Enhanced gene expression of calcium regulatory proteins in stunned porcine myocardium

Frass, Oliver M.; Sharma, Hari Shanker; Knöll, Ralph; Duncker, Dirk J.; McFalls, Edward O.; Verdouw, Pieter D.; Schäper, Wolfgang

doi:10.1093/cvr/27.11.2037

Cited by 46 publications

(29 citation statements)

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“…Schaper's laboratory provided pioneering studies on alterations in gene expression in swine models of ischemia͞reperfusion (20,26). These studies examined specifically the time course of changes in genes encoding protooncogenes and calcium-handling proteins (20,26). In contrast, we applied recently developed techniques of gene screening to determine the global change in gene expression in response to transient ischemia, rather than selecting specific targets.…”

Section: Discussionmentioning

confidence: 99%

Gene program for cardiac cell survival induced by transient ischemia in conscious pigs

Depré

Tomlinson

Kudej

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Therapy for ischemic heart disease has been directed traditionally at limiting cell necrosis. We determined by genome profiling whether ischemic myocardium can trigger a genetic program promoting cardiac cell survival, which would be a novel and potentially equally important mechanism of salvage. Although cardiac genomics is usually performed in rodents, we used a swine model of ischemia͞reperfusion followed by ventricular dysfunction (stunning), which more closely resembles clinical conditions. Gene expression profiles were compared by subtractive hybridization between ischemic and normal tissue of the same hearts. About one-third (23͞74) of the nuclear-encoded genes that were upregulated in ischemic myocardium participate in survival mechanisms (inhibition of apoptosis, cytoprotection, cell growth, and stimulation of translation). The specificity of this response was confirmed by Northern blot and quantitative PCR. Unexpectedly, this program also included genes not previously described in cardiomyocytes. Up-regulation of survival genes was more profound in subendocardium over subepicardium, reflecting that this response in stunned myocardium was proportional to the severity of the ischemic insult. Thus, in a swine model that recapitulates human heart disease, nonlethal ischemia activates a genomic program of cell survival that relates to the time course of myocardial stunning and differs transmurally in relation to ischemic stress, which induced the stunning. Understanding the genes up-regulated during myocardial stunning, including those not previously described in the heart, and developing strategies that activate this program may open new avenues for therapy in ischemic heart disease.apoptosis ͉ gene expression ͉ stunning O ne of the most important therapeutic targets in the treatment of cardiovascular disease has been the protection of ischemic myocardium from necrosis. This has been a major focus for basic and applied research over the past 30 years. More recently, mechanisms of programmed cardiac cell death (apoptosis) have also been studied extensively. Both necrosis and apoptosis result in the irreversible loss of contractile performance. An unexplored corollary to protection from cell death is the enhancement of cell survival. Our hypothesis is that myocardial ischemia elicits a genomic profile promoting cell survival, which would include the up-regulation of genes involved in prevention of apoptosis, cytoprotection, and cell growth. If a program of cell survival can be stimulated in the ischemic heart, it would represent a novel and important therapeutic strategy in the future.To address this hypothesis, we examined the genomic profile of ischemic myocardium in a model that is most relevant to clinical conditions, i.e., a swine model of transient ischemia.Although the majority of investigations on myocardial ischemia are conducted in rodent models, major differences exist between rodents and larger mammals (differences in heart rate, action potential, and calcium handling) (1, 2). We reasoned that th...

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Section: Discussionmentioning

confidence: 99%

Gene program for cardiac cell survival induced by transient ischemia in conscious pigs

Depré

Tomlinson

Kudej

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…3) as well as stunned myocardium (7,12). Because intracellular Ca 2ϩ overload is known to occur in I/R hearts (25, 26) and hypoxia-reoxygenated hearts (24), it is possible that intracellular Ca 2ϩ overload may produce alterations at the level of SR gene expression in I/R hearts.…”

