Cardioprotection During the Final Stage of the Late Phase of Ischemic Preconditioning Is Mediated by Neuronal NO Synthase in Concert With Cyclooxygenase-2

Wang, Yang; Kodani, Eitaro; Wang, Jianxun; Zhang, Shelley X.; Takano, Hitoshi; Tang, Xian Liang; Bolli, Roberto

doi:10.1161/01.res.0000133679.38825.a6

Cited by 56 publications

(49 citation statements)

References 41 publications

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“…WHPC also up-regulated the protein expression of MnSOD, but not copper-zinc SOD, in the lung (Figure 8). However, WHPC did not appear to affect the expression patterns of inducible NO synthase or cyclooxygenase-2, which were previously shown to mediate the protection afforded by ischemic preconditioning in the heart (28,29).…”

Section: Whpc Up-regulated Cytoprotective Genes In the Lungmentioning

confidence: 63%

Type I Epithelial Cells Are the Main Target of Whole-Body Hypoxic Preconditioning in the Lung

Zhang¹,

Miller²,

Stolz³

et al. 2009

Am J Respir Cell Mol Biol

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Whole-body hypoxic preconditioning (WHPC) prolongs survival of mice exposed to severe hypoxia by attenuating pulmonary edema and preserving gas exchange. However, the cellular and molecular mechanism(s) of this protection remains unclear. The objective of this study was to identify the cellular target(s) of WHPC in the lung. Conscious mice were exposed to hypoxia (7% O 2 ) for 6 hours with or without pretreatment of WHPC ([8% O 2 ] 3 10 min/[21% O 2 ] 3 10 min; 6 cycles). Hypoxia caused severe lung injury, as shown by the development of high-permeability-type pulmonary edema and the release of lactate dehydrogenase and creatine kinase into the airspace and the circulation. All these signs of hypoxic lung injury were significantly attenuated by WHPC. Hypoxia also caused a remarkable release of type I cell markers (caveolin-2 and receptor for advanced glycation end products) in lung lavage that was almost completely abolished by WHPC. Conversely, hypoxia-induced release of type II cell markers (surfactant-associated proteins A and D) was only marginal, and was unaffected by WHPC. Electron microscopic analysis demonstrated considerable hypoxic damage in alveolar type I cells and vascular endothelial cells. Notably, WHPC completely eliminated hypoxic damage in the former and alleviated it in the latter. Type II cells appeared normal. Furthermore, WHPC upregulated protein expression of cytoprotective genes in the lung, such as heat shock proteins and manganese superoxide dismutase. Thus, WHPC attenuates hypoxic lung injury through protection of cells constituting the respiratory membrane, especially hypoxiavulnerable type I epithelial cells. This beneficial effect may involve up-regulation of cytoprotective genes.

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Section: Whpc Up-regulated Cytoprotective Genes In the Lungmentioning

confidence: 63%

Type I Epithelial Cells Are the Main Target of Whole-Body Hypoxic Preconditioning in the Lung

Zhang¹,

Miller²,

Stolz³

et al. 2009

Am J Respir Cell Mol Biol

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“…However, the protective effect of 2-chloro-N 6 -cyclopentyladenosine was blocked by L-NAME. Wang et al (57) reported that nNOS mediates late preconditioning in rabbits. In the present experiment, there were no differences in nNOS levels between the WT, eNOS Ϫ/Ϫ , and iNOS Ϫ/Ϫ mice.…”

