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Endothelial PPAR? (Peroxisome Proliferator-Activated Receptor-?) Is Essential for Preventing Endothelial Dysfunction With Aging.

ABSTRACT: Little is known about mechanisms that control vascular aging, particularly at the cell-specific level. PPAR? (peroxisome proliferator-activated receptor-?) exerts protective effects in the vasculature when activated pharmacologically. To gain insight into the cell-specific impact of PPAR?, we examined the hypothesis that genetic interference with endothelial PPAR? would augment age-induced vascular dysfunction. We studied carotid arteries from adult (11.6±0.3 months) and old (24.7±0.6 months) mice with endothelial-specific expression of a human dominant negative mutation in PPAR? driven by the vascular cadherin promoter (E-V290M), along with age-matched, nontransgenic littermates. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation in arteries from adult nontransgenic and E-V290M mice and old nontransgenic mice. In contrast, responses to acetylcholine were reduced by >50% in old male and female E-V290M mice (P<0.01). Endothelial function in old E-V290M mice was not altered by an inhibitor of COX (cyclooxygenase) but was restored to normal by a superoxide scavenger, an inhibitor of NADPH oxidase, or inhibition of ROCK (Rho kinase). Relaxation of arteries to nitroprusside, which acts directly on vascular muscle, was similar in all groups. Vascular expression of IL (interleukin)-6, Nox-2, and CDKN2A (a marker of senescence) was significantly increased in old E-V290M mice compared with controls (P<0.05). These findings provide the first evidence that age-related vascular dysfunction, inflammation, and senescence is accelerated after interference with endothelial PPAR? via mechanisms involving oxidative stress and ROCK. The finding of an essential protective role for endothelial PPAR? has implications for vascular disease and therapy for vascular aging.

SUBMITTER: De Silva TM

PROVIDER: S-EPMC6002945 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

Endothelial PPARγ (Peroxisome Proliferator-Activated Receptor-γ) Is Essential for Preventing Endothelial Dysfunction With Aging.

De Silva T Michael TM Li Ying Y Kinzenbaw Dale A DA Sigmund Curt D CD Faraci Frank M FM

Hypertension (Dallas, Tex. : 1979) 20180507 1

Little is known about mechanisms that control vascular aging, particularly at the cell-specific level. PPARγ (peroxisome proliferator-activated receptor-γ) exerts protective effects in the vasculature when activated pharmacologically. To gain insight into the cell-specific impact of PPARγ, we examined the hypothesis that genetic interference with endothelial PPARγ would augment age-induced vascular dysfunction. We studied carotid arteries from adult (11.6±0.3 months) and old (24.7±0.6 months) mi ...[more]

PMID: 29735632

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Project description:Although MK886 was originally identified as an inhibitor of 5-lipoxygenase activating protein (FLAP), recent data demonstrate that this activity does not underlie its ability to induce apoptosis [Datta, Biswal and Kehrer (1999) Biochem. J. 340, 371--375]. Since FLAP is a fatty-acid binding protein, it is conceivable that MK886 may affect other such proteins. A family of nuclear receptors that are activated by fatty acids and their metabolites, the peroxisome-proliferator-activated receptors (PPARs), have been implicated in apoptosis and may represent a target for MK886. The ability of MK886 to inhibit PPAR-alpha, -beta and -gamma activity was assessed using reporter assay systems (peroxisome-proliferator response element--luciferase). Using a transient transfection system in monkey kidney fibroblast CV-1 cells, mouse keratinocyte 308 cells and human lung adenocarcinoma A549 cells, 10--20 microM MK886 inhibited Wy14,643 activation of PPAR alpha by approximately 80%. Similar inhibition of PPAR alpha by MK886 was observed with a stable transfection reporter system in CV-1 cells. Only minimal inhibitory effects were seen on PPAR beta and PPAR gamma. MK886 inhibited PPAR alpha by a non-competitive mechanism as shown by its effects on the binding of arachidonic acid to PPAR alpha protein, and a dose-response study using a transient transfection reporter assay in COS-1 cells. An assay assessing PPAR ligand-receptor interactions showed that MK886 prevents the conformational change necessary for active-complex formation. The expression of keratin-1, a protein encoded by a PPAR alpha-responsive gene, was reduced by MK886 in a culture of mouse primary keratinocytes, suggesting that PPAR inhibition has functional consequences in normal cells. Although Jurkat cells express all PPAR isoforms, various PPAR alpha and PPAR gamma agonists were unable to prevent MK886-induced apoptosis. This is consistent with MK886 functioning as a non-competitive inhibitor of PPAR alpha, but may also indicate that PPAR alpha is not directly involved in MK886-induced apoptosis. Although numerous PPAR activators have been identified, the results show that MK886 can inhibit PPAR alpha, making it the first compound identified to have such an effect.

Dataset Information

Endothelial PPAR? (Peroxisome Proliferator-Activated Receptor-?) Is Essential for Preventing Endothelial Dysfunction With Aging.

Publications

Endothelial PPARγ (Peroxisome Proliferator-Activated Receptor-γ) Is Essential for Preventing Endothelial Dysfunction With Aging.

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