Defective calcium handling in cardiomyocytes isolated from hearts subjected to ischemia-reperfusion

Saini, Harjot K.; Dhalla, Naranjan S.

doi:10.1152/ajpheart.01153.2004

Cited by 54 publications

(77 citation statements)

References 45 publications

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“…Whereas state 3 respiration was not altered in any experimental group, SOD plus CAT mixture was observed to increase the mitochondrial state 3 and uncoupled respiration as well as RCI and OPR in control hearts. Similar effects of SOD plus CAT mixture in control preparations were also observed with respect to KCl-and ATP-induced increase in intracellular [Ca 2ϩ ] in cardiomyocytes (36,37); however, no attempt was made to explain the effects of SOD plus CAT.…”

Section: Effect Of Oxyradical Scavenging Mixture On I/r Heartsmentioning

confidence: 66%

“…In some experiments, global ischemia was induced for 20 min followed by 30 min of reperfusion. Antioxidant treatment of I/R hearts was carried out by infusion of a mixture of SOD (5 ϫ 10 4 U/l; Sigma-Aldrich, Oakville, ON, Canada) plus CAT (7.5 ϫ 10 4 U/l; Fisher Scientific, Nepean, ON, Canada), N-acetyl-L-cysteine (NAC; 100 M; Sigma-Aldrich) or N-2-mercaptopropionylglycine (MPG, 300 M; Sigma-Aldrich) for 10 min before ischemia and during the reperfusion period as described previously (2,14,36,37,41). The effect of antioxidant treatment with SOD plus CAT, NAC, or MPG on mechanical function and mitochondrial activity of the nonischemic hearts was examined according to the same protocol, except that no global ischemia was induced.…”

Section: Methodsmentioning

confidence: 99%

“…Mitochondrial preparation was loaded with fura-2 AM in a manner similar to that described elsewhere (36). Ca 2ϩ uptake was measured in fura-2 AM-loaded mitochondria in the presence of different concentrations of extracellular Ca 2ϩ .…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies have indicated that changes in sarcolemmal and sarcoplasmic reticular membranes lead to the development of Ca 2ϩ -handling abnormalities and intracellular Ca 2ϩ overload due to the occurrence of oxidative stress in the I/R hearts (15,25,29,36,37,42,48). On the other hand, only scattered and conflicting information regarding the status of mitochondrial function with respect to their respiratory and oxidative phosphorylation activities in the I/R hearts is available in the literature (3,19).…”

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confidence: 99%

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Role of oxidative stress in alterations of mitochondrial function in ischemic-reperfused hearts

Makazan¹,

Saini²,

Dhalla³

2007

American Journal of Physiology-Heart and Circulatory Physiology

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Makazan Z, Saini HK, Dhalla NS. Role of oxidative stress in alterations of mitochondrial function in ischemic-reperfused hearts. Am J Physiol Heart Circ Physiol 292: H1986 -H1994, 2007. First published December 15, 2006; doi:10.1152/ajpheart.01214.2006.-To study the mechanisms of mitochondrial dysfunction due to ischemiareperfusion (I/R) injury, rat hearts were subjected to 20 or 30 min of global ischemia followed by 30 min of reperfusion. After recording both left ventricular developed pressure (LVDP) and end-diastolic pressure (LVEDP) to monitor the status of cardiac performance, mitochondria from these hearts were isolated to determine respiratory and oxidative phosphorylation activities. Although hearts subjected to 20 min of ischemia failed to generate LVDP and showed a marked increase in LVEDP, no changes in mitochondrial respiration and phosphorylation were observed. Reperfusion of 20-min ischemic hearts depressed mitochondrial function significantly but recovered LVDP completely and lowered the elevated LVEDP. On the other hand, depressed LVDP and elevated LVEDP in 30-min ischemic hearts were associated with depressions in both mitochondrial respiration and oxidative phosphorylation. Reperfusion of 30-min ischemic hearts elevated LVEDP, attenuated LVDP, and decreased mitochondrial state 3 and uncoupled respiration, respiratory control index, ADP-to-O ratio, as well as oxidative phosphorylation rate. Alterations of cardiac performance and mitochondrial function in I/R hearts were attenuated or prevented by pretreatment with oxyradical scavenging mixture (superoxide dismutase and catalase) or antioxidants [N-acetyl-L-cysteine or N-(2-mercaptopropionyl)-glycine]. Furthermore, alterations in cardiac performance and mitochondrial function due to I/R were simulated by an oxyradical-generating system (xanthine plus xanthine oxidase) and an oxidant (H 2O2) either upon perfusing the heart or upon incubation with mitochondria. These results support the view that oxidative stress plays an important role in inducing changes in cardiac performance and mitochondrial function due to I/R. cardiac performance; oxidative phosphorylation; mitochondrial respiration; oxyradicals; antioxidants BY VIRTUE OF THEIR ABILITY to carry on the processes of oxidative phosphorylation and electron transport, mitochondria are the major source of energy production in the form of ATP, which is required for cardiac contraction and relaxation (19,26,46). Mitochondria are also known to accumulate a substantial amount of Ca 2ϩ and are considered to serve as a sink to maintain the intracellular concentration of free Ca 2ϩ within certain limits (18,19,26). However, an excessive amount of intracellular Ca 2ϩ results in the overloading of mitochondria with Ca 2ϩ

