Adaptation to Chronic Hypoxia Confers Tolerance to Subsequent Myocardial Ischemia by Increased Nitric Oxide Production

Baker, John E.; Holman, Patricia; Kalyanaraman, B.; Griffith, Owen W.; Pritchard, Kirkwood A.

doi:10.1111/j.1749-6632.1999.tb09239.x

Cited by 56 publications

(60 citation statements)

References 39 publications

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“…RouetBenzineb et al also indicated that after 15 days of hypoxia there was a two-fold increase in iNOS protein abundance in rat left ventricles [22] . However, Baker et al demonstrated that increased tolerance to ischemia in rabbit hearts adapted to chronic hypoxia was associated with increased expression of eNOS isozymes, which led to an increase in myocardial nitrite/nitrate content and cGMP level [23] . The signaling functions of NO begin with its binding to protein receptors, such as guanylyl cyclase, which generates cGMP.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, the elevated expression of myocardial iNOS in IH hearts compared to control hearts was also consistent with Zhong et al's report [6] , which showed that the myocardial cGMP level in IH rats increased compared to normoxia control rats. Baker et al suggested that a small increase in NO levels appears to be cardioprotective, whereas a large increase in NO production may be detrimental, resulting in vasodilation, decreased blood pressure and, perhaps, vascular leakage [23] . Importantly, in our study the magnitude of iNOS upregulation caused by IH was mild.…”

Section: Discussionmentioning

confidence: 99%

“…The total number of exposures was 42-day. The temperature in the chamber was maintained at [22][23][24] o C. The animals were examined the day after the last hypoxic exposure. The control group of animals was kept under normoxic environmental conditions.…”

Section: Methodsmentioning

confidence: 99%

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Inducible nitric oxide synthase contributes to intermittent hypoxia against ischemia/reperfusion injury1

Ding

Zhu

Dong

et al. 2005

Acta Pharmacologica Sinica

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Aim: To investigate the role of inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) in the cardioprotection of intermittent hypoxia (IH) against ischemia/reperfusion (I/R) injury. Methods: Langendorff-perfused isolated rat hearts were used to measure variables of left ventricular function during baseline perfusion, ischemia, and reperfusion period. Nitrate plus nitrite (NOx) content in myocardium was measured using a biochemical method. iNOS mRNA and protein expression in rat left ventricles were detected using reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. Results: Myocardial function recovered better in IH rat hearts than in normoxic control hearts. The iNOS-selective inhibitor aminoguanidine (AG) (100 µmol/L) significantly inhibited the protective effects of IH, but had no influence on normoxic rat hearts. The baseline content of NOx in IH hearts was higher than that in normoxic hearts. After 30 min ischemia, the NOx level in normoxic hearts increased compared to the corresponding baseline level, whereas there was no significant change in IH hearts. However, the NOx level in IH hearts was still higher than that of normoxic hearts during ischemia and reperfusion period. AG 100 µmol/L significantly diminished the NOx content in IH and normoxic hearts during ischemia and reperfusion period. The baseline levels of iNOS mRNA and protein in IH hearts were higher than those of normoxic hearts. Compared to the corresponding baseline level, iNOS mRNA and protein levels in normoxic rat hearts increased and those in IH rat hearts decreased after reperfusion. The addition of AG 100 µmol/L significantly decreased iNOS mRNA and protein expression in IH rat hearts after I/R. Conclusion: IH upregulated the baseline level of iNOS mRNA and protein expression leading to an increase in NO production, which may play an important role in the cardiac protection of IH against I/R injury.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Inducible nitric oxide synthase contributes to intermittent hypoxia against ischemia/reperfusion injury1

Ding

Zhu

Dong

et al. 2005

Acta Pharmacologica Sinica

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“…Adaptation to chronic hypoxia has been shown to confer the heart an improved tolerance to all major deleterious consequences of acute O 2 deprivation, resulting in cardioprotection, in a similar way to preconditioning (98). NO has been extensively proposed as one of the molecular messengers involved in this type of adaptation (6). However, the subcellular localization and the identity of the NOS implicated in the increased tolerance to ischemic injury remains to be fully established.…”

