Morphine-induced delayed pre-conditioning against anoxia/reoxygenation injury in pulmonary artery endothelial cells: The role of mitochondrial KATP channels

Prophylactic treatment with d- myo-inositol 1,4,5-trisphosphate hexasodium [d- myo-Ins(1,4,5)P3], the sodium salt of the endogenous second messenger Ins(1,4,5)P3, triggers a reduction of infarct size comparable in magnitude to that seen with ischemic preconditioning (PC). However, the mechanisms underlying d- myo-Ins(1,4,5)P3-induced protection are unknown. Accordingly, our aim was to investigate the role of four archetypal mediators implicated in PC and other cardioprotective strategies (i.e., PKC, PI3-kinase/Akt, and mitochondrial and/or sarcolemmal KATP channels) in the infarct-sparing effect of d- myo-Ins(1,4,5)P3. Fifteen groups of isolated buffer-perfused rabbit hearts [5 treated with d- myo-Ins(1,4,5)P3, 5 treated with PC, and 5 control cohorts] underwent 30 min of coronary artery occlusion and 2 h of reflow. One set of control, d- myo-Ins(1,4,5)P3, and PC groups received no additional treatment, whereas the remaining sets were infused with chelerythrine, LY-294002, 5-hydroxydecanoate (5-HD), or HMR-1098 [inhibitors of PKC, PI3-kinase, and mitochondrial and sarcolemmal ATP-sensitive K+ (KATP) channels, respectively]. Infarct size (delineated by tetrazolium staining) was, as expected, significantly reduced in both d- myo-Ins(1,4,5)P3- and PC-treated hearts versus controls. d- myo-Ins(1,4,5)P3-induced cardioprotection was blocked by 5-HD but not HMR-1098, thereby implicating the involvement of mitochondrial, but not sarcolemmal, KATP channels. Moreover, the benefits of d- myo-Ins(1,4,5)P3 were abrogated by LY-294002, whereas, in contrast, chelerythrine had no effect. These latter pharmacological data were corroborated by immunoblotting: d- myo-Ins(1,4,5)P3 evoked a significant increase in expression of phospho-Akt but had no effect on the activation/translocation of the cardioprotective ε-isoform of PKC. Thus PI3-kinase/Akt signaling and mitochondrial KATP channels participate in the reduction of infarct size afforded by prophylactic administration of d- myo-Ins(1,4,5)P3.

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Differential role of sarcolemmal and mitochondrial KATP channels in adenosine-enhanced ischemic preconditioning

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.6.h2694 ◽

2000 ◽

Vol 279 (6) ◽

pp. H2694-H2703 ◽

Cited By ~ 45

Author(s):

Yoshiya Toyoda ◽

Ingeborg Friehs ◽

Robert A. Parker ◽

Sidney Levitsky ◽

James D. McCully

Keyword(s):

Infarct Size ◽

Functional Recovery ◽

Ischemic Preconditioning ◽

Channel Blocker ◽

Katp Channels ◽

Size Reduction ◽

Ischemia And Reperfusion ◽

Infarct Size Reduction ◽

Mitochondrial Katp Channels

Adenosine-enhanced ischemic preconditioning (APC) extends the protection afforded by ischemic preconditioning (IPC) by both significantly decreasing infarct size and significantly enhancing postischemic functional recovery. The purpose of this study was to determine whether APC is modulated by ATP-sensitive potassium (KATP) channels and to determine whether this modulation occurs before ischemia or during reperfusion. The role of KATP channels before ischemia (I), during reperfusion (R), or during ischemia and reperfusion (IR) was investigated using the nonspecific KATP blocker glibenclamide (Glb), the mitochondrial (mito) KATP channel blocker 5-hydroxydecanoate (5-HD), and the sarcolemmal (sarc) KATPchannel blocker HMR-1883 (HMR). Infarct size was significantly increased ( P < 0.05) in APC hearts with Glb-I, Glb-R, and 5-HD-I treatment and partially with 5-HD-R. Glb-I and Glb-R treatment significantly decreased APC functional recovery ( P < 0.05 vs. APC), whereas 5-HD-I and 5-HD-R had no effect on APC functional recovery. HMR-IR significantly decreased postischemic functional recovery ( P < 0.05 vs. APC) but had no effect on infarct size. These data indicate that APC infarct size reduction is modulated by mitoKATP channels primarily during ischemia and suggest that functional recovery is modulated by sarcKATP channels during ischemia and reperfusion.

