Myocardial Function in the Working Mouse Heart Overexpressing Cardiac A1Adenosine Receptors

Ns, Gauthier; Jp, Headrick; Gp, Matherne

doi:10.1006/jmcc.1997.0585

Cited by 36 publications

(44 citation statements)

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“…Cardiac overexpression of A 1 ARs in mouse heart results in substantial protection from ischaemia-reperfusion injury [71][72][73] . Hearts isolated from transgenic animals with overexpression of A 1 ARs have a lower basal rate than those of control mice 71 .…”

Section: Ischaemiamentioning

confidence: 99%

Adenosine receptors as therapeutic targets

Jacobson

Gao

2006

Nat Rev Drug Discov

1,291

1,361

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Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer.

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Section: Ischaemiamentioning

confidence: 99%

Adenosine receptors as therapeutic targets

Jacobson

Gao

2006

Nat Rev Drug Discov

1,291

1,361

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“…10 In contrast, recent studies have reported that high levels of overexpression of A 1 -AR or A 3 -AR in the heart can have untoward effects. [11][12][13] Indeed, overexpression of high levels of A 3 -AR results in the development of a dilated cardiomyopathy. However, information is not available on changes in adenosine signaling in the failing heart.…”

Section: Clinical Perspective P 2315mentioning

confidence: 99%

A ₁ Adenosine Receptor Upregulation Accompanies Decreasing Myocardial Adenosine Levels in Mice With Left Ventricular Dysfunction

et al. 2007

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Background-It is well known that adenosine levels are increased during ischemia and protect the heart during ischemia/reperfusion. However, less is known about the role of adenosine-adenosine receptor (AR) pathways in hearts with left ventricular dilation and dysfunction. Therefore, we assessed adenosine levels and selective AR expression in transgenic mice with left ventricular systolic dysfunction secondary to overexpression of tumor necrosis factor-␣ (TNF 1.6). Methods and Results-Cardiac adenosine levels were reduced by 70% at 3 and 6 weeks of age in TNF 1.6 mice. This change was accompanied by a 4-fold increase in the levels of A 1 -AR and a 50% reduction in the levels of A 2A -AR. That the increase in A 1 -AR density was of physiological significance was shown by the fact that chronotropic responsiveness to the A 1 -AR selective agonist 2-chloro-N 6 -cyclopentanyladenosine was enhanced in the TNF 1.6 mice. Similar changes in adenosine levels were found in 2 other models of heart failure, mice overexpressing calsequestrin and mice after chronic pressure overload, suggesting that the changes in adenosine-AR signaling were secondary to myocardial dysfunction rather than to TNF overexpression. Conclusions-Cardiac dysfunction secondary to the overexpression of TNF is associated with marked alterations in myocardial levels of adenosine and ARs. Modulation of the myocardial adenosine system and its signaling pathways may be a novel therapeutic target in patients with heart failure.

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“…Although our past work was critical in establishing the long-term cardioprotective potential of A 1 -AR overexpression, these studies were conducted in isolated hearts from a line of mice with a 300-fold level of overexpression. In this study, we sought to determine whether A 1 -AR overexpression could also protect intact mice against ischemiareperfusion injury.Although cardiac-specific 300-fold A 1 -AR overexpression provided cardioprotection in globally ischemic, isolated heart models of ischemia-reperfusion injury, this was associated with adverse side effects such as significant resting bradycardia [heart rate (HR) of 620 Ϯ 14 beats/min (bpm) vs. 713 Ϯ 8 bpm in WT mice] and a blunted inotropic response to catecholamines (11,12,19). These side effects caused high mortality rates in pilot in vivo experiments, making this line of animals unsuitable for whole animal investigations.…”

mentioning

confidence: 99%

“…Although cardiac-specific 300-fold A 1 -AR overexpression provided cardioprotection in globally ischemic, isolated heart models of ischemia-reperfusion injury, this was associated with adverse side effects such as significant resting bradycardia [heart rate (HR) of 620 Ϯ 14 beats/min (bpm) vs. 713 Ϯ 8 bpm in WT mice] and a blunted inotropic response to catecholamines (11,12,19). These side effects caused high mortality rates in pilot in vivo experiments, making this line of animals unsuitable for whole animal investigations.…”

mentioning

confidence: 99%

Cardiac overexpression of A₁-adenosine receptor protects intact mice against myocardial infarction