Section: Role Of No In the Regulation Of Heart Functionmentioning

confidence: 99%

Strategic localization of heart mitochondrial NOS: a review of the evidence

Zaobornyj

Ghafourifar²

2012

American Journal of Physiology-Heart and Circulatory Physiology

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chondria play a central role in cell energy provision and in signaling. Nitric oxide (NO) is a free radical with primary regulatory functions in the heart and involved in a broad array of key processes in cardiac metabolism. Specific NO synthase (NOS) isoforms are confined to distinct locations in cardiomyocytes. The present article reviews the chemical reactions through which NO interacts with biomolecules and exerts some of its crucial roles. Specifically, the article discusses the reactions of NO with mitochondrial targets and the subcellular localization of NOS within the myocardium and analyzes the available data about heart mitochondrial NOS activity and identity. The article also describes the regulation of heart mtNOS by the distinctive mitochondrial environment by showing the effects of Ca 2ϩ , O2, L-arginine, mitochondrial transmembrane potential, and the metabolic states on heart mitochondrial NO production. The article depicts the effects of NO on heart function and highlights the relevance of NO production within mitochondria. Finally, the evidence on the functional implications of heart mitochondrial NOS is delineated with emphasis on chronic hypoxia and ischemia-reperfusion studies. mitochondrial nitric oxide synthase; calcium; transmembrane potential; hypoxia; ischemia-reperfusion SINCE THE RECOGNITION OF MITOCHONDRIA as the powerhouses of the cells, numerous studies have shown that these organelles play a central role in various biological processes. Under physiological conditions, mitochondria provide the cell with both the energy and the signals involved in the genetic expression and metabolic regulation (35). About two decades ago, the discovery that nitric oxide (NO) is the endothelium-derived relaxing factor caused a paradigm shift in the understanding of cardiovascular physiology and pathophysiology (68,102). NO is a gaseous uncharged 30-Da molecule. It is highly diffusible in aqueous and lipid phases and possesses a biochemistry that supports its role as one of the most versatile molecules in various biological regulatory and signaling processes (76,86,134).In the cardiovascular system, NO plays integral roles not only in the regulation of vascular smooth muscle tone but also in the function of ion channels, myocyte contraction, O 2 consumption, apoptosis, and hypertrophic myocardial remodeling (36, 92). In cardiac endothelial cells and myocytes, NO is generated by NO synthase (NOS) isozymes: neuronal NOS (nNOS or NOS1), inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3) (71, 75). Initially, eNOS was considered to be the only isoform constitutively expressed in myocytes and thus the source of NO involved in the autocrine regulation of myocardial contraction and Ca 2ϩ homeostasis (7, 37). However, subsequent studies showed that NOS is targeted to the cardiac sarcoplasmic reticulum (SR) (137) and localized in cardiac mitochondria (72). Additionally, iNOS has been shown to be expressed in the myocardium upon induction by cytokines (8) during inflammatory responses implicated in...

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“…6 These data confirm that shifting the balance of ·NO and superoxide toward superoxide increases susceptibility to ischemic injury and that restoring ·NO increases resistance to ischemia as proposed earlier. 2,14 …”

Section: Effects Of Geldanamycin and Gsno On Functional Recoverymentioning

confidence: 99%

Chronic Hypoxia Increases Endothelial Nitric Oxide Synthase Generation of Nitric Oxide by Increasing Heat Shock Protein 90 Association and Serine Phosphorylation

Shi

Baker

Zhang

et al. 2002

Circulation Research

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Abstract-Chronic hypoxia increases endothelial nitric oxide synthase (eNOS) production of nitric oxide (·NO) and cardioprotection in neonatal rabbit hearts. However, the mechanism by which this occurs remains unclear. Recent studies suggest that heat shock protein 90 (hsp90) alters eNOS function. In the present study, we examined the role of hsp90 in eNOS-dependent cardioprotection in neonatal rabbit hearts. Chronic hypoxia increased recovery of postischemic left ventricular developed pressure (LVDP). Geldanamycin (GA), which inhibits hsp90 and increases oxidative stress, decreased functional recovery in normoxic and hypoxic hearts. To determine if a loss in ·NO, afforded by GA, decreased recovery, GA-treated hearts were perfused with S-nitrosoglutathione (GSNO) as a source of ·NO. GSNO increased recovery of postischemic LVDP in GA-treated normoxic and hypoxic hearts to baseline levels. Although chronic hypoxia decreased phosphorylated eNOS (S1177) levels by Ϸ4-to 5-fold and total Akt and phosphorylated Akt by 4-and 5-fold, it also increased hsp90 association with eNOS by more than 3-fold. Using hydroethidine (HEt), a fluorescent probe for superoxide, we found that hypoxic hearts contained less ethidine (Et) staining than normoxic hearts. Normoxic hearts generated 3 times more superoxide by an N -nitro-L-arginine methyl ester (L-NAME)-inhibitable mechanism than hypoxic hearts. Taken together, these data indicate that the association of hsp90 with eNOS is important for increasing ·NO production and limiting eNOS-dependent superoxide anion generation. Such changes in eNOS function appear to play a critical role in protecting the myocardium against ischemic injury. (Circ Res. 2002;91:300-306.) Key Words: chronic hypoxia Ⅲ endothelial NOS Ⅲ heat shock protein 90 Ⅲ superoxide anion Ⅲ nitric oxide N itric oxide plays an important role in protecting the heart against ischemic injury. S-nitrosoglutathione (GSNO), a nitric oxide (·NO) donor, improves functional recovery after ischemia, which is associated with increased cGMP. 1 Chronic hypoxia from birth in a neonatal rabbit model increases recovery of postischemic left ventricular developed pressure (LVDP) compared with recovery in normoxic hearts. 2 It is important to note that nitric oxide synthase (NOS) inhibitors, N -nitro-Larginine methyl ester (L-NAME) and N G -methyl-L-arginine (L-NMA), decrease functional recovery of postischemic LVDP in hypoxic hearts after ischemia but do not decrease recovery in normoxic hearts. 2,3 These findings suggest that chronic hypoxia may alter the function of endothelial nitric oxide synthase (eNOS), the most abundant NOS isozyme in the rabbit heart, to increase cardioprotection. 2 An increase in the association of heat shock protein 90 (hsp90) with eNOS increases production and activity of ·NO in response to growth factor stimulation. 4 Disruption of this protein-protein interaction decreases ·NO and blocks vasodilation in response to agonists. 4 -7 Geldanamycin (GA), which inhibits conformational changes in hsp90 8 and increases ox...

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Adaptation to Chronic Hypoxia Confers Tolerance to Subsequent Myocardial Ischemia by Increased Nitric Oxide Production

Cited by 56 publications

References 39 publications

Inducible nitric oxide synthase contributes to intermittent hypoxia against ischemia/reperfusion injury1

Inducible nitric oxide synthase contributes to intermittent hypoxia against ischemia/reperfusion injury1

Strategic localization of heart mitochondrial NOS: a review of the evidence

Chronic Hypoxia Increases Endothelial Nitric Oxide Synthase Generation of Nitric Oxide by Increasing Heat Shock Protein 90 Association and Serine Phosphorylation

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