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Anti-apoptotic effect of morphine-induced delayed preconditioning on pulmonary artery endothelial cells with anoxia/reoxygenation injury

Chinese Medical Journal ◽

10.1097/00029330-200807020-00013 ◽

2008 ◽

Vol 121 (14) ◽

pp. 1313-1318 ◽

Cited By ~ 9

Author(s):

Wen-gang DING ◽

Hua-cheng ZHOU ◽

Xiao-guang CUI ◽

Wen-zhi LI ◽

Yue-ping GUO ◽

...

Keyword(s):

Endothelial Cells ◽

Pulmonary Artery ◽

Apoptotic Effect ◽

Reoxygenation Injury

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The role of mitochondrial KATP channels in the antiarrhythmic effects of ischaemic preconditioning in dogs

British Journal of Pharmacology ◽

10.1038/sj.bjp.0704965 ◽

2002 ◽

Vol 137 (7) ◽

pp. 939-940 ◽

Cited By ~ 7

Author(s):

Garrett J Gross

Keyword(s):

Katp Channels ◽

Ischaemic Preconditioning ◽

Mitochondrial Katp Channels ◽

Antiarrhythmic Effects

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Role of 12-lipoxygenase in hypoxia-induced rat pulmonary artery smooth muscle cell proliferation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00114.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. L367-L374 ◽

Cited By ~ 61

Author(s):

Ioana R. Preston ◽

Nicholas S. Hill ◽

Rod R. Warburton ◽

Barry L. Fanburg

Keyword(s):

Endothelial Cells ◽

Pulmonary Hypertension ◽

Smooth Muscle ◽

Pulmonary Artery ◽

Protein Expression ◽

Pulmonary Arteries ◽

Mek Inhibitor ◽

Gene And Protein Expression ◽

12 Lipoxygenase

The 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism stimulates cell growth and metastasis of various cancer cells and the 12-LO metabolite, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], enhances proliferation of aortic smooth muscle cells (SMCs). However, pulmonary vascular effects of 12-LO have not been previously studied. We sought evidence for a role of 12-LO and 12(S)-HETE in the development of hypoxia-induced pulmonary hypertension. We found that 12-LO gene and protein expression is elevated in lung homogenates of rats exposed to chronic hypoxia. Immunohistochemical staining with a 12-LO antibody revealed intense staining in endothelial cells of large pulmonary arteries, SMCs (and possibly endothelial cells) of medium and small-size pulmonary arteries and in alveolar walls of hypoxic lungs. 12-LO protein expression was increased in hypoxic cultured rat pulmonary artery SMCs. 12(S)-HETE at concentrations as low as 10−5 μM stimulated proliferation of pulmonary artery SMCs. 12(S)-HETE induced ERK 1/ERK 2 phosphorylation but had no effect on p38 kinase expression as assessed by Western blotting. 12(S)-HETE-stimulated SMC proliferation was blocked by the MEK inhibitor PD-98059, but not by the p38 MAPK inhibitor SB-202190. Hypoxia (3%)-stimulated pulmonary artery SMC proliferation was blocked by both U0126, a MEK inhibitor, and baicalein, an inhibitor of 12-LO. We conclude that 12-LO and its product, 12(S)-HETE, are important intermediates in hypoxia-induced pulmonary artery SMC proliferation and may participate in hypoxia-induced pulmonary hypertension.

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