Amelioration of ischemic calcium overload correlates with high-energy phosphates in senescent myocardium

Tsukube, Takuro; McCully, James D.; Metz, Kenneth R.; Cook, Colin U.; Levitsky, Sidney

doi:10.1152/ajpheart.1997.273.1.h418

Cited by 39 publications

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“…These effects are ameliorated by CP. In this report and in previous studies, we have shown that CP significantly preserves mitochondrial structure and function and significantly enhances the preservation and resynthesis of ATP levels (11,22,29,41). These effects resulted is a significant enhancement of postischemic functional recovery and myocardial cellular and sarcomere structural preservation (22,29).…”

Section: Resultssupporting

confidence: 58%

Transcriptomic and proteomic analysis of global ischemia and cardioprotection in the rabbit heart

McCully

Bhasin

Daly

et al. 2009

Physiological Genomics

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scriptomic and proteomic analysis of global ischemia and cardioprotection in the rabbit heart. Physiol Genomics 38: 125-137, 2009. First published May 19, 2009 doi:10.1152/physiolgenomics.00033.2009Cardioplegia is used to partially alleviate the effects of surgically induced global ischemia injury; however, the molecular mechanisms involved in this cardioprotection remain to be elucidated. To improve the understanding of the molecular processes modulating the effects of global ischemia and the cardioprotection afforded by cardioplegia, we constructed rabbit heart cDNA libraries and isolated, sequenced, and identified a compendium of nonredundant cDNAs for use in transcriptomic and proteomic analyses. New Zealand White rabbits were used to compare the effects of global ischemia and cardioplegia compared with control (nonischemic) hearts. The effects of RNA and protein synthesis on the cardioprotection afforded by cardioplegia were investigated separately by preperfusion with either ␣-amanitin or cycloheximide. Our results demonstrate that cardioplegia partially ameliorates the effects of global ischemia and that the cardioprotection is modulated by RNA-and protein-dependent mechanisms. Transcriptomic and proteomic enrichment analyses indicated that global ischemia downregulated genes/proteins associated with mitochondrial function and energy production, cofactor catabolism, and the generation of precursor metabolites of energy. In contrast, cardioplegia significantly increased differentially expressed genes/proteins associated with the mitochondrion and mitochondrial function and significantly upregulated the biological processes of muscle contraction, involuntary muscle contraction, carboxylic acid and fatty acid catabolic processes, fatty acid ␤-oxidation, and fatty acid metabolic processes. mitochondrion; ischemia-reperfusion MYOCARDIAL ISCHEMIA-REPERFUSION INJURY occurs as the result of the attenuation or cessation of coronary blood flow such that oxygen delivery to the myocardium is insufficient to meet energy demands. The cessation of myocardial coronary blood flow induces a cascade of cellular events that rapidly alter myocardial cellular homeostasis, leading to cellular dysfunction and/or death and postischemic functional impairment (23).To alleviate the effects of surgically induced ischemia/ reperfusion injury, surgeons use cardioplegia (CP) solutions that allow for the rapid electromechanical arrest of the myocardium through the alteration of cellular electrochemical gradients (40). In a series of studies, we have shown that magnesium-supplemented potassium CP with the addition of diazoxide significantly decreases myocardial cell death and significantly enhances postischemic functional recovery (22,40,43).The mechanisms through which CP affords cardioprotection are complex and cannot be investigated as a single entity; rather, they must be investigated as a system. In previous reports, we and others have used a variety of methods to identify the RNAs and proteins associated with global ischemia (GI) a...

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Section: Resultssupporting

confidence: 58%

Transcriptomic and proteomic analysis of global ischemia and cardioprotection in the rabbit heart

McCully

Bhasin

Daly

et al. 2009

Physiological Genomics

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“…These data indicate that a lack of AMPK activation does not play a role in the poor hypoxic tolerance of the old heart. Rather, the accelerated activation of the ␣2-isoform of AMPK in the aged heart could be regarded as an adaptive or compensatory response to the more severe energetic deterioration that others have reported (6,25,28,31).…”

Section: Discussionmentioning

confidence: 99%

Effects of aging on cardiac and skeletal muscle AMPK activity: basal activity, allosteric activation, and response to in vivo hypoxemia in mice