Section: Discussionmentioning

confidence: 99%

“…More studies are needed to investigate the transcription factors regulating the expression of each gene under different diseased conditions. Studies conducted by Schaper and co-workers (7,12) showed an increase in the transcript levels for SERCA2a, PLB, and CQS due to one cycle of 10-min coronary occlusion and 90-min reperfusion (7), whereas two cycles of 10-min coronary occlusion followed by 60-min reperfusion under in vivo conditions showed a tendency toward a decrease in the mRNA levels. In fact, transcriptional modulation has been implicated as a major player in alterations of SR gene expression in cardiac pathology (12) as well as during cardiac differentiation and myogenesis (13,17).…”

Section: Discussionmentioning

confidence: 99%

Preconditioning prevents alterations in cardiac SR gene expression due to ischemia-reperfusion

Temsah

Kawabata

Chapman

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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Temsah, Rana M., Kenichi Kawabata, Donald Chapman, and Naranjan S. Dhalla. Preconditioning prevents alterations in cardiac SR gene expression due to ischemiareperfusion. Am J Physiol Heart Circ Physiol 282: H1461-H1466, 2002; 10.1152/ajpheart.00447.2001.-We have previously shown that ischemic preconditioning (IP) improves cardiac performance and sarcoplasmic reticulum (SR) function in hearts subjected to ischemia-reperfusion (I/R). In this study, we examined the effect of IP on I/R-induced changes in gene expression for SR proteins such as the Ca 2ϩ release channel, Ca 2ϩ pump ATPase, phospholamban, and calsequestrin in the isolated rat heart. Normal isolated rat hearts exposed to three brief cycles of IP (5-min ischemia and 5-min reperfusion) exhibited a significant decrease in the transcript levels of SR genes. Nonpreconditioned I/R hearts when subjected to 30-min ischemia and 30-min reperfusion showed a marked decrease in mRNA levels for the SR proteins compared with normal hearts; this decrease was attenuated by preconditioning. Although hearts subjected to Ca 2ϩ paradox (CP) have been shown to exhibit intracellular Ca 2ϩ overload and SR dysfunction like those in I/R hearts, virtually nothing is known regarding the effect of CP on cardiac SR gene expression. Accordingly, CP (5-min Ca 2ϩ -free perfusion and 30-min reperfusion with normal medium) was observed to produce dramatic changes in SR gene expression, and the heart failed to contract; these alterations were attenuated by IP. Our results show that 1) both I/R and CP depress SR gene expression in the normal heart, 2) IP attenuates I/R-and CP-induced depression in cardiac function and SR gene expression, and 3) intracellular Ca 2ϩ overload may play a role in depressing SR gene expression in both I/R and CP hearts. ischemic preconditioning; ischemia-reperfusion; cardiac mRNA levels; Ca 2ϩ paradoxic heart ISCHEMIC PRECONDITIONING (IP) was first defined by Murry et al. (14) as repetitive cycles of brief ischemia and reperfusion that protected the heart against a subsequent period of prolonged ischemic injury. IP has been shown to enhance the recovery of cardiac function (4, 16), decrease the incidence of arrhythmias (8,19), and reduce infarct size (8) in hearts subjected to ischemia-reperfusion (I/R) injury. Several endogenous mediators such as adenosine, norepinephrine, protein kinase C, and free radicals have been proposed to mediate the beneficial effects of IP (11). Earlier, we (9) reported that IP improved cardiac performance not only in hearts exposed to I/R (16) but also in hearts subjected to Ca 2ϩ paradox (CP). CP is known to occur as a consequence of a brief period of Ca 2ϩ depletion followed by Ca 2ϩ repletion (28) and is considered to be an appropriate model for studying the effect of intracellular Ca 2ϩ overload as a contributing factor in the pathogenesis of cardiac dysfunction (1, 2).By virtue of its ability to regulate the intracellular concentration of free Ca 2ϩ , the sarcoplasmic reticulum (SR) plays a central role in the cardiac contracti...

