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Cardiovascular Research Center, Departments of 1 Biomedical Engineering, 2 Pediatrics, and 3 Radiology, University of Virginia Health System, Charlottesville, Virginia 22908
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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 ischemia-reperfusion 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 = 10) and moderate-level A1-AR TG (n = 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 ± 3%, whereas overexpression of A1-ARs in the TG mice markedly reduced infarct size to 31 ± 3% (P < 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
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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REPETITIVE A1-adenosine receptor (A1-AR) activation can maintain the heart in a protected state against myocardial ischemia-reperfusion injury (6). However, prolonged activation of A1-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 A1-ARs resulting from continuous stimulation by A1-AR agonists. Using transgenic techniques, we showed (11-15, 19, 21) that cardiac A1-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 A1-AR has the potential to provide continuous cardioprotection (21). Although our past work was critical in establishing the long-term cardioprotective potential of A1-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 A1-AR overexpression could also protect intact mice against ischemia-reperfusion injury.
Although cardiac-specific 300-fold A1-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 ± 14 beats/min (bpm) vs. 713 ± 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. We therefore selected a line of transgenic (TG) mice with moderate overexpression of the A1-AR (~30-fold) that exhibited minimal bradycardia (681 ± 11 bpm). If this level of A1-AR overexpression afforded protection against myocardial infarction (MI) in vivo, then strategies designed to moderately increase the density of A1-ARs in the myocardium might have clinical potential because this could produce a sustained form of cardioprotection without adverse side effects. In this study, we found that MI size can indeed be substantially reduced by overexpressing A1-ARs at moderate levels in the heart. Additionally, we used cardiac magnetic resonance imaging (MRI) to show that moderate overexpression of the A1-AR had no effects on baseline morphology or function yet helped preserve left ventricular (LV) ejection fraction after MI.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Transgenic mice.
All experiments were performed in accordance with the Guide for
the Care and Use of Laboratory Animals (NIH Publication No. 85-23, revised 1996), and the work was approved by the Institutional Animal
Care and Use Committee. TG mice overexpressing the rat A1-AR cDNA were produced as described previously
(12). Mice were screened for the transgene by PCR
amplification of a 550-bp fragment of the transgene with a 350-bp
fragment of the endogenous A3-adenosine receptor
(A3-AR) gene as a positive control (Fig. 1A). Primers used to detect
the rat A1-AR gene were forward:
5'-CTCTGACAGAGAAGCAGGCACTTTACA- TGG-3', reverse:
5'-CCAGTGACACGATGAAGCAGAAGGTGGCAT-3'. Primers used to detect the
endogenous mouse A3-AR gene were forward:
5'-CTTTCTGAGAAGAGTCTCTAAGA-3'; reverse:
5'-GGAGACAATGAAATAGAACGTG-3'. Copy numbers for both high- and
moderate-level A1-AR overexpression were determined by
Southern analysis (Fig. 1B). The rat A1-AR cDNA
probe hybridizes to both the endogenous mouse A1-AR gene
(2.6 kb) and the rat A1-AR transgene (1.6 kb).
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Experimental mouse model. Surgical procedures were the same as reported previously (26, 27). Briefly, WT and TG mice, comparable in body weight (28.5 ± 1.1 vs. 28.8 ± 1.3 g; P > 0.05), were anesthetized, the upper portion of the trachea was exposed, and an endotracheal tube was inserted orally. Artificial respiration was maintained with a SAR-830/P ventilator (inspired O2 fraction 0.80, rate 100 strokes/min, stroke volume 2.0-2.5 ml). After intubation, a chest incision was made to open the left pleural cavity. A piece of 7-0 silk suture was passed underneath the left anterior descending (LAD) coronary artery at the level of the lower left atrium, and MI was induced by tying down the suture over PE-10 tubing. Reperfusion was achieved by loosening the suture. Occlusion was confirmed through visualization of pallor of region at risk and by observation of electrocardiogram (ECG) changes such as widening of QRS and ST-T segment elevation (monitored by MacLab). A volume of 1-1.5 ml 5% dextrose was given intraperitoneally to replace fluids. Body temperature was monitored with a rectal probe and maintained between 36.5 and 37.5°C with a heating pad.
Pilot experiments.
Experimental MI was initially induced in TG mice (n = 5) with high-level A1-AR overexpression (~300-fold).
