Cardioprotection with adenosine metabolism inhibitors in ischemic–reperfused mouse heart

Peart, Jason Nigel John; Matherne, Paul; Cerniway, Rachel; Headrick, John P.

doi:10.1016/s0008-6363(01)00360-1

Cited by 42 publications

(53 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data are consistent with and build on previous findings in mouse heart, which demonstrated a role for extracellular Ado and A 1 Ado receptor activation in cardioprotection (Peart et al, 2001). Moreover, this study suggested that cardioprotection may be enhanced by activation of other adenosine receptor subtypes (e.g., A 3 Ado receptors) and that an adenosine salvage pathway was likely to be essential for the full effects of adenosine cardioprotection to be realized.…”

Section: Discussionsupporting

confidence: 92%

The Adenosine Transporter, mENT1, Is a Target for Adenosine Receptor Signaling and Protein Kinase Cϵ in Hypoxic and Pharmacological Preconditioning in the Mouse Cardiomyocyte Cell Line, HL-1

Chaudary

Naydenova²,

Shuralyova³

et al. 2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Brief exposure of the heart to hypoxia results in less cellular damage after subsequent hypoxia, an effect known as preconditioning (PC). PC has been widely studied but is still not fully understood. Adenosine (Ado), adenosine receptors, and protein kinase C (PKC) have been implicated as integral components of PC. Adenosine (nucleoside) transporters (NTs) facilitate flux of Ado across cell membranes, but their role in PC is unknown. Therefore, we used the murine cardiomyocyte cell line, HL-1, and asked if there was feedback regulation of NTs by Ado, Ado receptors, and PKC following either hypoxic or pharmacological PC. Activation (by specific agonists) of A 1 or A 3 Ado receptors or PKC resulted in PC in HL-1. The A 1 (but not A 3 ) receptor is coupled to PKC⑀, and activation of PKC⑀ (by specific peptide agonist) resulted in PC. Moreover, PKC⑀ stimulates Ado uptake via the predominant NT in HL-1, mouse equilibrative nucleoside transporter 1 (mENT1). Studies in primary neonatal mouse cardiomyocytes confirmed our observations in HL-1 cells. Hypoxic challenge led to a rapid increase in, and efflux of, intracellular Ado from cells, which was blocked by NT inhibitors (dipyridamole/nitrobenzylthioinosine). Moreover, NT inhibition during hypoxia or PC was highly protective, suggesting that Ado loss contributes to decreased cell viability. Our data suggest that hypoxic challenge causes an efflux of Ado via ENTs, activation of A 1 and/or A 3 receptors, signaling through PKC⑀, and activation of ENT1. Since Ado is required for ATP synthesis on reperfusion, this feedback regulation of mENT1 would promote reuptake of Ado.Ischemia (reduced blood flow) and hypoxia (reduced oxygen) are serious problems in cardiology, from prenatal to geriatric settings, and we need a better understanding of the causes and consequences of ischemia/hypoxia to develop strategies to combat resultant damage. Although cardiomyocytes cannot rapidly proliferate to replace damaged tissues, they can respond to, and resist, the cellular stress caused by ischemia/hypoxia. Thus, cardiomyocytes are less damaged by ischemia/hypoxia if they have previously been briefly exposed to ischemia/hypoxia, a phenomenon known as ischemic or hypoxic preconditioning

show abstract

Section: Discussionsupporting

confidence: 92%

The Adenosine Transporter, mENT1, Is a Target for Adenosine Receptor Signaling and Protein Kinase Cϵ in Hypoxic and Pharmacological Preconditioning in the Mouse Cardiomyocyte Cell Line, HL-1

Chaudary

Naydenova²,

Shuralyova³

et al. 2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…This corresponds to Ͼ90% inhibition of enzyme activity. Studies in the rat (32) and mouse (227) verify that the majority of adenosine is normally cycled back to 5Ј-AMP and that salvage is markedly inhibited by ischemia. Reduced flux through adenosine kinase has also been reported in deenergized myocytes (295).…”

Section: Generation Of Endogenous Adenosine During Insultmentioning

confidence: 99%

“…Recently, studies employing modulators of adenosine salvage reveal that bypassing phosphorylation enhances ischemic tolerance (226,227). Moreover, protective effects of adenosine are limited by blockade of adenosine kinase, supporting a role for phosphorylation in cardioprotection with adenosine itself (228).…”

