SUMO modification inhibits its own transactivation. After ERK5 kinase activation induced by MEK5 binding and TEY motif phosphorylation with de-SUMOylation of K6/K22 sites, ERK5 transcriptional activity at the C-terminus region is fully activated. In contrast athero-prone flow increases ERK5-SUMOylation and ERK5 S496 phosphorylation and inhibits ERK5 transcriptional activity.

Figure 2

Figure 2. Model for the ERK5-PPARγ interaction-mediated PPARγ transactivation

The position of Helix 12 is regulated by ligand binding. When the PPARγ ligand binds to the receptor, Helix 12 folds back to form a part of the co-activator binding surface, and inhibits corepressor (such as SMRT) binding to PPARγ. The co-repressor interaction surface requires Helix 3-5. We found a critical role of the PPARγ hinge-helix 1 domain in ERK5-mediated PPARγ transactivation. The inactive N-terminus kinase domain of ERK5 inhibits its own transactivation and PPARγ binding. After ERK5 activation the inhibitory effect of the N-terminus domain decreases, and subsequently the middle region can fully interact with the hinge-helix 1 region of PPARγ. The association of ERK5 with the hinge-helix 1 region of PPARγ releases co-repressor of SMRT and induces full activation of PPARγ. AF-1/2: Activating function (AF)-1/2 transactivation domain, DBD: DNA binding domain. Reprinted and modified from Akaike et al.

Figure 3

Figure 3. The regulation of SUMOylation pathway

Protein SUMOylation is achieved by a recycle system consisting of conjugation and deconjugation pathway. SUMO conjugation to a target substrate requires an enzymatic cascade, which involves three classes of enzymes (E1→E2→E3). The sentrin/SUMO-specific proteases (SENPs) are responsible for the deconjugation pathway as well as the maturation process of newly synthesized SUMO protein. The primary subcellular localization of each SENP is also listed. Reprinted and modified from Woo et al. with permission of the publisher.

Figure 4

Figure 4. Athero-prone flow increases p53 SUMOylation via PKCζ-PIAS4 binding

(A) Athero-prone flow uniquely activates PKCζ, which increases PKCζ-PIAS4 binding and PIAS4 SUMO E3 ligase activity, and subsequently increases p53 SUMOylation. SUMOylation causes p53 nuclear export and binds to Bcl-2, which inhibits anti-apoptotic function of Bcl-2 and increases apoptosis. (B) p53 nuclear export and stabilization. Masking of the C-terminus NES results in nuclear localization of unmodified p53, but a low level of ubiquitination by MDM2 exposes the NES, causing the p53-Ub fusion protein to come out of the nucleus. When MDM2 levels are low, ubiquitination promotes the interaction of p53 with PIAS4 and further modification of p53 by SUMOylation that causes the release of MDM2 and nuclear export, which may increase the cytoplasmic apoptotic function of p53. Under conditions of high MDM2, persistent binding and activity of MDM2 leads to polyubiquitination and degradation of p53. These data suggest important roles of SUMOylation in p53 stabilization, localization, and subsequent apoptosis. Reprinted and modified from Carter et al with permission of the publisher. (C) PKCζ-mediated p53 SUMOylation requires PKCζ-PIAS4 binding at SP-RING domain, not PKCζ-mediated phosphorylation of PIAS4. SAP: scaffold attachment factor-A/B, acinus and PIAS domain; SP-RING: Siz/PIAS-RING domain.

Figure 5

Figure 5. Athero-prone flow increases p90RSK activation, leading to p90RSK-ERK5 association and ERK5 S496 phosphorylation, and subsequently decreases in ERK5 transcriptional activity

At the basal level, inactive p90RSK inhibits the D-domain to bind ERK5. Once p90RSK is activated, the inhibition of the kinase domain is released and the D-domain of p90RSK associates with the ERK5 C-terminus domain and increases ERK5 S496 phosphorylation, which inhibits ERK5 transcriptional activity. NTKD: NH2-terminal kinase domain, CTKD: COOH-terminal kinase domain, D-domain: NH2-terminal docking domain.

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