These animals demonstrated significant baseline bradycardia that
worsened on LAD occlusion (Fig. 2),
resulting in 100% mortality (Table 1;
Fig. 2) and making these mice unsuitable for the study of MI. A line
with moderate level A1-AR overexpression (~30-fold) was
then examined as follows.
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Experimental groups. Forty-four 10- to 15-wk-old mice of either gender were used and matched in gender in the two study groups to assess the effect of moderate level (30-fold) A1-AR overexpression on infarct size. WT (littermate wild type; n = 19) and TG (moderate A1-AR overexpression; n = 15) mice underwent 45-min LAD occlusion and 24-h reperfusion. Twenty-four hours after reperfusion, cardiac structure (LV end-systolic and diastolic volumes, LVESV and LVEDV) and function (LV ejection fraction, LVEF) in WT (n = 5) and TG (n = 4) mice were studied by in vivo cardiac MRI. After euthanasia, hearts were excised and stained with triphenyltetrazolium chloride (TTC) and phthalo blue for measurement of MI as a percentage of the area at risk. To assess neutrophil infiltration, tissue myeloperoxidase (MPO) was assayed in WT (n = 4) and TG (n = 4) mice after MI and 24-h reperfusion. Sham-operated control groups of WT (n = 5) and TG (n = 5) mice were also evaluated for MPO. Sham-operated mice underwent the same procedures as mice subjected to MI, but the suture placed around the LAD was not tightened (Table 1).
Analysis of MI. After excision, hearts were perfused with 0.9% NaCl solution and then 1.0% TTC in phosphate buffer (pH 7.4) to assess tissue viability. The LAD was then reoccluded, and the hearts were perfused with 10% phthalo blue to delineate the nonischemic tissue. The hearts were frozen, and the LV was cut into five to seven transverse slices and fixed in 10% buffered formalin. Slices were weighed and photographed from both sides. The images were digitally analyzed for infarct area, ischemic area (risk region, RR), and LV area. The weights of the infarcted area and RR were then calculated as percentages of the total weight of each LV slice.
Determination of cardiac structure and function by cardiac MRI. Cardiac MRI was used to assess cardiac function before and after MI. Imaging was performed with a Helmholtz RF coil on a Varian Inova 4.7-T MRI equipped with Magnex gradients (80 G/cm maximum strength). An ECG-triggered two-dimensional cine FLASH sequence was used with a slice thickness of 1 mm and an in-plane resolution of 100 × 100 µm2. The flip angle was 20° with a repetition time of 12-20 ms. During each session, the LV was scanned using six to nine contiguous short-axis slices. Raw data from the imaging were scaled and converted for image analysis with ARGUS (Siemens Medical Systems, Iselin, NJ). End-systolic and end-diastolic phases from each set of contiguous short-axis slices were used to determine LVESV and LVEDV so that LVEF could be calculated.
Measurement of tissue MPO activity. The heart was flushed with cold phosphate-buffered saline to remove blood from the vasculature. The LV was homogenized in a solution containing 0.5% hexadecyltrimethylammonium bromide and centrifuged for 30 min at 20,000 g and 4°C. An aliquot of the supernatant was reacted with a solution of tetramethylbenzidine (1.6 mmol/l) and 0.1 mmol/l H2O2. The rate of the change in absorbance was measured with a spectrophotometer at 650 nm. MPO activity was calculated as described previously (27).
Statistical analysis. Data are reported as means ± SE. Infarct size, RR, and cardiac function were analyzed with ANOVA, followed by Student's t-tests for unpaired data with Bonferroni correction. MPO activity was analyzed by ANOVA, followed by Tukey's post hoc test. P < 0.05 was considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hemodynamics. In our pilot studies with TG mice overexpressing the A1-AR at high levels (300-fold), conscious resting HR recorded by a tail cuff BP 2000 Analysis System (Visitech, Apex, NC) was found to be significantly lower than in WT controls (620 ± 14 vs. 713 ± 8 bpm; P < 0.05). During coronary occlusion, bradycardia was aggravated in the high-level A1-AR-overexpressing mice, resulting in 100% mortality within 10 min after the LAD was occluded (Fig. 2). To overcome this problem, we used a different line of TG mice that overexpresses the A1-AR at more moderate levels (30-fold). Resting bradycardia (681 ± 11 bpm) in this line was much less severe than in the line with 300-fold overexpression of the A1-AR (620 ± 14 bpm; P < 0.05).
