Skip to main content
Journal ArticleOPEN ACCESS

The role of Nrf2 signaling in PPARβ/δ-mediated vascular protection against hyperglycemia-induced oxidative stress

Oxidative Medicine and Cellular Longevity (2018) 2018
DOI: 10.1155/2018/5852706
36Citations
Citations of this article
32Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

Hyperglycemia induces oxidative stress and plays a substantial role in the progression of vascular diseases. Here, we demonstrated the potentiality of peroxisome proliferator-activated receptor (PPAR)β/δ activation in attenuating high glucose-induced oxidative stress in endothelial cells and diabetic rats, pointing to the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2). HUVECs exposed to high glucose showed increased levels of reactive oxygen species (ROS) and upregulated NOX-2, NOX-4, Nrf2, and NQO-1 effects that were significantly reversed by the PPARβ/δ agonists GW0742 and L165041. Both PPARβ/δ agonists, in a concentration-dependent manner, induced transcriptional and protein upregulation of heme oxygenase-1 (HO-1) under low- and high-glucose conditions. All effects of PPARβ/δ agonists were reversed by either pharmacological inhibition or siRNA-based downregulation of PPARβ/δ. These in vitro findings were confirmed in diabetic rats treated with GW0742. In conclusion, PPARβ/δ activation confers vascular protection against hyperglycemia-induced oxidative stress by suppressing NOX-2 and NOX-4 expression plus a direct induction of HO-1; with the subsequent downregulation of the Nrf2 pathway. Thus, PPARβ/δ activation could be of interest to prevent the progression of diabetic vascular complications.

Figures

  • Figure 1: Effects of PPARβ/δ agonists on Nrf2 expression. (a, c) mRNA and (b, d) protein expression of Nrf2 in HUVECs exposed to low (5mM, LG) or high glucose (30mM, HG) for 24 h with or without GW0742 (GW) or L165041 (L) alone or preincubated with the PPARβ/δ antagonist GSK0660 (GSK). mRNA data presented as a ratio of arbitrary units of mRNA (2−ΔΔCt). All data are mean ± SEM (n = 8), and experiments were repeated at least three times independently. Protein data presented as densitometric values and protein band normalized to the corresponding α-actin; the bands are representative of n = 3–5. ∗∗P < 0 01 versus LG. #P < 0 05 versus HG. †P < 0 05 versus L and GW column, respectively.
  • Figure 2: Effect of PPARβ/δ agonist, GW0742, on Nrf2 target gene induction. (a, b) mRNA and (c) protein expression of NOQ-1 and HO-1. HUVECs, exposed to low- (LG) or high-glucose (HG) medium for 24 h, were coincubated with GW0742 (GW) alone or preincubated with the GSK0660 (GSK) followed by GW0742. mRNA data presented as a ratio of arbitrary units of mRNA (2−ΔΔCt). All data are mean ± SEM (n = 8), and experiments were repeated at least three times independently. Protein data presented as densitometric values and protein band normalized to the corresponding α-actin; the bands are representative of n = 3–5. ∗P < 0 05 and ∗∗P < 0 01 versus LG. #P < 0 05 versus HG. +P < 0 05 versus GW column.
  • Figure 3: Effect of PPARβ/δ agonist, L165041, on Nrf2 target genes. (a, b) mRNA and (c) protein expression of NOQ-1 and HO-1. HUVECs, exposed to low- (LG) or high-glucose (HG) medium for 24 h, were coincubated with L165041 (L) alone or preincubated with the GSK0660 (GSK) followed by L165041. mRNA data presented as a ratio of arbitrary units of mRNA (2−ΔΔCt). All data are mean± SEM (n = 8), and experiments were repeated at least three times independently. Protein data presented as densitometric values and protein band normalized to the corresponding α-actin; the bands are representative of n = 3–5. ∗P < 0 05 and ∗∗P < 0 01 versus LG. #P < 0 05 and ##P < 0 01 versus HG. +P < 0 05 versus L column.
  • Figure 4: Role of the PPARβ/δ activation on the Nrf2/ARE pathway. mRNA expression levels of (a) Nrf2, (b) NOQ-1, and (c) HO-1 in control siRNA and siRNA PPARβ/δ cells incubated in low- (LG) or high-glucose (HG) medium for 24 h, in the presence or absence of GW0742 (GW, 10−6M). mRNA data presented as a ratio of arbitrary units of mRNA (2−ΔΔCt). All data are mean± SEM (n = 8), and experiments were repeated at least three times independently. ∗P < 0 05 versus LG. #P < 0 01 and ##P < 0 01 versus HG.
  • Figure 5: Effect of PPARβ/δ agonists in intracellular ROS production. (a) ROS and (b–d) mRNA expression levels of NOX-4 (b), NOX-1 (c), and NOX-2 (d) in HUVEC transfected with PPARβ/δ-specific siRNA (siRNA PPARβ/δ) incubated in low- (LG) or high-glucose (HG) medium for 24 h in the presence or absence of either L165041 (L, 10−6M) or GW0742 (GW, 10−6M), respectively. GSK0660 (10−6M) was added 30min before the incubation with L165041. mRNA data presented as a ratio of arbitrary units of mRNA (2−ΔΔCt). All data are mean± SEM (n = 8), and experiments were repeated at least three times independently. ∗P < 0 05 versus LG. #P < 0 01 and ##P < 0 01 versus HG.
  • Figure 6: Effect of GW0742 on blood glucose levels of control and diabetic rats. Plasma glucose concentrations were measured by colorimetric method. Values are expressed as mean± SEM of n = 8 –10 rats. ∗∗P < 0 01, diabetic versus control rats.
  • Figure 7: Effect of oral GW0742 on the Nrf2 pathway in the aorta of diabetic rats. mRNA expression of (a) Nrf2, (b) NQO-1, and (c) HO-1 in the aorta of all experimental groups. Data are presented as the ratio of arbitrary units of mRNA (2−ΔΔCt). Results are shown as mean± SEM n = 8–10 rats. ∗P < 0 05, diabetic versus control group. #P < 0 05, GW0472-treated diabetic versus nontreated diabetic rats.
  • Figure 8: GW0742 decreases vascular ROS and NADPH oxidase activity. (a) The left panel shows blue fluorescence of the nuclear stain DAPI (×400 magnification), and the right panel shows arteries incubated in the presence of DHE which produces a red fluorescence when oxidized to ethidium by ROS. (b) Averaged values, mean± SEM (n = 8–10 rings from different rats), of the red ethidium fluorescence normalized to the blue DAPI fluorescence. (c) NADPH oxidase activity measured by lucigenin-enhanced chemiluminescence (n = 6–10). ∗P < 0 05 and ∗∗P < 0 01, diabetic versus control group. #P < 0 05 and ##P < 0 01, GW0472-treated diabetic versus nontreated diabetic rats.

