Abstract
BackgroundWe test the hypothesis that intra-coronary tacrolimus administration can limit infarct size and preserve left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) through ligating left anterior descending coronary artery (LAD) in mini-pigs.MethodsTwelve male mini-pigs were randomized into AMI-saline (MI-only) group and AMI-tacrolimus (MI-Tac) group that received intra-coronary saline (3.0 mL) and tacrolimus (0.5 mg in 2.5 mL saline) injection, respectively, beyond site of ligation 30 minutes after LAD occlusion.ResultsLarger infarct area was noted in MI-only group (p < 0.001). Inflammatory biomarkers at protein [oxidative stress, tumor necrotic factor-α, nuclear factor-κB], gene (matrix metalloproteinase-9, plasminogen activator inhibitor-1), and cellular (CD40+, CD68+ inflammatory cells) levels were remarkably higher in MI-only animals (p < 0.01). Conversely, anti-inflammatory biomarkers at gene level (Interleukin-10), gene and protein level (endothelial nitric oxide synthase), and anti-oxidant biomarkers at both gene and protein levels [heme oxygenase 1, NAD(P)H:quinone oxidoreductase] were lower in MI-only group (p < 0.01). Number of apoptotic nuclei and apoptotic biomarkers expressions at gene and protein levels (Bax, caspase 3) were notably higher, whereas anti-apoptotic biomarkers at gene and protein levels (Bcl-2), LVEF, and fractional shortening were markedly lower in MI-only group (p < 0.001).ConclusionIntra-coronary administration of tacrolimus significantly attenuated infarct size and preserved LV function.
Highlights
We test the hypothesis that intra-coronary tacrolimus administration can limit infarct size and preserve left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) through ligating left anterior descending coronary artery (LAD) in mini-pigs
In view of the fact that immune and inflammatory reactions are one of the major contributors to death of cardiomyocytes after AMI [6,7,8,9,10,11,12,13,17] and that tacrolimus is a more potent immunosuppressant compared to cyclosporine, we propose that tacrolimus may limit the extent of myocardial infarction and improve Left ventricular (LV) function in the setting of AMI
No difference was noted in left ventricular end-systolic dimension (LVEDs) and LVEVs at papillary level between these two groups of animals at day 14 after AMI induction
Summary
We test the hypothesis that intra-coronary tacrolimus administration can limit infarct size and preserve left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) through ligating left anterior descending coronary artery (LAD) in mini-pigs. Acute myocardial infarction (AMI) is the leading cause of death of patients hospitalized for cardiovascular disease [1,2]. Tacrolimus prevents the dephosphorylation of NF-AT [14] through reducing the peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP12 (i.e. FK506 binding protein) to create a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin, thereby inhibiting both T-lymphocyte signal transduction and IL-2 transcription [15]. The action of tacrolimus is similar to that of cyclosporine, studies have shown that tacrolimus had significantly greater 6-year graft survival and a higher projected graft half-life than those receiving cyclosporin [16]
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