Yang

Cerniway

Byford

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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Previous studies have shown that high-level (300-fold normal) cardiac overexpression of A1-adenosine receptors (A1-ARs) in transgenic (TG) mice protects isolated hearts against ischemiareperfusion injury. However, this high level of overexpression is associated with bradycardia and increased incidence of arrhythmia during ischemia in intact mice, which interfered with studies to determine whether this line of TG mice might also be protected against myocardial infarction (MI) in vivo. For these studies, we therefore selected a line of TG mice that overexpresses the A1-AR at more moderate levels (30-fold normal), which affords cardioprotection in the isolated heart while minimizing bradycardia and arrhythmia during ischemia in intact mice. Wild-type (WT; n ϭ 10) and moderate-level A1-AR TG (n ϭ 10) mice underwent 45 min of left anterior descending coronary artery occlusion, followed by 24-h reperfusion. Infarct size and region at risk were determined by triphenyltetrazolium chloride and phthalo blue staining, respectively. Infarct size (% region at risk) in WT mice was 52 Ϯ 3%, whereas overexpression of A1-ARs in the TG mice markedly reduced infarct size to 31 Ϯ 3% (P Ͻ 0.05). Furthermore, contractile function (left ventricular ejection fraction) as determined by cardiac magnetic resonance imaging 24 h after MI was better preserved in TG vs. WT mice. Cardiac overexpression of A1-ARs reduces infarct size by 40% and preserves cardiac function in intact mice after MI.ischemia-reperfusion; cardioprotection; transgenic mice; magnetic resonance imaging REPETITIVE A 1 -adenosine receptor (A 1 -AR) activation can maintain the heart in a protected state against myocardial ischemia-reperfusion injury (6). However, prolonged activation of A 1 -ARs with pharmacological agents induces a state of tolerance that blunts this cardioprotective effect (25). One possible explanation for this tolerance is the desensitization of A 1 -ARs resulting from continuous stimulation by A 1 -AR agonists. Using transgenic techniques, we showed (11-15, 19, 21) that cardiac A 1 -AR overexpression activates endogenous protective mechanisms that provide the heart with increased resistance to ischemia-reperfusion injury. Unlike transient ischemic preconditioning that occurs in wild-type (WT) animals, the constitutive preconditioning secondary to transgenic overexpression of the A 1 -AR has the potential to provide continuous cardioprotection (21). Although our past work was critical in establishing the long-term cardioprotective potential of A 1 -AR overexpression, these studies were conducted in isolated hearts from a line of mice with a 300-fold level of overexpression. In this study, we sought to determine whether A 1 -AR overexpression could also protect intact mice against ischemiareperfusion injury.Although cardiac-specific 300-fold A 1 -AR overexpression provided cardioprotection in globally ischemic, isolated heart models of ischemia-reperfusion injury, this was associated with adverse side effects such as significant resting bradycardia [h...

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Myocardial Function in the Working Mouse Heart Overexpressing Cardiac A1Adenosine Receptors

Cited by 36 publications

References 0 publications

Adenosine receptors as therapeutic targets

Adenosine receptors as therapeutic targets

A ₁ Adenosine Receptor Upregulation Accompanies Decreasing Myocardial Adenosine Levels in Mice With Left Ventricular Dysfunction

Cardiac overexpression of A₁-adenosine receptor protects intact mice against myocardial infarction

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Myocardial Function in the Working Mouse Heart Overexpressing Cardiac A1Adenosine Receptors

Cited by 36 publications

References 0 publications

Adenosine receptors as therapeutic targets

Adenosine receptors as therapeutic targets

A 1 Adenosine Receptor Upregulation Accompanies Decreasing Myocardial Adenosine Levels in Mice With Left Ventricular Dysfunction

Cardiac overexpression of A1-adenosine receptor protects intact mice against myocardial infarction

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A ₁ Adenosine Receptor Upregulation Accompanies Decreasing Myocardial Adenosine Levels in Mice With Left Ventricular Dysfunction

Cardiac overexpression of A₁-adenosine receptor protects intact mice against myocardial infarction