Rosiglitazone preserves pulmonary vascular function in lambs with increased pulmonary blood flow

Peter E. Oishi, Shruti Sharma, Sanjeev A. Datar, Sanjiv Kumar, Saurabh Aggarwal, Qing Lu, Gary W Raff, Anthony Azakie, Jong Hau Hsu, Eniko Sajti, Sohrab Fratz, Stephen M. Black, Jeffrey R. Fineman

Research output: Contribution to journalArticle

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Abstract

Pulmonary vascular function is impaired with increased pulmonary blood flow (PBF). We hypothesized that a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist would mitigate this effect.Methods:An aorta-to-pulmonary-artery shunt was placed in 11 fetal lambs. Lambs received the PPAR-γ agonist rosiglitazone (RG, 3 mg/kg/d, n = 6) or vehicle (n = 5) for 4 wk. Lung tissue from five normal 4-wk-old lambs was used for comparisons.Results:At 4 wk, pulmonary artery pressure (PAP) and vascular resistance (PVR) decreased with inhaled nitric oxide (NO) in RG-and vehicle-treated shunt lambs. PAP and PVR decreased with acetylcholine (Ach) in RG-treated, but not vehicle-treated, shunt lambs. In vehicle-treated shunt lambs, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, rac1, superoxide, and 3-nitrotyrosine (3-NT) levels were increased, and Ser1177 endothelial NO synthase (eNOS) protein was decreased as compared with normal lambs. In RG-treated shunt lambs, NOx, Ser1177 eNOS protein, and eNOS activity were increased, and NADPH activity, rac1, superoxide levels, and 3-NT levels were decreased, as compared with vehicle-treated shunt lambs. PPAR-γ protein expression was lower in vehicle-treated shunt lambs than in normal and RG-treated shunt lambs.Conclusion:The PPAR-γ agonist RG prevents the loss of agonist-induced endothelium-dependent pulmonary vascular relaxation in lambs with increased PBF, in part, due to decreased oxidative stress and/or increased NO production.

Original languageEnglish (US)
Pages (from-to)54-61
Number of pages8
JournalPediatric Research
Volume73
Issue number1
DOIs
StatePublished - Jan 2013

Fingerprint

rosiglitazone
Peroxisome Proliferator-Activated Receptors
Blood Vessels
Lung
Pulmonary Artery
NADP
Nitric Oxide Synthase
Superoxides
Vascular Resistance
Nitric Oxide
Pressure
Proteins
Nitric Oxide Synthase Type III
Vasodilation
Acetylcholine
Aorta
Oxidoreductases
Oxidative Stress

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Oishi, P. E., Sharma, S., Datar, S. A., Kumar, S., Aggarwal, S., Lu, Q., ... Fineman, J. R. (2013). Rosiglitazone preserves pulmonary vascular function in lambs with increased pulmonary blood flow. Pediatric Research, 73(1), 54-61. https://doi.org/10.1038/pr.2012.149

Rosiglitazone preserves pulmonary vascular function in lambs with increased pulmonary blood flow. / Oishi, Peter E.; Sharma, Shruti; Datar, Sanjeev A.; Kumar, Sanjiv; Aggarwal, Saurabh; Lu, Qing; Raff, Gary W; Azakie, Anthony; Hsu, Jong Hau; Sajti, Eniko; Fratz, Sohrab; Black, Stephen M.; Fineman, Jeffrey R.

In: Pediatric Research, Vol. 73, No. 1, 01.2013, p. 54-61.

Research output: Contribution to journalArticle

Oishi, PE, Sharma, S, Datar, SA, Kumar, S, Aggarwal, S, Lu, Q, Raff, GW, Azakie, A, Hsu, JH, Sajti, E, Fratz, S, Black, SM & Fineman, JR 2013, 'Rosiglitazone preserves pulmonary vascular function in lambs with increased pulmonary blood flow', Pediatric Research, vol. 73, no. 1, pp. 54-61. https://doi.org/10.1038/pr.2012.149
Oishi, Peter E. ; Sharma, Shruti ; Datar, Sanjeev A. ; Kumar, Sanjiv ; Aggarwal, Saurabh ; Lu, Qing ; Raff, Gary W ; Azakie, Anthony ; Hsu, Jong Hau ; Sajti, Eniko ; Fratz, Sohrab ; Black, Stephen M. ; Fineman, Jeffrey R. / Rosiglitazone preserves pulmonary vascular function in lambs with increased pulmonary blood flow. In: Pediatric Research. 2013 ; Vol. 73, No. 1. pp. 54-61.
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abstract = "Pulmonary vascular function is impaired with increased pulmonary blood flow (PBF). We hypothesized that a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist would mitigate this effect.Methods:An aorta-to-pulmonary-artery shunt was placed in 11 fetal lambs. Lambs received the PPAR-γ agonist rosiglitazone (RG, 3 mg/kg/d, n = 6) or vehicle (n = 5) for 4 wk. Lung tissue from five normal 4-wk-old lambs was used for comparisons.Results:At 4 wk, pulmonary artery pressure (PAP) and vascular resistance (PVR) decreased with inhaled nitric oxide (NO) in RG-and vehicle-treated shunt lambs. PAP and PVR decreased with acetylcholine (Ach) in RG-treated, but not vehicle-treated, shunt lambs. In vehicle-treated shunt lambs, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, rac1, superoxide, and 3-nitrotyrosine (3-NT) levels were increased, and Ser1177 endothelial NO synthase (eNOS) protein was decreased as compared with normal lambs. In RG-treated shunt lambs, NOx, Ser1177 eNOS protein, and eNOS activity were increased, and NADPH activity, rac1, superoxide levels, and 3-NT levels were decreased, as compared with vehicle-treated shunt lambs. PPAR-γ protein expression was lower in vehicle-treated shunt lambs than in normal and RG-treated shunt lambs.Conclusion:The PPAR-γ agonist RG prevents the loss of agonist-induced endothelium-dependent pulmonary vascular relaxation in lambs with increased PBF, in part, due to decreased oxidative stress and/or increased NO production.",
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AU - Oishi, Peter E.

