Chronic inhibition of PPAR-γ signaling induces endothelial dysfunction in the juvenile lamb

Shruti Sharma, Jubilee Barton, Ruslan Rafikov, Saurabh Aggarwal, Hsuan Chang Kuo, Peter E. Oishi, Sanjeev A. Datar, Jeffrey R. Fineman, Stephen Matthew Black

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

We have recently shown that the development of endothelial dysfunction in lambs with increased pulmonary blood flow (PBF) correlates with a decrease in peroxisome proliferator activated receptor-γ (PPAR-γ) signaling. Thus, in this study we determined if the loss of PPAR-γ signaling is necessary and sufficient to induce endothelial dysfunction by exposing lambs with normal PBF to the PPAR-γ antagonist, GW9662. Two-weeks of exposure to GW9662 significantly decreased both PPAR-γ protein and activity. In addition, although eNOS protein and nitric oxide metabolites (NOx) were significantly increased, endothelial dependent pulmonary vasodilation in response to acetylcholine was attenuated, indicative of endothelial dysfunction. To elucidate whether downstream mediators of vasodilation were impaired we examined soluble guanylate cyclase (sGC)-α and β subunit protein, cGMP levels, and phosphodiesterase 5 (PDE5) protein and activity, but we found no significant changes. However, we found that peroxynitrite levels were significantly increased in GW9662-treated lambs and this correlated with a significant increase in protein kinase G-1α (PKG-1α) nitration and a reduction in PKG activity. Peroxynitrite is formed by the interaction of NO with superoxide and we found that there was a significant increase in superoxide generation in GW9662-treated lambs. Further, we identified dysfunctional mitochondria as the primary source of the increased superoxide. Finally, we found that the mitochondrial dysfunction was due to a disruption in carnitine metabolism. We conclude that loss of PPAR-γ signaling is sufficient to induce endothelial dysfunction confirming its important role in maintaining a healthy vasculature.

Original languageEnglish (US)
Pages (from-to)271-280
Number of pages10
JournalPulmonary Pharmacology and Therapeutics
Volume26
Issue number2
DOIs
StatePublished - Apr 1 2013

Fingerprint

Peroxisome Proliferator-Activated Receptors
Superoxides
Peroxynitrous Acid
Vasodilation
Lung
Blood
Type 5 Cyclic Nucleotide Phosphodiesterases
Nitration
Cyclic GMP-Dependent Protein Kinases
Proteins
Mitochondria
Carnitine
Guanylate Cyclase
Protein Subunits
Metabolites
Metabolism
Acetylcholine
Nitric Oxide
Thermodynamic properties
2-chloro-5-nitrobenzanilide

Keywords

  • Carnitine metabolism
  • Mitochondrial dysfunction
  • NO signaling
  • Oxidative stress

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Pharmacology (medical)
  • Biochemistry, medical

Cite this

Chronic inhibition of PPAR-γ signaling induces endothelial dysfunction in the juvenile lamb. / Sharma, Shruti; Barton, Jubilee; Rafikov, Ruslan; Aggarwal, Saurabh; Kuo, Hsuan Chang; Oishi, Peter E.; Datar, Sanjeev A.; Fineman, Jeffrey R.; Black, Stephen Matthew.

In: Pulmonary Pharmacology and Therapeutics, Vol. 26, No. 2, 01.04.2013, p. 271-280.

Research output: Contribution to journalArticle

Sharma, S, Barton, J, Rafikov, R, Aggarwal, S, Kuo, HC, Oishi, PE, Datar, SA, Fineman, JR & Black, SM 2013, 'Chronic inhibition of PPAR-γ signaling induces endothelial dysfunction in the juvenile lamb', Pulmonary Pharmacology and Therapeutics, vol. 26, no. 2, pp. 271-280. https://doi.org/10.1016/j.pupt.2012.12.004
Sharma, Shruti ; Barton, Jubilee ; Rafikov, Ruslan ; Aggarwal, Saurabh ; Kuo, Hsuan Chang ; Oishi, Peter E. ; Datar, Sanjeev A. ; Fineman, Jeffrey R. ; Black, Stephen Matthew. / Chronic inhibition of PPAR-γ signaling induces endothelial dysfunction in the juvenile lamb. In: Pulmonary Pharmacology and Therapeutics. 2013 ; Vol. 26, No. 2. pp. 271-280.
@article{91ec2bd3a2d44f429c8edf9cb7f2fd7c,
title = "Chronic inhibition of PPAR-γ signaling induces endothelial dysfunction in the juvenile lamb",
abstract = "We have recently shown that the development of endothelial dysfunction in lambs with increased pulmonary blood flow (PBF) correlates with a decrease in peroxisome proliferator activated receptor-γ (PPAR-γ) signaling. Thus, in this study we determined if the loss of PPAR-γ signaling is necessary and sufficient to induce endothelial dysfunction by exposing lambs with normal PBF to the PPAR-γ antagonist, GW9662. Two-weeks of exposure to GW9662 significantly decreased both PPAR-γ protein and activity. In addition, although eNOS protein and nitric oxide metabolites (NOx) were significantly increased, endothelial dependent pulmonary vasodilation in response to acetylcholine was attenuated, indicative of endothelial dysfunction. To elucidate whether downstream mediators of vasodilation were impaired we examined soluble guanylate cyclase (sGC)-α and β subunit protein, cGMP levels, and phosphodiesterase 5 (PDE5) protein and activity, but we found no significant changes. However, we found that peroxynitrite levels were significantly increased in GW9662-treated lambs and this correlated with a significant increase in protein kinase G-1α (PKG-1α) nitration and a reduction in PKG activity. Peroxynitrite is formed by the interaction of NO with superoxide and we found that there was a significant increase in superoxide generation in GW9662-treated lambs. Further, we identified dysfunctional mitochondria as the primary source of the increased superoxide. Finally, we found that the mitochondrial dysfunction was due to a disruption in carnitine metabolism. We conclude that loss of PPAR-γ signaling is sufficient to induce endothelial dysfunction confirming its important role in maintaining a healthy vasculature.",
keywords = "Carnitine metabolism, Mitochondrial dysfunction, NO signaling, Oxidative stress",
author = "Shruti Sharma and Jubilee Barton and Ruslan Rafikov and Saurabh Aggarwal and Kuo, {Hsuan Chang} and Oishi, {Peter E.} and Datar, {Sanjeev A.} and Fineman, {Jeffrey R.} and Black, {Stephen Matthew}",
year = "2013",
month = "4",
day = "1",
doi = "10.1016/j.pupt.2012.12.004",
language = "English (US)",
volume = "26",
pages = "271--280",
journal = "Pulmonary Pharmacology and Therapeutics",
issn = "1094-5539",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Chronic inhibition of PPAR-γ signaling induces endothelial dysfunction in the juvenile lamb

