- Inflammation and acute myocardial ischemia-reperfusion injury using a closed-chest mouse model
R.J. de Winter
H. ten Cate
- Award date
- 14 December 2017
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Acute myocardial ischemia- reperfusion (I/R) results in activation of the innate immune system. The immune reactions can be separately investigated by using mice deficient for a gene that codes for one of the immune components. However, the chest has to be opened to temporally occlude the left anterior descending artery. This intervention leads to the undesirable induction of the immune system, together with the I/R reactions. Therefore, we applied a closed-chest model with a preparative surgery one week before the actual I/R. We used the anesthetic mixture fentanyl- fluanisone- midazolam (FFM) during the preparative surgeries, because it resulted in stable mean arterial pressures and heart rates. Under FFM anesthesia, IL-6 deficient mice had smaller infarcts than wild type (WT) mice after 1h ischemia and 3 or 24h reperfusion. IL-1β and TNF-α levels peaked at 3h reperfusion, but showed no differences between the groups. Influx of neutrophils and activation of fibrin/ fibrinogen and tissue factor in the area at risk were also similar between the groups. Under pentobarbital anesthesia, Nlrp3 deficient and WT mice had similar infarct sizes after ½ and 1h ischemia and 3h reperfusion and after ischemic preconditioning (IPC). Myocardial NLRP3 expression was undetectable in the closed-chest model, whereas it was detectable in the open-chest model. In isolated Langendorff-perfused hearts, IPC resulted in protection of ASC deficient and WT but not of Nlrp3 deficient hearts. The Nlrp3 deficient hearts had significantly decreased IL-6 and STAT3 levels at end reperfusion, suggesting abrogation of IPC through diminished IL-6 signaling.
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