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

Bulhak, Aliaksandr; Sjöquist, Per-Ove; Xu, Cang‐Bao; Edvinsson, Lars; Pernow, John

doi:10.1007/s00395-005-0580-1

Cited by 63 publications

(45 citation statements)

References 34 publications

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“…2B). It is interesting that treatment of ischemic rats with a PPAR-␣ ligand has been shown to be cardioprotective as a result of nitric oxide production (Bulhak et al, 2006), which has also been shown to repress Cyp1a2 mRNA (Mulero-Navarro et al, 2003). Although definitive proof is still lacking, these findings and the observations in Fig.…”

Section: Discussionmentioning

confidence: 80%

Induction of Cyp1a1 Is a Nonspecific Biomarker of Aryl Hydrocarbon Receptor Activation: Results of Large Scale Screening of Pharmaceuticals and Toxicants in Vivo and in Vitro

Hu¹,

et al. 2007

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Section: Discussionmentioning

confidence: 80%

Induction of Cyp1a1 Is a Nonspecific Biomarker of Aryl Hydrocarbon Receptor Activation: Results of Large Scale Screening of Pharmaceuticals and Toxicants in Vivo and in Vitro

Hu¹,

et al. 2007

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“…At the same time, NOS actions might play a protective role against inflammatory injury by mature leukocytes which have been recently been described in the cremaster muscle 36 and in ischemia and reperfusion injury to the heart. 37 NOS might be a determinant for tissue to decide about the amount of inflammation and regeneration.…”

Section: Stem Cell Adhesion Requires Enosmentioning

confidence: 99%

Endothelial NOS is required for SDF-1α/CXCR4-mediated peripheral endothelial adhesion of c-kit+ bone marrow stem cells

Kaminski

Donndorf

et al. 2008

Laboratory Investigation

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In the era of intravascular approaches for regenerative cell therapy, the underlying mechanisms of stem cell migration to non-marrow tissue have not been clarified. We hypothesized that next to a local inflammatory response implying adhesion molecule expression, endothelial nitric oxide synthase (eNOS)-dependent signaling is required for stromalcell-derived factor-1 alpha (SDF-1a)-induced adhesion of c-kit þ cells to the vascular endothelium. SDF-1a/tumor necrosis factor-alpha (TNF-a)-induced c-kit þ -cell shape change and migration capacity was studied in vitro using immunohistochemistry and Boyden chamber assays. In vivo interaction of c-kit þ cells from bone marrow with the endothelium in response to SDF-1a/TNF-a stimulation was visualized in the cremaster muscle microcirculation of wild-type (WT) and eNOS (À/À) mice using intravital fluorescence microscopy. In addition, NOS activity was inhibited with N-nitro-Larginine-methylester-hydrochloride in WT mice. To reveal c-kit þ -specific adhesion behavior, endogenous leukocytes (EL) and c-kit þ cells from peripheral blood served as control. Moreover, intercellular adhesion molecule-1 (ICAM-1) and CXCR4 were blocked systemically to determine their role in inflammation-related c-kit þ -cell adhesion. In vitro, SDF-1a enhanced c-kit þ -cell migration. In vivo, SDF-1a alone triggered endothelial rolling-not firm adherence-of c-kit þ cells in WT mice. While TNF-a alone had little effect on adhesion of c-kit þ cells, it induced maximum endothelial EL adherence. However, after combined treatment with SDF-1a þ TNF-a, endothelial adhesion of c-kit þ cells increased independent of their origin, while EL adhesion was not further incremented. Systemic treatment with anti-ICAM-1 and anti-CXCR4-monoclonal antibody completely abolished endothelial c-kit þ -cell adhesion. In N-nitro-L-arginine-methylester-hydrochloride-treated WT mice as well as in eNOS (À/À) mice, firm endothelial adhesion of c-kit þ cells was entirely abrogated, while EL adhesion was significantly increased. The chemokine SDF-1a mediates firm adhesion c-kit þ cells only in the presence of TNF-a stimulation via an ICAM-1-and CXCR4-dependent mechanism. The presence of eNOS appears to be a crucial and specific factor for firm c-kit þ -cell adhesion to the vascular endothelium.