Section: Nonreceptor-mediated Cardioprotectionmentioning

confidence: 99%

“…The latter response has been attributed to reduced generation of xanthine oxidase-derived radicals (301) or enhanced purine salvage (27, 130). However, protective actions of adenosine deaminase inhibition are abrogated by adenosine receptor activation, supporting enhanced receptor agonism as the underlying mechanism (227). Indeed, the notion that inhibition of adenosine deaminase substantially limits ROS generation is flawed because the vast majority of postischemic purine catabolism occurs via inosine 5'-monophosphate versus AMP catabolism (38, 117, 227), the kinetics of the xanthine oxidase reaction indicate the path will be saturated by levels of hypoxanthine-xanthine generated during ischemia (301,302), and uric acid generated in the same process is an antioxidant.…”

Section: Nonreceptor-mediated Cardioprotectionmentioning

confidence: 99%

See 1 more Smart Citation

Acute adenosinergic cardioprotection in ischemic-reperfused hearts

Headrick

Hack

Ashton

2003

American Journal of Physiology-Heart and Circulatory Physiology

150

164

View full text Add to dashboard Cite

. Acute adenosinergic cardioprotection in ischemic-reperfused hearts. Am J Physiol Heart Circ Physiol 285: H1797-H1818, 2003; 10.1152/ajpheart.00407. 2003.-Cells of the cardiovascular system generate and release purine nucleoside adenosine in increasing quantities when constituent cells are "stressed" or subjected to injurious stimuli. This increased adenosine can interact with surface receptors in myocardial, vascular, fibroblast, and inflammatory cells to modulate cellular function and phenotype. Additionally, adenosine is rapidly reincorporated back into 5Ј-AMP to maintain the adenine nucleotide pool. Via these receptor-dependent and independent (metabolic) paths, adenosine can substantially modify the acute response to ischemic insult, in addition to generating a more sustained ischemia-tolerant phenotype (preconditioning). However, the molecular basis for acute adenosinergic cardioprotection remains incompletely understood and may well differ from more widely studied preconditioning. Here we review current knowledge and some controversies regarding acute cardioprotection via adenosine and adenosine receptor activation.adenosine; adenosine receptor activation; ischemia; reperfusion injury THE HEART possesses its own intrinsic protective responses, including the adenosine receptor system, which enhance resistance to ischemic insult. An understanding of the mechanisms involved in these responses not only informs us of how the heart reacts to injurious stimuli, but may provide avenues for developing novel protective strategies applicable in the setting of ischemia-reperfusion. The purine nucleoside adenosine was attributed with cardioregulatory functions almost 75 years ago (64), and since then has emerged as a crucially important control substance in essentially every tissue of the body. In the heart adenosine not only plays a role in regulating growth and differentiation, angiogenesis, coronary blood flow, cardiac conduction and heart rate, substrate metabolism, and sensitivity to adrenergic stimulation (23,67,68,73,74,260,271,283), but may play a role as an endogenous determinant of ischemic tolerance (189,225,245,259,311,312,318). From a therapeutic viewpoint, adenosine-based therapies protect against ischemic injury in a variety of animal models (72,177,208,265,288) and in human cardiac tissue (34, 36, 37,240,296). However, much remains unclear regarding the roles and mechanisms of action of adenosine in producing acute protection against ischemia and reperfusion. Generation of Endogenous Adenosine During InsultEndogenous adenosine levels increase rapidly with ischemic insult (104,109,285,286) to mediate a retaliatory response. This protective pool of adenosine can be formed via dephosphorylation of 5Ј-AMP by intra-and extracellular 5Ј-nucleotidases and from S-adenosylhomocysteine (SAH) via SAH hydrolase. Extracellular adenosine is rapidly taken into cells via a facilitative transporter (131). Within cells it is either deaminated by adenosine deaminase or rephosphorylated to 5Ј-AMP via adenosine kinase. O...

show abstract

“…ADENOSINE AND ADENOSINE RECEPTOR agonists have been shown to protect the myocardium from ischemia-reperfusion injury (48)(49)(50). Earlier research focused on the role of the A 1 adenosine receptor (A 1 AR); however, recent evidence suggests that the A 3 adenosine receptor (A 3 AR) may also afford cardioprotection (29,48,50,63).…”

mentioning

confidence: 99%

Adenosine and opioid receptor-mediated cardioprotection in the rat: evidence for cross-talk between receptors

