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Protection against myocardial ischaemia/reperfusion injury by PPAR-alpha activation is related to production of nitric oxide and endothelin-1

Bulhak, A ; Sjoquist, PO ; Xu, Cang-Bao LU ; Edvinsson, Lars LU and Pernow, J (2006) In Basic Research in Cardiology 101(3). p.244-252
Abstract
Background Ligands of peroxisome proliferator-activated receptor alpha (PPAR-alpha) have been shown to reduce ischaemia/reperfusion injury. The mechanisms behind this effect are not well known. We hypothesized that activation of PPAR-alpha exerts cardioprotection via a mechanism related to nitric oxide (NO) and endothelin-1 (ET-1). Methods Five groups of anaesthetized open-chest Sprague-Dawley rats were given the PPAR-alpha agonist WY 14643 1 mg/kg (WY; n = 7), dimethyl sulfoxide (DMSO, vehicle for WY; n = 6), the combination of WY and the NO synthase inhibitor N-nitro-L-arginine (L-NNA, 2 mg/kg) (n = 7), L-NNA only (n = 8) or 0.9% sodium chloride (NaCl, vehicle for DMSO and L-NNA; n = 8) i.v. before a 30 min period of coronary artery... (More)
Background Ligands of peroxisome proliferator-activated receptor alpha (PPAR-alpha) have been shown to reduce ischaemia/reperfusion injury. The mechanisms behind this effect are not well known. We hypothesized that activation of PPAR-alpha exerts cardioprotection via a mechanism related to nitric oxide (NO) and endothelin-1 (ET-1). Methods Five groups of anaesthetized open-chest Sprague-Dawley rats were given the PPAR-alpha agonist WY 14643 1 mg/kg (WY; n = 7), dimethyl sulfoxide (DMSO, vehicle for WY; n = 6), the combination of WY and the NO synthase inhibitor N-nitro-L-arginine (L-NNA, 2 mg/kg) (n = 7), L-NNA only (n = 8) or 0.9% sodium chloride (NaCl, vehicle for DMSO and L-NNA; n = 8) i.v. before a 30 min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), eNOS and iNOS protein and ET-1 mRNA expression were determined. Results There were no haemodynamic differences between the groups during the experiment. The IS was 78 +/- 3% of the area at risk in the DMSO group and 77 +/- 2% in the NaCl group (P = NS). WY reduced IS to 56 +/- 3% (P < 0.001 vs. DMSO group). When WY was administered in combination with L-NNA the cardioprotective effect was abolished (IS 73 +/- 3%, P < 0.01 vs. WY 14643). L-NNA did not affect IS per se (78 +/- 2%, P = NS). The expression of eNOS but not iNOS protein in ischaemic myocardium from rats was increased in the group given WY (P < 0.05). ET-1 mRNA levels were lower in the ischaemic myocardium following WY administration. Conclusion The results suggest that the PPAR-alpha activation protects the rat myocardium against ischaemia/ reperfusion injury via a mechanism related to production of NO, and possibly ET-1. (Less)
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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ischaemia/reperfusion, endothelin-1, nitric oxide, PPAR-alpha ligands, endothelial function
in
Basic Research in Cardiology
volume
101
issue
3
pages
244 - 252
publisher
Springer
external identifiers
  • wos:000236643000006
  • scopus:33645734144
ISSN
0300-8428
DOI
10.1007/s00395-005-0580-1
language
English
LU publication?
yes
id
22196288-0ad6-483e-84c8-b3aecd023435 (old id 414658)
date added to LUP
2016-04-01 17:10:56
date last changed
2021-05-25 01:55:47
@article{22196288-0ad6-483e-84c8-b3aecd023435,
  abstract     = {Background Ligands of peroxisome proliferator-activated receptor alpha (PPAR-alpha) have been shown to reduce ischaemia/reperfusion injury. The mechanisms behind this effect are not well known. We hypothesized that activation of PPAR-alpha exerts cardioprotection via a mechanism related to nitric oxide (NO) and endothelin-1 (ET-1). Methods Five groups of anaesthetized open-chest Sprague-Dawley rats were given the PPAR-alpha agonist WY 14643 1 mg/kg (WY; n = 7), dimethyl sulfoxide (DMSO, vehicle for WY; n = 6), the combination of WY and the NO synthase inhibitor N-nitro-L-arginine (L-NNA, 2 mg/kg) (n = 7), L-NNA only (n = 8) or 0.9% sodium chloride (NaCl, vehicle for DMSO and L-NNA; n = 8) i.v. before a 30 min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), eNOS and iNOS protein and ET-1 mRNA expression were determined. Results There were no haemodynamic differences between the groups during the experiment. The IS was 78 +/- 3% of the area at risk in the DMSO group and 77 +/- 2% in the NaCl group (P = NS). WY reduced IS to 56 +/- 3% (P &lt; 0.001 vs. DMSO group). When WY was administered in combination with L-NNA the cardioprotective effect was abolished (IS 73 +/- 3%, P &lt; 0.01 vs. WY 14643). L-NNA did not affect IS per se (78 +/- 2%, P = NS). The expression of eNOS but not iNOS protein in ischaemic myocardium from rats was increased in the group given WY (P &lt; 0.05). ET-1 mRNA levels were lower in the ischaemic myocardium following WY administration. Conclusion The results suggest that the PPAR-alpha activation protects the rat myocardium against ischaemia/ reperfusion injury via a mechanism related to production of NO, and possibly ET-1.},
  author       = {Bulhak, A and Sjoquist, PO and Xu, Cang-Bao and Edvinsson, Lars and Pernow, J},
  issn         = {0300-8428},
  language     = {eng},
  number       = {3},
  pages        = {244--252},
  publisher    = {Springer},
  series       = {Basic Research in Cardiology},
  title        = {Protection against myocardial ischaemia/reperfusion injury by PPAR-alpha activation is related to production of nitric oxide and endothelin-1},
  url          = {http://dx.doi.org/10.1007/s00395-005-0580-1},
  doi          = {10.1007/s00395-005-0580-1},
  volume       = {101},
  year         = {2006},
}