Abstract
Understanding the dynamics of the immune response following late myocardial reperfusion is critical for the development of immunomodulatory therapy for myocardial infarction (MI). Cyclosporine A (CSA) possesses multiple therapeutic applications for MI, but its effects on the inflammation caused by acute MI are not clear. This study aimed to determine the dynamics of the immune response following myocardial ischemia/reperfusion (I/R) and the effects of CSA in a mouse model of prolonged myocardial ischemia designated to represent the human condition of late reperfusion. Adult C57BL/6 mice were subjected to 90 min of closed-chest myocardial I/R, which induced severe myocardial injury and excessive inflammation in the heart. Multicomponent analysis of the immune response caused by prolonged I/R revealed that the peak of cytokines/chemokines in the systemic circulation was synchronized with the maximal influx of neutrophils and T-cells in the heart 1 day after MI. The peak of cytokine/chemokine secretion in the infarcted heart coincided with the maximal macrophage and natural killer cell infiltration on day 3 after MI. The cellular composition of the mediastinal lymph nodes changed similarly to that of the infarcted hearts. CSA (10 mg/kg/day) given after prolonged I/R impaired heart function, enlarged the resulting scar, and reduced heart vascularization. It did not change the content of immune cells in hearts exposed to prolonged I/R, but the levels of MCP-1 and MIP-1α (hearts) and IL-12 (hearts and serum) were significantly reduced in the CSA-treated group in comparison to the untreated group, indicating alterations in immune cell function. Our findings provide new knowledge necessary for the development of immunomodulatory therapy targeting the immune response after prolonged myocardial ischemia/reperfusion.
Highlights
Myocardial infarction (MI) is a leading cause of morbidity and mortality throughout the world
Assessment of the area at risk (AAR) after 24 h of reperfusion revealed no difference between 30 and 90 min of ischemia, while the infarcted area (IA)/ AAR significantly increased in 90 min of ischemia compared with 30 min of ischemia (Fig. 1a)
Flow cytometric analysis at day 3 after MI showed a significant difference in inflammatory cell influx between 30 and 90 min of I/R: there were 3 times more CD45+ cells detected in the infarcted hearts after 90 min of ischemia than after 30 min of ischemia (Fig. 1e)
Summary
Myocardial infarction (MI) is a leading cause of morbidity and mortality throughout the world. Coronary artery reperfusion therapy is one of the most successful therapies in modern medicine. Reperfusion is obviously a preferred therapy for myocardial infarction. Kim and Braunwald [3] have proposed that late reperfusion – too late to reduce myocardial infarct size, but early enough to favorably affect infarct healing – appears to limit infarct expansion and left ventricular (LV) remodeling (the open-artery hypothesis). Late reperfusion has shown its efficacy in both animal and human research [2,3,4,5]. Understanding the pathophysiological basis of late reperfusion is a prerequisite for developing additional therapy for those patients
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