Abstract 20396: Induction of Ischemia-Reperfusion Injury by Extracellular RNA: A case for Tumor Necrosis Factor (TNF-α) - Shedding
Introduction: During acute myocardial infarction, cardiomyocyte death has a great impact on the quality of life and survival of patients. Despite reopening/reperfusion of stenosed vessels, a major organ damage remains. The initial mechanistic triggers of this myocardial “ischemia/reperfusion (I/R) injury” remain greatly unexplained.
Hypothesis: We hypothesized that extracellular RNA (eRNA), derived from damaged tissue, and tumor-necrosis-factor-a (TNF-α), may dictate cardiac I/R injury.
Methods and Results: Following myocardial I/R in mice or I/R induced in the isolated Langendorff rat heart, increased eRNA levels were found together with cardiac injury markers. Likewise, eRNA was released from cardiomyocytes under hypoxia and subsequently induced TNF-α liberation by activation of TNF-α converting enzyme (TACE) to provoke cardiomyocyte death. Conversely, TNF-α promoted eRNA release especially under hypoxia, feeding a vicious cell damaging cycle during I/R. Administration of RNase1 or TAPI (a TACE-inhibitor) prevented cell death and myocardial infarction. Likewise, RNase1 significantly reduced I/R-mediated energy exhaustion, opening of mitochondrial permeability transition pores as well as oxidative damage in cardiomyocytes.
Conclusions: RNase1 and TACE-inhibitor provide novel therapeutic regimen to interfere with the adverse eRNA-TNF-α interplay and significantly reduce or prevent the pathological outcome of ischemic heart disease. This uncovered fundamental pathomechanism is likely to operate in other organs and tissues as well.
Author Disclosures: H.A. Cabrera-Fuentes: None. K.T. Preissner: None.
- © 2014 by American Heart Association, Inc.