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GW501516 for sale, The vascular smooth muscle cells (VSMCs) are the major cell type in the blood vessel walls. The proliferation and migration of VSMCs play a pivotal role in the development of vascular lesions that are commonly found in atherosclerosis and restenosis.40,41 PPARδ is abundantly expressed in VSMC and is upregulated during vascular lesion formation. VSMC treated with platelet-derived growth factor (PDGF) can induce PPARδ expression.42,43 However, the effects of the upregulation of PPARδ on the proliferation of VSMC are controversial. Initial study showed that PPARδ overexpression promotes postconfluent cell proliferation in VSMCs by increasing cyclin A and cyclin-dependent kinase 2 (CDK2) and decreasing p57kip2.42 Conversely, a few later studies yielded opposite results. Activation of PPARδ by GW501516 significantly inhibits PDGF-induced proliferation in human pulmonary artery smooth muscle cells (HPASMCs) by repressing expression of cyclin D1, cyclin D3, CDK2, and CDK4.43 GW501516 treatment in these cells also enhances the expression of the cell cycle inhibitory genes G0S2 and p27kip1.43 Consistent with this result, PPARδ agonist L-165041 inhibits rat VSMC proliferation via inhibition of PDGF-induced expression of cyclin D1 and CDK4 and thus cell cycle.44 Furthermore, GW501516 inhibits IL-1β-stimulated proliferation accompanied by cell cycle arrest at the G1 to S phase transition by the induction of p21 and p53, along with decreased expression of CDK4.45 Similarly, PPARδ ligand (e.g., GW501516) inhibits PDGF- or IL-1β-induced cell migration.43–45 Differences in species (humans vs. rats), tissues (pulmonary artery vs. aorta), and experiment approaches (ligand treatment vs. PPARδ overexpression) may account for the opposite results. However, at least PPARδ agonists appear to exert largely an inhibiting effect on VSMC proliferation.
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VSMC senescence is an independent risk factor contributing to the development of atherosclerosis in human.46 Aging induces VSMC phenotypic modulation that could have influence on cell senescence and loss of plasticity and reprogramming.46 Vascular aging is characterized by increased oxidative stress, which is a key factor associated with VSMC senescence.47,48 The importance of PPARδ signaling in the VSMCs is also related to its role in regulating antioxidant defense. Activation of PPARδ counteracts angiotensin II-induced ROS generation in VSMCs.49 As in the endothelial cells, PI3K/Akt signaling pathway in VSMC is one of the signaling pathways involved in this process. Ablation of Akt with siRNA further enhances the inhibitory effects of GW501516 in angiotensin II-induced superoxide production. Ligand-activated PPARδ blocks angiotensin II-induced translocation of Rac1 to the cell membrane, inhibiting the activation of NADPH oxidases and consequently ROS generation.49 Activation of PPARδ by GW501516 substantially attenuates angiotensin II-induced superoxide production in VSMCs following upregulation of genes encoding antioxidant genes, such as glutathione peroxidase 1, thioredoxin 1, manganese SOD2, and HO-1, in VSMCs.50 Additionally, GW501516 prevents angiotensin II-induced expression of p53 and p21, two key proteins in the senescence pathway, and upregulates expression of PTEN (phosphatase and tensin homolog deleted on chromosome 10), subsequently suppressing the PI3K/Akt pathway.51 Therefore, these studies demonstrate that PPARδ activation can prevent VSMC senescence via multiple mechanisms.
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The preservation of vascular integrity and structure is dependent not only on VSMC proliferation and migration but also on the integrity of the extracellular matrix (ECM). The integrity of the ECM can be a determinant of VSMC apoptosis. PPARδ regulates ECM synthesis and degradation through transforming growth factor-β1 (TGF-β1) and its effector, Smad3, thus augmenting the expression of type I and III collagen, fibronectin, elastin, and tissue inhibitor of metalloproteinases-3 (TIMP-3), but not the expression of TIMP-1, MMP-2, or MMP-9.52 The MMP family is a class of zinc-dependent endoproteases that degrades structural proteins of ECM.53 The activation of MMPs is one major pathogenic factor involved in many neurological disorders, such as stroke. A recent study demonstrated that VSMC-specific PPARδ knockout in mice exacerbates cerebrovascular permeability and brain infarction after middle cerebral artery occlusion (MCAO).54 The reduction of PPARδ is correlated with increased MMP-9 activity in cultured VSMCs after oxygen–glucose deprivation and also in the cerebral cortex of mice following MCAO. PPARδ activation in VSMCs diminishes oxygen–glucose deprivation-induced MMP-9 activity. Since MMP-9 is a direct target of PPARδ-mediated transrepression, PPARδ in VSMCs can prevent ischemic brain injury by inhibiting MMP-9 activation and attenuation of postischemic inflammation.54 Therefore, it appears that PPARδ-induced upregulation of ECM proteins and suppression of ECM degradation may be a key mechanism underpinning the protective role of PPARδ in the vascular system.
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Taken together, current studies suggest that PPARδ plays a crucial role in maintaining VSMC homeostasis by repressing proliferation and migration; enhancing antioxidant, antiapoptosis, and anti-inflammation; and maintaining ECM (Fig. 14.2).
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