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“…All treatments were given as intravenous injections 30 min before coronary artery occlusion. The dose of WY, L-NNA, and wortmannin (Sigma, St. Louis, MO) and the concentration of DMSO were based on previous studies of myocardial ischemia-reperfusion injury (5,28,36).…”

mentioning

confidence: 99%

PPAR-α activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-Kinase/Akt and NO pathway

Bulhak

Jung²,

Östenson³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

111

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Bulhak AA, Jung C, Ö stenson C, Lundberg JO, Sjö quist P, Pernow J. PPAR-␣ activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-kinase/Akt and NO pathway. Am J Physiol Heart Circ Physiol 296: H719 -H727, 2009. First published January 16, 2009 doi:10.1152/ajpheart.00394.2008.-Several clinical studies have shown the beneficial cardiovascular effects of fibrates in patients with diabetes and insulin resistance. The ligands of peroxisome proliferatoractivated receptor-␣ (PPAR-␣) reduce ischemia-reperfusion injury in nondiabetic animals. We hypothesized that the activation of PPAR-␣ would exert cardioprotection in type 2 diabetic Goto-Kakizaki (GK) rats, involving mechanisms related to nitric oxide (NO) production via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. GK rats and agematched Wistar rats (n Ն 7) were given either 1) the PPAR-␣ agonist WY-14643 (WY), 2) dimethyl sulfoxide (DMSO), 3) WY and the NO synthase inhibitor N G -nitro-L-arginine (L-NNA), 4) L-NNA, 5) WY and the PI3K inhibitor wortmannin, or 6) wortmannin alone intravenously before a 35-min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), expression of endothelial NO synthase (eNOS), inducible NO synthase, and Akt as well as nitrite/ nitrate were determined. The IS was 75 Ϯ 3% and 72 Ϯ 4% of the area at risk in the Wistar and GK DMSO groups, respectively. WY reduced IS to 56 Ϯ 3% in Wistar (P Ͻ 0.05) and to 46 Ϯ 5% in GK rats (P Ͻ 0.001). The addition of either L-NNA or wortmannin reversed the cardioprotective effect of WY in both Wistar (IS, 70 Ϯ 5% and 65 Ϯ 5%, respectively) and GK (IS, 66 Ϯ 4% and 64 Ϯ 4%, P Ͻ 0.05, respectively) rats. The expression of eNOS and eNOS Ser1177 in the ischemic myocardium from both strains was increased after WY. The expression of Akt, Akt Ser473, and Akt Thr308 was also increased in the ischemic myocardium from GK rats following WY. Myocardial nitrite/nitrate levels were reduced in GK rats (P Ͻ 0.05). The results suggest that PPAR-␣ activation protects the type 2 diabetic rat myocardium against ischemia-reperfusion injury via the activation of the PI3K/Akt and NO pathway.peroxisome proliferator-activated receptor-␣ ligand; endothelial function; phosphatidylinositol 3-kinase

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

Abstract: 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.

Cited by 63 publications

References 34 publications

Induction of Cyp1a1 Is a Nonspecific Biomarker of Aryl Hydrocarbon Receptor Activation: Results of Large Scale Screening of Pharmaceuticals and Toxicants in Vivo and in Vitro

Induction of Cyp1a1 Is a Nonspecific Biomarker of Aryl Hydrocarbon Receptor Activation: Results of Large Scale Screening of Pharmaceuticals and Toxicants in Vivo and in Vitro

Endothelial NOS is required for SDF-1α/CXCR4-mediated peripheral endothelial adhesion of c-kit+ bone marrow stem cells

PPAR-α activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-Kinase/Akt and NO pathway

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