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Section: Effect Of Oxyradical Scavenging Mixture On I/r Heartsmentioning

confidence: 66%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Role of oxidative stress in alterations of mitochondrial function in ischemic-reperfused hearts

Makazan¹,

Saini²,

Dhalla³

2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…It appears that a critical level of LVEDP needs to be achieved for the occurrence of intracellular Ca 2+ overload for inducing depression in cardiac gene expression in hearts subjected to CP. It should be emphasized that there are varying degrees of depression in SL, SR and MF gene expression, protein content and functional activities in hearts subjected to ischemia-reperfusion and these alterations have been attributed to the occurrence of intracellular Ca 2+ overload (7)(8)(9)(31)(32)(33)(34)(35)(36)38). Furthermore, intracellular Ca 2+ overload has been suggested to play a critical role in the development of alterations in SL, SR and MF gene expression, protein content and functional activities in hearts failing due to myocardial infarction (1)(2)(3)(4)(5)(6).…”

Section: Discussionmentioning

confidence: 99%

Role of intracellular Ca2+ overload in inducing changes in cardiac gene expression

Özçeli̇kay¹,

Chapman²

2014

Curr Res Cardiol

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Normal expression of cardiac genes for Ca 2+ transport and contractile proteins is known to play a critical role in the maintenance of the function of subcellular organelles such as sarcolemma (SL), sarcoplasmic reticulum (SR) and myofibrils (MFs) in cardiomyocytes. Previous studies have revealed varying degrees of depression in gene expression for SL, SR and MF proteins, as well as defects in subcellular organelles during the development of heart failure in patients and experimental animal models (1-6). Accordingly, it has been suggested that cardiac dysfunction in failing hearts is due to subcellular remodelling as a consequence of changes in cardiac gene expression (2,(7)(8)(9). Although the occurrence of intracellular Ca 2+ overload is believed to be intimately involved in the genesis of cardiac dysfunction in heart failure (10-15), its role in inducing defects in cardiac gene expression is not fully understood. It was, therefore, the purpose of the present study to investigate whether alterations in gene expression of SL, SR and MF proteins occur during the development of intracellular Ca 2+ overload in the myocardium.Isolated heart reperfused with high concentrations of Ca 2+ following a brief period of perfusion with Ca 2+ -free medium has been demonstrated to be an excellent model (Ca 2+ paradox [CP]) for investigating the effects of intracellular Ca 2+ overload (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). We have reported that the inability of CP hearts to recover contractile function was associated with a marked increase in intracellular Ca 2+ , as well as the development of cardiac contracture, ultrastructural damage and subcellular defects (11,13,15,16,21,23). In the present study, we examined whether hearts perfused with Ca 2+ -free medium followed by reperfusion with medium containing different concentrations of Ca 2+ exhibit alterations in gene expression for SL Na + -K + ATPase and Na + -Ca 2+ exchanger, SR Ca 2+ -pump ATPase, Ca 2+ -release channel and phospholamban (PLB), as well as MF α-and β-myosin heavy chain proteins. Because subcellular remodelling in the failing heart is dependent on the balance between changes in gene expression and activities of proteolytic enzymes, such as calpain (27-33), messenger RNA (mRNA) levels for both calpain-1 and calpain-2 were measured in CP hearts. It may be noted that subcellular remodelling in failing hearts has also been suggested to be the result of activation of different proteolytic enzymes (27,28). METHODSMale Sprague Dawley rats, each weighing 250 g to 300 g, were used in the present study. All experiments were conducted according to the protocol approved by the Animal Care Committee of the University of Manitoba (Winnipeg, Manitoba) as per guidelines established by the Canadian Council on Animal Care. Isolated hearts were perfused according to the Langendorff technique with Krebs-Henselite medium (gassed with 95% O 2 and 5% CO 2 ) containing 1.25 mM Ca 2+ at 37°C for 20 min. The left ventricular developed pressure and the left ventricular end dias...

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Subcellular Remodeling and Cardiac Dysfunction Due to Ischemia–Reperfusion Injury

et al. 2013

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Defective calcium handling in cardiomyocytes isolated from hearts subjected to ischemia-reperfusion

Cited by 54 publications

References 45 publications

Role of oxidative stress in alterations of mitochondrial function in ischemic-reperfused hearts

Role of oxidative stress in alterations of mitochondrial function in ischemic-reperfused hearts

Role of intracellular Ca2+ overload in inducing changes in cardiac gene expression

Subcellular Remodeling and Cardiac Dysfunction Due to Ischemia–Reperfusion Injury

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