There was no significant difference in mean arterial blood pressure between moderate-level A1-AR-overexpressing TG and WT mice (69 ± 5 vs. 67 ± 10 mmHg) under anesthesia. Furthermore, there was no significant difference between TG and WT mice in anesthetized HR monitored by ECG before the LAD occlusion (baseline) (368 ± 17 vs. 398 ± 21 bpm; Fig. 2). HR increased in response to LAD occlusion and reperfusion to similar degrees in both TG and WT mice (Fig. 2). There was no difference in perioperative mortality between the TG and WT mice when the moderate-level A1-AR-overexpressing mice were used (2 of 24 in WT vs. 1 of 20 in TG).Cardiac overexpression of A1-AR protects intact heart
against MI.
Moderate (30-fold) overexpression of the A1-AR
significantly reduced infarct size in intact mice after 45-min LAD
occlusion and 24 h of reperfusion. Histological examination of the
infarcted hearts after phthalo blue staining revealed that there was no difference in the region at risk (39 ± 2% vs. 42 ± 2%)
between WT and TG mice. However, as illustrated in Fig.
3, infarct sizes (pale areas) in TG mice
were significantly smaller than in WT mice, even though the
ischemic regions (sum of pale and red areas) were comparable.
Infarct size was 52 ± 3% in WT mice compared with 31 ± 3%
in TG mice (P < 0.05; Fig.
4). No differences were found between WT
and TG mice in heart weight after MI (148 ± 7 vs. 145 ± 8 mg).
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Tissue MPO activity.
To assess the role of inflammation in this model, MPO activity was
measured 24 h after MI as an indicator of neutrophil infiltration (Fig. 5). To control for any potential
effect of the operative procedure on myocardial MPO activity, TG
(n = 5) and WT (n = 5) mice were
subjected to a sham operation in which the chest was opened for 50 min
and a suture was passed around the LAD but not tightened. As expected,
MPO activity was low in both the WT and TG sham-operated groups, with
no difference observed. Twenty-four hours after MI, MPO activity was
markedly increased in both groups, but to a significantly lower level
in TG compared with WT mice (Fig. 5).
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Cardiac overexpression of A1-AR preserves cardiac
function 24 h after MI.
Cardiac function was evaluated by cardiac MRI before MI and 24 h
after reperfusion. There was no significant difference in heart rate
during MRI. At baseline (i.e., under anesthetic but with no
experimental intervention), there were no significant differences in
LVEDV, LVESV, or LVEF between WT and TG mice (Fig. 6). MI increased LVESV to a similar
extent in the two groups and showed a trend toward elevated LVEDV in TG
mice (Fig. 6, A and B). As shown in Fig.
6C, LVEF was similar between the two groups at baseline
(69 ± 4% in WT and 63 ± 4% in TG). Both groups suffered a
significant loss of LVEF as a result of MI; however, LVEF 24 h
after MI was significantly better in TG mice (47 ± 2%) than it
was in WT mice (34 ± 2%; P < 0.05).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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It is now well established that the autacoid adenosine functions as a potent intrinsic cardioprotectant (8). The binding of adenosine to the A1-AR is the initial step in triggering this protective mechanism against myocardial stunning and infarction (2, 3, 6, 9, 17, 22, 23). Recently we demonstrated (19) that the effects of adenosine are limited by receptor number rather than by agonist concentration in ischemic murine myocardium. Thus transgenic overexpression of A1-ARs improves tolerance to ischemia-reperfusion injury, whereas continuous exogenous activation of A1-AR is less effective. In our previous studies with isolated heart models, we found that TG hearts with >300-fold A1-AR overexpression demonstrated significantly increased resistance to myocardial ischemia-reperfusion injury. This cardioprotection was due in part to an improved metabolic and/or bioenergetic state in response to ischemia-reperfusion injury (13). The increased myocardial A1-AR density in these mice constitutively activates endogenous signaling pathways, which includes activation of mitochondrial ATP-sensitive potassium (KATP) channels, and continuously protects the heart against ischemia-reperfusion injury (14, 15). This cardioprotective effect of A1-AR overexpression was blocked by selective A1-AR antagonist (19, 21). Although our previous studies conducted in isolated heart models were critical in exploring the mechanisms underlying the cardioprotective potential of A1-AR manipulation, it nevertheless remained to be demonstrated that tissue-specific overexpression of A1-ARs in the heart could produce clinically relevant cardioprotection in vivo.