Peart

Gross

2003

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Peart, Jason N., and Garrett J. Gross. Adenosine and opioid receptor-mediated cardioprotection in the rat: evidence for cross-talk between receptors. Am J Physiol Heart Circ Physiol 285: H81-H89, 2003. First published March 13, 2003 10.1152/ajpheart.00985.2002The relative roles of free-radical production, mitochondrial ATP-sensitive K ϩ (mitoKATP) channels and possible receptor cross-talk in both opioid and adenosine A 1 receptor (A1AR) mediated protection were assessed in a rat model of myocardial infarction. Sprague-Dawley rats were subjected to 30 min of occlusion and 90 min of reperfusion. The untreated rats exhibited an infarct of 58.8 Ϯ 2.9% [infarct size (IS)/area at risk (AAR), %] at the end of reperfusion. Pretreatment with either the nonselective opioid receptor agonist morphine or the selective A1AR agonist 2-chloro-cyclopentyladenosine (CCPA) dramatically reduced IS/AAR to 41.1 Ϯ 2.2% and 37.9 Ϯ 5.5%, respectively (P Ͻ 0.05). Protection afforded by either morphine or CCPA was abolished by the reactive oxygen species scavenger N-(2-mercaptopropionyl)glycine or the mitoKATP channel blocker 5-hydroxydecanoate. Both morphine-and CCPA-mediated protection were attenuated by the selective A1AR antagonist 1,3-dipropyl-8-cyclopentylxanthine and the selective ␦ 1-opioid receptor (DOR) antagonist 7-benzylidenealtrexone. Simultaneous administration of morphine and CCPA failed to enhance the infarct-sparing effect of either agonist alone. These data suggest that both DOR and A 1AR-mediated cardioprotection are mitoK ATP and reactive oxygen species dependent. Furthermore, these data suggest that there are converging pathways and/or receptor cross-talk between A 1AR-and DOR-mediated cardioprotection.reactive oxygen species; ATP-sensitive potassium channel ADENOSINE AND ADENOSINE RECEPTOR agonists have been shown to protect the myocardium from ischemia-reperfusion injury (48-50). Earlier research focused on the role of the A 1 adenosine receptor (A 1 AR); however, recent evidence suggests that the A 3 adenosine receptor (A 3 AR) may also afford cardioprotection (29,48,50,63). Both A 1 AR and A 3 AR activation may be important triggers of both early preconditioning (EPC) and delayed preconditioning (DPC) (4, 58, 67); however, separate signaling pathways may be involved (38). Activation of opioid receptors has also been demonstrated to trigger EPC and DPC, primarily through the ␦-opioid receptor (DOR) (45,47,54). Indeed, blockade of the DOR abrogates the infarct-sparing effect of ischemic preconditioning (55).The signal-transduction pathways responsible for both DOR and A 1 /A 3 AR-mediated cardioprotection appear to be similar. A 1 ARs and A 3 ARs activate phospholipase C and phospholipase D, respectively (44). Activation of the DOR has also been reported to activate phospholipase C (33, 41). Activation of phospholipase C or phospholipase D results in translocation of specific isoforms of protein kinase C (PKC) (59, 61). Translocation of PKC may then lead to opening of a mitochondrial ATP-sensitive K ϩ (K ATP ) chan...

show abstract

Cardioprotection with adenosine metabolism inhibitors in ischemic–reperfused mouse heart

Cited by 42 publications

References 44 publications

The Adenosine Transporter, mENT1, Is a Target for Adenosine Receptor Signaling and Protein Kinase Cϵ in Hypoxic and Pharmacological Preconditioning in the Mouse Cardiomyocyte Cell Line, HL-1

The Adenosine Transporter, mENT1, Is a Target for Adenosine Receptor Signaling and Protein Kinase Cϵ in Hypoxic and Pharmacological Preconditioning in the Mouse Cardiomyocyte Cell Line, HL-1

Acute adenosinergic cardioprotection in ischemic-reperfused hearts

Adenosine and opioid receptor-mediated cardioprotection in the rat: evidence for cross-talk between receptors

Contact Info

Product

Resources

About