González¹,

Kumar²,

Mulligan³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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. Effects of aging on cardiac and skeletal muscle AMPK activity: basal activity, allosteric activation, and response to in vivo hypoxemia in mice. Am J Physiol Regul Integr Comp Physiol 287: R1270 -R1275, 2004. First published July 29, 2004 doi:10.1152/ajpregu.00409.2004.-Although a diminished ability of tissues and organisms to tolerate stress is a clinically important hallmark of normal aging, little is known regarding its biochemical basis. Our goal was to determine whether age-associated changes in AMP-activated protein kinase (AMPK), a key regulator of cellular metabolism during the stress response, might contribute to the poor stress tolerance of aged cardiac and skeletal muscle. Basal AMPK activity and the degree of activation of AMPK by AMP and by in vivo hypoxemia (arterial PO2 of 39 mmHg) were measured in cardiac and skeletal muscle (gastrocnemius) from 5-and 24-mo-old C57Bl/6 mice. In the heart, neither basal AMPK activity nor its allosteric activation by AMP was affected by age. However, after 10 min of hypoxemia, the activity of ␣2-AMPK, but not ␣1-AMPK, was significantly higher in the hearts from old than from young mice (P Ͻ 0.005), this difference being due to differences in phosphorylation of ␣2-AMPK. Significant activation of AMPK in the young hearts did not occur until 30 min of hypoxemia (P Ͻ 0.01), stress that was poorly tolerated by the old mice (mortality ϭ 67%). In contrast, AMPK activity in gastrocnemius muscle was unaffected by age or hypoxemia. We conclude that the age-associated decline in hypoxic tolerance in cardiac and skeletal muscle is not caused by changes in basal AMPK activity or a blunted AMPK response to hypoxia. Activation of AMPK by in vivo hypoxia is slower and more modest than might be predicted from in vitro and ex vivo experiments.

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“…The aged myocardium is characterized by anatomic, mechanical, ultrastructual and biochemical changes that compromise adaptive response of the heart [3,4]. It has been shown that these aging-related changes affect calcium homeostasis and cause increased cytosolic calcium ([Ca 2+ ] i ) accumulation during normothermic ischemia, leading to reduced functional recovery in the aged heart [5,6]. In addition, sarcoplasmic reticulum Ca 2+ -ATPase protein (SERCA2a) which uptakes [Ca 2+ ] i into sarcoplasmic reticulum is known to be downregulated in the aged heart [7,8].…”

Section: Introductionmentioning

confidence: 99%

Na<sup>+</sup>/H<sup>+</sup> Exchanger Inhibitor HOE642 Offers Myoprotection in Senescent Myocardium Independent of Ischemic Preconditioning Mechanisms

Nakai¹,

Horimoto²,

Mieno³

et al. 2002

Eur Surg Res

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Background: Inhibition of Na⁺/H⁺ exchange has been shown to provide functional protection during ischemia and reperfusion in mature heart. This study was undertaken to elucidate the effect of Na⁺/H⁺ exchange inhibitor HOE642 in the aged rabbit heart. Methods: Isolated rabbit hearts were subjected to 1 h of left descending coronary artery (LAD) ischemia and 1 h of reperfusion. To determine the effects of HOE642 on ischemia/reperfusion injury, seven aged or mature hearts received the Na⁺/H⁺ exchange inhibitor HOE642 (1 µM) for 15 min before the ischemia and for 30 min after reperfusion. Seven aged (more than 135 weeks) or mature (15–20 weeks) rabbit hearts served as a control (untreated) with no interventions. Left ventricular pressures, monophasic action potentials and coronary flows were measured throughout the experiment and infarct size was detected at the end of experiment. Results: (1) In the mature hearts, HOE642 improved postischemic functional recovery (63.1 ± 5.0% vs. 84.4 ± 5.4%, mature untreated vs. mature HOE, p < 0.05) and reduced infarct size as compared to untreated hearts (42.0 ± 2.5% vs. 24.8 ± 2.3%, mature untreated vs. mature HOE, p < 0.05). (2) Although infarct size in aged untreated hearts was significantly decreased as compared to mature untreated hearts (42.0 ± 2.5% vs. 19.3 ± 1.6%, mature untreated vs. aged untreated, p < 0.05), there are no significant differences regarding postischemic functional recovery between mature and aged untreated hearts (63.1 ± 5.0% vs. 59.5 ± 5.9%, mature untreated vs. aged untreated, p = n.s.). (3) In the aged hearts, HOE642 improved postischemic functional recovery as compared to untreated hearts (59.5 ± 5.9% vs. 85.9 ± 8.1%, aged untreated vs. aged HOE, p < 0.05). Conclusion: Na⁺/H⁺ exchange inhibitor HOE642 is effective against ischemia-reperfusion injury in senescent as well as mature hearts.

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Amelioration of ischemic calcium overload correlates with high-energy phosphates in senescent myocardium

Cited by 39 publications

References 0 publications

Transcriptomic and proteomic analysis of global ischemia and cardioprotection in the rabbit heart

Transcriptomic and proteomic analysis of global ischemia and cardioprotection in the rabbit heart

Effects of aging on cardiac and skeletal muscle AMPK activity: basal activity, allosteric activation, and response to in vivo hypoxemia in mice

Na<sup>+</sup>/H<sup>+</sup> Exchanger Inhibitor HOE642 Offers Myoprotection in Senescent Myocardium Independent of Ischemic Preconditioning Mechanisms

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