AU - Sharma, Shruti

AU - Datar, Sanjeev A.

AU - Kumar, Sanjiv

AU - Aggarwal, Saurabh

AU - Lu, Qing

AU - Raff, Gary W

AU - Azakie, Anthony

AU - Hsu, Jong Hau

AU - Sajti, Eniko

AU - Fratz, Sohrab

AU - Black, Stephen M.

AU - Fineman, Jeffrey R.

PY - 2013/1

Y1 - 2013/1

N2 - Pulmonary vascular function is impaired with increased pulmonary blood flow (PBF). We hypothesized that a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist would mitigate this effect.Methods:An aorta-to-pulmonary-artery shunt was placed in 11 fetal lambs. Lambs received the PPAR-γ agonist rosiglitazone (RG, 3 mg/kg/d, n = 6) or vehicle (n = 5) for 4 wk. Lung tissue from five normal 4-wk-old lambs was used for comparisons.Results:At 4 wk, pulmonary artery pressure (PAP) and vascular resistance (PVR) decreased with inhaled nitric oxide (NO) in RG-and vehicle-treated shunt lambs. PAP and PVR decreased with acetylcholine (Ach) in RG-treated, but not vehicle-treated, shunt lambs. In vehicle-treated shunt lambs, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, rac1, superoxide, and 3-nitrotyrosine (3-NT) levels were increased, and Ser1177 endothelial NO synthase (eNOS) protein was decreased as compared with normal lambs. In RG-treated shunt lambs, NOx, Ser1177 eNOS protein, and eNOS activity were increased, and NADPH activity, rac1, superoxide levels, and 3-NT levels were decreased, as compared with vehicle-treated shunt lambs. PPAR-γ protein expression was lower in vehicle-treated shunt lambs than in normal and RG-treated shunt lambs.Conclusion:The PPAR-γ agonist RG prevents the loss of agonist-induced endothelium-dependent pulmonary vascular relaxation in lambs with increased PBF, in part, due to decreased oxidative stress and/or increased NO production.

AB - Pulmonary vascular function is impaired with increased pulmonary blood flow (PBF). We hypothesized that a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist would mitigate this effect.Methods:An aorta-to-pulmonary-artery shunt was placed in 11 fetal lambs. Lambs received the PPAR-γ agonist rosiglitazone (RG, 3 mg/kg/d, n = 6) or vehicle (n = 5) for 4 wk. Lung tissue from five normal 4-wk-old lambs was used for comparisons.Results:At 4 wk, pulmonary artery pressure (PAP) and vascular resistance (PVR) decreased with inhaled nitric oxide (NO) in RG-and vehicle-treated shunt lambs. PAP and PVR decreased with acetylcholine (Ach) in RG-treated, but not vehicle-treated, shunt lambs. In vehicle-treated shunt lambs, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, rac1, superoxide, and 3-nitrotyrosine (3-NT) levels were increased, and Ser1177 endothelial NO synthase (eNOS) protein was decreased as compared with normal lambs. In RG-treated shunt lambs, NOx, Ser1177 eNOS protein, and eNOS activity were increased, and NADPH activity, rac1, superoxide levels, and 3-NT levels were decreased, as compared with vehicle-treated shunt lambs. PPAR-γ protein expression was lower in vehicle-treated shunt lambs than in normal and RG-treated shunt lambs.Conclusion:The PPAR-γ agonist RG prevents the loss of agonist-induced endothelium-dependent pulmonary vascular relaxation in lambs with increased PBF, in part, due to decreased oxidative stress and/or increased NO production.

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