References Powered by Scopus

Free radicals and antioxidants in normal physiological functions and human disease

International Journal of Biochemistry and Cell Biology
11489Citations
N/AReaders
Get full text

Biochemistry and molecular cell biology of diabetic complications

Nature
7651Citations
N/AReaders
Get full text

Mechanisms of increased vascular superoxide production in human diabetes mellitus: Role of NAD(P)H oxidase and endothelial nitric oxide synthase

Circulation
924Citations
N/AReaders
Get full text
View more at Scopus

Cited by Powered by Scopus

Beneficial effects of citrus flavonoids on cardiovascular and metabolic health

Oxidative Medicine and Cellular Longevity
226Citations
N/AReaders
Get full text

Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy

Life Sciences
119Citations
N/AReaders
Get full text

Cardiac and pulmonary toxicity of mesoporous silica nanoparticles is associated with excessive ROS production and redox imbalance in Wistar rats

Biomedicine and Pharmacotherapy
93Citations
N/AReaders
Get full text
View more at Scopus

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Cite

CITATION STYLE

APA

Jimenez, R., Toral, M., Gómez-Guzmán, M., Romero, M., Sanchez, M., Mahmoud, A. M., & Duarte, J. (2018). The role of Nrf2 signaling in PPARβ/δ-mediated vascular protection against hyperglycemia-induced oxidative stress. Oxidative Medicine and Cellular Longevity, 2018. https://doi.org/10.1155/2018/5852706

Readers over time

‘18‘19‘20‘21‘22‘23‘2402468

Readers' Seniority

Tooltip

PhD / Post grad / Masters / Doc 9

53%

Professor / Associate Prof. 3

18%

Researcher 3

18%

Lecturer / Post doc 2

12%

Readers' Discipline

Tooltip

Medicine and Dentistry 4

36%

Biochemistry, Genetics and Molecular Bi... 3

27%

Pharmacology, Toxicology and Pharmaceut... 2

18%

Nursing and Health Professions 2

18%

Save time finding and organizing research with Mendeley

Sign up for free
0