However, adverse side effects associated with high-level overexpression of the A1-AR made it difficult to use this line of mice for studying regional MI in vivo. In particular, hearts overexpressing A1-ARs at levels 300-fold above normal exhibited resting bradycardia and a blunted inotropic response to catecholamines (13-15). In a pilot study conducted with this line of TG mice, bradycardia was worsened on anesthesia and a 100% mortality rate was incurred during the LAD occlusion (Table 1; Fig. 2). The purpose of the present study, therefore, was to examine a different line of TG mice with a more moderate level of A1-AR overexpression (Fig. 1) to determine the effect of A1-AR overexpression on MI in an in vivo model.
Moderate myocardial A1-AR overexpression protects heart against MI. Moderate overexpression of myocardial A1-AR caused mild resting bradycardia that disappeared under anesthesia compared with mice with high-level (300-fold) overexpression (Fig. 2). There was also no significant difference in blood pressure or cardiac structure and function measured at baseline by cardiac MRI. Thus the moderate-level A1-AR-overexpressing TG mice were comparable to the littermate WT mice before the surgery. In contrast, moderate overexpression of myocardial A1-ARs in TG mice markedly reduced infarct size and preserved cardiac function at 24 h after MI (Figs. 3, 4, and 6). This protective effect on myocardial function may be attributed not only to a smaller infarction but also to a better preserved noninfarct myocardial compliance, as indicated by the trend of higher LVEDV in TG mice (Fig. 6A).
To examine the role of inflammation in this model, we measured tissue MPO activity in TG and WT mice 24 h after infarction or a sham operation. MPO is generated by neutrophils as they accumulate in the infarct and peri-infarct regions early after ischemia-reperfusion injury in response to the degranulation of mast cells and other inflammatory stimuli (10). We found that TG mice with moderate overexpression of A1-ARs had lower levels of tissue MPO activity compared with WT mice (Fig. 5). It is likely that the observed reduction in the inflammatory mediator MPO is secondary to the decrease in cell death, because dying and necrotic cells provide potent stimuli for neutrophil recruitment after MI. Additional studies, however, will be needed to determine whether the reduction in neutrophil infiltration is a direct result of smaller infarct size or whether other mechanisms related to A1-AR overexpression are involved.Models of cardioprotection utilizing genetically manipulated mice. The study presented here is the first step toward using genetic manipulation to harness an intrinsic cardioprotective mechanism against ischemia-reperfusion injury. Other recently developed murine models using TG and knockout technology have also demonstrated promise by improving myocardial function and reducing MI as a result of ischemia-reperfusion injury. These include TG mice overexpressing the inducible heat shock protein 70 (24) and the antioxidant enzyme manganese superoxide dismutase (5). Furthermore, overexpression of glutathione peroxidase is protective (28), and knockout of the glutathione peroxidase gene has been shown to increase susceptibility to myocardial ischemia-reperfusion injury (29).
Signaling mechanisms involved in cardioprotection by A1-AR overexpression. Genetically manipulated mouse models contribute substantially to our understanding of the mechanisms of pathophysiological processes. The signaling mechanisms involved in A1-adenosine receptor activation have been extensively studied, but there is still no universal agreement regarding the specific pathway(s) or end-effectors responsible for the observed cardioprotection. Our previous studies with isolated heart models have shown that A1-AR overexpression increases myocardial resistance to ischemia by constitutively activating endogenous signaling pathways, with mitochondrial KATP channels being critical effectors (14, 21). Because A1-AR-mediated cardiac protection shares at least some common mechanisms with ischemic preconditioning (17, 21), it is logical that other signaling intermediates [such as protein kinase C (16, 18) and tyrosine kinase] are also held in common. Recently, p38 mitogen-activated protein kinase was found to be an important signaling component in the cardioprotection induced by preconditioning and adenosine (4, 7, 20). Furthermore, it is likely that other end-effectors implicated in cardioprotection from preconditioning, such as the activation of heat shock proteins or inhibition of apoptosis (1, 18), will be involved in A1-AR-mediated cardiac protection.
