Gábor Koncsos1, Zsófia Onódi1, Viktória Éva Tóth1, Zoltán Giricz1, Péter Ferdinandy1, Zoltán V. Varga1,
1 Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
Introduction: Neutrophil granulocytes play a central role in tissue destruction during myocardial infarction. Neutrophils undergo a specific form of cell death called NETosis, where extracellular traps (NET) are formed mainly from the decondensed nuclear DNA. NETosis plays a role in acute ischemia/reperfusion injury, but its role in the long-term remodeling of the heart after infarction, as well as in fibrosis and in various regenerative processes has not been investigated so far.
Aims: To examine the role of NETosis in a clinically relevant porcine infarct model and to assess the expression of various components and kinetics of NETosis. Furthermore, we would like to examine the role of NETosis in clinically relevant human heart failure samples.
Methods: Protein samples were isolated from control (sham) and 3-hour, 3-day and 2-month survived porcine ischemic myocardial tissues. Human non-ischemic, dilatative and ischemic cardiomyopathic hearts were also investigated. Markers of NETosis and inflammasome activation were tested by Western blot.
Results: Expression of AIM2, NLRC4 and IL-18 proteins, which are markers of inflammasome activation, were significantly increased in 2-month ischemic porcine heart samples and expression of cleaved IL-1-beta, IL-18 and NLRC4 proteins in 3-day ischemic porcine heart samples compared to sham group. The expression of NETosis marker peptidyl-citrulline was increased in 3-day ischemic porcine hearts compared to the sham group. Furthermore, expression of H4-citrulline was decreased in both dilatative and ischemic cardiomyopathic human hearts compared to the control.
Conclusion: We have shown that the activation of inflammasomes starts 3 days after ischemia, which can be also detected after 2 months. Although activation of NETosis may be increased in post-infarction, further studies are needed to clarify whether it can be associated with inflammasome activation.
Doctoral School: Pharmaceutical Sciences Doctoral School
Program: Experimental and Clinical Pharmacology
Supervisor: Zoltán Giricz PharmD., PhD; Zoltán V. Varga MD., PhD
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