AU - Sharma, Shruti

AU - Barton, Jubilee

AU - Rafikov, Ruslan

AU - Aggarwal, Saurabh

AU - Kuo, Hsuan Chang

AU - Oishi, Peter E.

AU - Datar, Sanjeev A.

AU - Fineman, Jeffrey R.

AU - Black, Stephen Matthew

PY - 2013/4/1

Y1 - 2013/4/1

N2 - We have recently shown that the development of endothelial dysfunction in lambs with increased pulmonary blood flow (PBF) correlates with a decrease in peroxisome proliferator activated receptor-γ (PPAR-γ) signaling. Thus, in this study we determined if the loss of PPAR-γ signaling is necessary and sufficient to induce endothelial dysfunction by exposing lambs with normal PBF to the PPAR-γ antagonist, GW9662. Two-weeks of exposure to GW9662 significantly decreased both PPAR-γ protein and activity. In addition, although eNOS protein and nitric oxide metabolites (NOx) were significantly increased, endothelial dependent pulmonary vasodilation in response to acetylcholine was attenuated, indicative of endothelial dysfunction. To elucidate whether downstream mediators of vasodilation were impaired we examined soluble guanylate cyclase (sGC)-α and β subunit protein, cGMP levels, and phosphodiesterase 5 (PDE5) protein and activity, but we found no significant changes. However, we found that peroxynitrite levels were significantly increased in GW9662-treated lambs and this correlated with a significant increase in protein kinase G-1α (PKG-1α) nitration and a reduction in PKG activity. Peroxynitrite is formed by the interaction of NO with superoxide and we found that there was a significant increase in superoxide generation in GW9662-treated lambs. Further, we identified dysfunctional mitochondria as the primary source of the increased superoxide. Finally, we found that the mitochondrial dysfunction was due to a disruption in carnitine metabolism. We conclude that loss of PPAR-γ signaling is sufficient to induce endothelial dysfunction confirming its important role in maintaining a healthy vasculature.

AB - We have recently shown that the development of endothelial dysfunction in lambs with increased pulmonary blood flow (PBF) correlates with a decrease in peroxisome proliferator activated receptor-γ (PPAR-γ) signaling. Thus, in this study we determined if the loss of PPAR-γ signaling is necessary and sufficient to induce endothelial dysfunction by exposing lambs with normal PBF to the PPAR-γ antagonist, GW9662. Two-weeks of exposure to GW9662 significantly decreased both PPAR-γ protein and activity. In addition, although eNOS protein and nitric oxide metabolites (NOx) were significantly increased, endothelial dependent pulmonary vasodilation in response to acetylcholine was attenuated, indicative of endothelial dysfunction. To elucidate whether downstream mediators of vasodilation were impaired we examined soluble guanylate cyclase (sGC)-α and β subunit protein, cGMP levels, and phosphodiesterase 5 (PDE5) protein and activity, but we found no significant changes. However, we found that peroxynitrite levels were significantly increased in GW9662-treated lambs and this correlated with a significant increase in protein kinase G-1α (PKG-1α) nitration and a reduction in PKG activity. Peroxynitrite is formed by the interaction of NO with superoxide and we found that there was a significant increase in superoxide generation in GW9662-treated lambs. Further, we identified dysfunctional mitochondria as the primary source of the increased superoxide. Finally, we found that the mitochondrial dysfunction was due to a disruption in carnitine metabolism. We conclude that loss of PPAR-γ signaling is sufficient to induce endothelial dysfunction confirming its important role in maintaining a healthy vasculature.

KW - Carnitine metabolism

KW - Mitochondrial dysfunction

KW - NO signaling

KW - Oxidative stress

UR - http://www.scopus.com/inward/record.url?scp=84874558989&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84874558989&partnerID=8YFLogxK

U2 - 10.1016/j.pupt.2012.12.004

DO - 10.1016/j.pupt.2012.12.004

M3 - Article

VL - 26

SP - 271

EP - 280

JO - Pulmonary Pharmacology and Therapeutics

JF - Pulmonary Pharmacology and Therapeutics

SN - 1094-5539

IS - 2

ER -