By examining a line of TG mice with moderate overexpression of myocardial A1-ARs (30-fold above normal), we could extend the conclusions drawn from our previous isolated heart studies into intact animals. This line of A1-AR TG mice exhibits minimal bradycardia and normal hemodynamic responses to MI. The moderate overexpression of A1-ARs makes the heart more resistant to ischemia-reperfusion injury, as indicated by reduced infarct size and reduced contractile dysfunction after MI. The results of these in vivo studies establish a foundation for future research aimed at evaluating the potential of A1-AR manipulation in altering the myocardial response to ischemia-reperfusion injury. Ultimately, these studies may have clinical relevance because the direct transfer of genes encoding A1-ARs to the heart may provide for an effective and durable form of cardioprotective gene therapy.| |
ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute (NHLBI) Grant R01-HL-59419 to G. P. Matherne and American Heart Association (AHA) Mid-Atlantic Beginning Grant-in-Aid to Z. Yang. Z. Yang is also supported by a Whitaker Foundation Biomedical Engineering Research Grant and is the recipient of a Partners Fund Award from the University of Virginia Cardiovascular Institute. B. A. French is supported by NHLBI Grant R01-HL-58582. B. A. French and G. P. Matherne are recipients of AHA Established Investigator Awards.
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FOOTNOTES |
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* Z. Yang and R. J. Cerniway contributed equally to this work.
Address for reprint requests and other correspondence: G. P. Matherne, Dept. of Pediatrics, Univ. of Virginia Health System, Box 801356, Charlottesville, VA 22908 (E-mail: gpm2y{at}virginia.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00741.2001
Received 17 August 2001; accepted in final form 5 November 2001.
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METHODS
RESULTS
DISCUSSION
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  N. Ojha, S. Roy, J. Radtke, O. Simonetti, S. Gnyawali, J. L. Zweier, P. Kuppusamy, and C. K. Sen Characterization of the structural and functional changes in the myocardium following focal ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2435 - H2443. [Abstract] [Full Text] [PDF]
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H. Funakoshi, T. O. Chan, J. C. Good, J. R. Libonati, J. Piuhola, X. Chen, S. M. MacDonnell, L. L. Lee, D. E. Herrmann, J. Zhang, et al. Regulated Overexpression of the A1-Adenosine Receptor in Mice Results in Adverse but Reversible Changes in Cardiac Morphology and Function Circulation, November 21, 2006; 114(21): 2240 - 2250. [Abstract] [Full Text] [PDF]
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A. R. Lankford, J.-N. Yang, R. Rose'Meyer, B. A. French, G. P. Matherne, B. B. Fredholm, and Z. Yang Effect of modulating cardiac A1 adenosine receptor expression on protection with ischemic preconditioning Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1469 - H1473. [Abstract] [Full Text] [PDF]
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Y. Xu, Y. Huo, M.-C. Toufektsian, S. I. Ramos, Y. Ma, A. D. Tejani, B. A. French, and Z. Yang Activated platelets contribute importantly to myocardial reperfusion injury Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H692 - H699. [Abstract] [Full Text] [PDF]
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Z. Yang, Y.-J. Day, M.-C. Toufektsian, S. I. Ramos, M. Marshall, X.-Q. Wang, B. A. French, and J. Linden Infarct-Sparing Effect of A2A-Adenosine Receptor Activation Is Due Primarily to Its Action on Lymphocytes Circulation, May 3, 2005; 111(17): 2190 - 2197. [Abstract] [Full Text] [PDF]
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W. D. Gilson, Z. Yang, B. A. French, and F. H. Epstein Measurement of myocardial mechanics in mice before and after infarction using multislice displacement-encoded MRI with 3D motion encoding Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1491 - H1497. [Abstract] [Full Text] [PDF]
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 A. R. Lankford, A. M. Byford, K. J. Ashton, B. A. French, J. K. Lee, J. P. Headrick, and G. P. Matherne Gene expression profile of mouse myocardium with transgenic overexpression of A1 adenosine receptors Physiol Genomics, October 29, 2002; 11(2): 81 - 89. [Abstract] [Full Text] [PDF]
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, Individual mice; 
,
means ± SE.