Section: Role Of Inosmentioning

confidence: 99%

Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice

Ye¹,

Lin²,

Manickavasagam³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Ye Y, Lin Y, Manickavasagam S, Perez-Polo JR, Tieu BC, Birnbaum Y. Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice. Am J Physiol Heart Circ Physiol 295: H2436 -H2446, 2008. First published October 17, 2008 doi:10.1152/ajpheart.00690.2008.-Endothelial nitric oxide synthase (eNOS) activation with subsequent inducible NOS (iNOS), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase-2 (COX2) activation is essential to statin inhibition of myocardial infarct size (IS). In the rat, the peroxisome proliferator-activated receptor-␥ agonist pioglitazone (Pio) limits IS, upregulates and activates cPLA 2 and COX2, and increases myocardial 6-keto-PGF1␣ levels without activating eNOS and iNOS. We asked whether Pio also limits IS in eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ mice. Male C57BL/6 wild-type (WT), eNOS Ϫ/Ϫ , and iNOS Ϫ/Ϫ mice received 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 Pio (Pioϩ) or water alone (PioϪ) for 3 days. Mice underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts were harvested and subjected to ELISA and immunoblotting. As a result, Pio reduced IS in the WT (15.4 Ϯ 1.4% vs. 39.0 Ϯ 1.1%; P Ͻ 0.001), as well as in the eNOS Ϫ/Ϫ (32.0 Ϯ 1.6% vs. 44.2 Ϯ 1.9%; P Ͻ 0.001) and iNOS Ϫ/Ϫ (18.0 Ϯ 1.2% vs. 45.5 Ϯ 2.3%; P Ͻ 0.001) mice. The protective effect of Pio in eNOS Ϫ/Ϫ mice was smaller than in the WT (P Ͻ 0.001) and iNOS Ϫ/Ϫ (P Ͻ 0.001) mice. Pio increased myocardial Ser633 and Ser1177 phosphorylated eNOS levels in the WT and iNOS Ϫ/Ϫ mice. iNOS was undetectable in all six groups. Pio increased cPLA 2, COX2, and PGI2 synthase levels in the WT, as well as in the eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ , mice. Pio increased the myocardial 6-keto-PGF 1␣ levels and cPLA2 and COX2 activity in the WT, eNOS Ϫ/Ϫ , and iNOS Ϫ/Ϫ mice. In conclusion, the myocardial protective effect of Pio is iNOS independent and may be only partially dependent on eNOS. Because eNOS activity decreases with age, diabetes, and advanced atherosclerosis, this effect may be relevant in a clinical setting and should be further characterized. endothelial nitric oxide synthase; inducible nitric oxide synthase; peroxisome proliferator-activated receptor-␥ PROTECTION AGAINST ischemia-reperfusion injury may have a potential benefit in three distinct clinical situations: 1) limiting reperfusion injury in patients presenting with ST-elevation acute myocardial infarction before undergoing reperfusion therapy; 2) short-to intermediate-term treatment before elective procedures that may pose a risk for myocardial ischemia, such as cardiac or noncardiac surgery or percutaneous coronary interventions; and 3) long-term treatment in patients with established coronary artery disease to minimize the damage from an effort-induced ischemia or a potential future myocardial infarction. In the present study we studied whether the myocardial protection effects of intermediate-term pretreatment with pioglitazone (Pio) is dependent on nitric oxide (NO) synthases (NOSs), using a model that may be relevant to the second option mentioned above....

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“…COX-2 is accordingly discussed as an important factor of heart protection in the late phase of ischemic preconditioning (4,23,40,48). COX-2 selective inhibitors interfere with protective effects in the late phase of ischemic preconditioning (40).…”

Section: Role Of Cox-2 In the Negative Inotropic Effect Of Postischemmentioning

confidence: 99%

COX-2-dependent and potentially cardioprotective effects of negative inotropic substances released after ischemia

Birkenmeier

Staudt²,

Schunck³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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During reperfusion, cardiodepressive factors are released from isolated rat hearts after ischemia. The present study analyzes the mechanisms by which these substances mediate their cardiodepressive effect. After 10 min of global stop-flow ischemia, rat hearts were reperfused and coronary effluent was collected over a period of 30 s. We tested the effect of this postischemic effluent on systolic cell shortening and Ca2+ metabolism by application of fluorescence microscopy of field-stimulated rat cardiomyocytes stained with fura-2 AM. Cells were preincubated with various inhibitors, e.g., the cyclooxygenase (COX) inhibitor indomethacin, the COX-2 inhibitors NS-398 and lumiracoxib, the COX-1 inhibitor SC-560, and the potassium (ATP) channel blocker glibenclamide. Lysates of cardiomyocytes and extracts from whole rat hearts were tested for expression of COX-2 with Western blot analysis. As a result, in contrast to nonischemic effluent (control), postischemic effluent induced a reduction of Ca2+ transient and systolic cell shortening in the rat cardiomyocytes ( P < 0.001 vs. control). After preincubation of cells with indomethacin, NS-398, and lumiracoxib, the negative inotropic effect was attenuated. SC-560 did not influence the effect of postischemic effluent. The inducibly expressed COX-2 was detected in cardiomyocytes prepared for fluorescence microscopy. The effect of postischemic effluent was eliminated with applications of glibenclamide. Furthermore, postischemic effluent significantly reduced the intracellular diastolic and systolic Ca2+ increase ( P < 0.01 vs. control). In conclusion, the cardiodepressive effect of postischemic effluent is COX-2 dependent and protective against Ca2+ overload in the cells.

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Cardioprotection During the Final Stage of the Late Phase of Ischemic Preconditioning Is Mediated by Neuronal NO Synthase in Concert With Cyclooxygenase-2

Cited by 56 publications

References 41 publications

Type I Epithelial Cells Are the Main Target of Whole-Body Hypoxic Preconditioning in the Lung

Type I Epithelial Cells Are the Main Target of Whole-Body Hypoxic Preconditioning in the Lung

Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice

COX-2-dependent and potentially cardioprotective effects of negative inotropic substances released after ischemia

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