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“…In the porcine model of myocardial stunning (two periods of 10 rain coronary artery occlusion separated by 30 rain reperfusion) we and others have shown that reperfusion leads to the induction of several genes encoding proto-oncogenes [50,51], Ca 2+ binding proteins [52] and heat shock proteins (HSPs) [45,[53][54][55][56][57][58][59]. It has been observed that brief periods of myocardial ischemia and reperfusion do not only cause prolonged contractile dysfunction, but also increase the tolerance for irreversible damage during a subsequent sustained episode of ischemia ("ischemic preconditioning").…”

Section: Myocardial Stunningmentioning

confidence: 99%

Involvement of the sarcoplasmic reticulum calcium pump in myocardial contractile dysfunction: Comparison between chronic pressure-overload and stunning

Sharma

Verdouw

Lamers

1994

Cardiovasc Drug Ther

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Summary. Acute as well as chronic forms of heart failure involve mechanical dysfunction during systole and/or diastole. The rapid Ca 2+ release from and Ca ~+ reuptake into the tubuli of the sarcoplasmic reticulum are processes that critically determine normal systolic and diastolic myocardial function, which explains why in the last fifteen years so much attention has been paid to understand the performance of the sarcoplasmic reticulum Ca 2+ pump during myocardial contractile dysfunction. In this communication we have reviewed the literature data on sarcoplasmic reticulum Ca 2+ pump function in the chronically pressure-overloaded hypertrophied and stunned (post-ischemic reversibly injured) myocardium in the light of some new data from our laboratory. Results on the pressure-overloaded hypertrophied myocardium provide evidence that impaired relaxation is most likely due to a low capacity of the sarcoplasmic reticulum to pump Ca 2+, a consequence of a lower density of Ca2+-pumping sites within the sarcotubular membranes. Contractile dysfunction in stunned myocardium is accompanied by an upregulation of the sarcoplasmic reticulum Ca ~ + ATPase gene resulting in a slight increase of the Ca2 + pumping activity. The latter increase is likely an adaptive response of the reversibly injured myocardium which may contribute to the slow recovery of contractile function.Cardiovasc Drugs Ther 1994;8:461-468 Key Words. sarcoplasmic reticulum, Ca ~+ pump, hypertrophy, stunning, cardiac failureNormal systolic and diastolic function of the heart requires the release and reuptake of Ca 2+. The contractile state of the heart can be altered by two mechanisms which are both Ca 2+ dependent: changes in the availability of Ca ~÷ to the contractile proteins and changes in the responsiveness of the contractile proteins to activation by intracellular Ca 2+ [1]. The availability of intracellular Ca ~÷ is regulated by the sarcolemma (SL) and sarcoplasmic reticulum (SR) and the Ca 2+ responsiveness is controlled by the myofilaments and regulatory troponin-tropomyosin complex. Excitation-contraction (E-C) coupling is initiated when Ca 2+ channels are opened by depolarization of SL permitting Ca 2+ to enter the cytoplasm. This small Ca 2+ influx induces the release of a much larger quantity of activated Ca 2÷ from the intraeellutar stores in the SR [2,3]. The released Ca 2+ interacts with troponin C, which is part of the regulatory complex of the myofilaments, thereby initiating cardiac contraction. Relaxation starts when Ca 2+ is sequestered by the SR Ca 2+ pump, so that Ca2 ÷ dissociates from the contractile apparatus. Abnormal handling of intracellutar Ca ~+ at any of the steps in E-C coupling can cause cardiae contractile dysfunction and leads to failure. The signalling function of Ca 2+ demands a very low ionic concentration of Ca 2+ inside the myocardial cells (about 10,000 fold lower than outside) and significant changes can therefore be achieved easily. During each depolarization only a very small amount of Ca ~* entering the cell...

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Enhanced gene expression of calcium regulatory proteins in stunned porcine myocardium

Abstract: The results suggest specific repair mechanisms of stunned myocardium and point to the involvement of calcium regulatory proteins related to the sarcoplasmic reticulum in the pathogenesis of myocardial stunning.

Cited by 46 publications

References 0 publications

Gene program for cardiac cell survival induced by transient ischemia in conscious pigs

Gene program for cardiac cell survival induced by transient ischemia in conscious pigs

Preconditioning prevents alterations in cardiac SR gene expression due to ischemia-reperfusion

Involvement of the sarcoplasmic reticulum calcium pump in myocardial contractile dysfunction: Comparison between chronic pressure-overload and stunning

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