May-Kristin Skaug Torp‘s research indicate that the innate immune system could be a target for reducing ischemia-reperfusion injury.


  1. Proteasome activation is the major catabolic mechanism for interleukin-1β degradation in cardiac fibroblasts.

  2. Nucleolin inhibition might prevent uptake of damaged DNA and reduce ischemia related inflammation.
  3. Inhibiting Toll-like receptor 4 at reperfusion reduces infarct size.


Thesis: Targeting innate immunity in ischemia-reperfusion of the heart
Candidate: May-Kristin Skaug Torp
Time: December 16, 2019 at 13:15
Place: University of Oslo, Domus Medica, tilbygg: Runde auditorium
Link to university website


(1) Serum starvation reduces secretion of interleukin-1β induced by lipopolysaccharides and ATP in cardiac fibroblasts. Proteasome activation, not autophagy, is the major catabolic anti-inflammatory mechanism for interleukin-1β degradation.

Experiments were conducted in cardiac fibroblasts from mice, and the main findings were reinvestigated in human monocyte-derived macrophages. Inhibition of mTOR, a key regulator of protein metabolism, selectively restored synthesis of interleukin-1β and did not induce autophagy following serum starvation. On the contrary, the proteasome activator betulinic acid reduced pro-IL-1β.

(2) Blocking nucleolin reduces inflammation caused by damaged mitochondrial DNA. Mitochondrial DNA can be internalized in cardiomyocytes and induce inflammation following myocardial ischemia. Nucleolin, the DNA-binding protein, is expressed on the membrane of cardiomyocytes.

The experiments include isolated cardiomyocytes from adult mice. They were exposed to extracellular DNA during reoxygenation following hypoxia. Mitochondrial DNA, but not nuclear DNA, upregulated interleukin 1β and TNFα. By blocking nucleolin, the expression of these pro-inflammatory cytokines was reduced. Moreover, a nucleolin inhibitor reduced interleukin-6 release.

(3) Infarct size was reduced by toll-like receptor 4 inhibition at reperfusion following myocardial infarction in mice. Inhibition was induced in isolated hearts from adult male mice following 35 minutes of global ischemia. Inhibition significantly reduced cardiac damage and interleukin-6 release.

Moreover, cardiac mitochondrial debris and lipopolysaccharides activated interleukin-6 expression in isolated cardiomyocytes. Toll-like receptor 4 inhibition abolished this effect.

(4) Intracellular C3 is expressed in cardiomyocytes and cardiac fibroblasts, and protects the heart against ischemia-reperfusion.

(5) Formyl-peptide receptors are not expressed in cardiomyocytes. Thus, mitochondrial N-formyl peptides have no direct effect in cardiomyocytes.


(1) Torp, M. K., Yang, K., Ranheim, T., Lauritzen, K. H., Alfsnes, K., Vinge, L. E., Aukrust, P., Stensløkken, K.-O., Yndestad, A., & Sandanger, Ø. (2019). Mammalian target of rapamycin (mTOR) and the proteasome attenuates IL-1β expression in primary mouse cardiac fibroblasts. Frontiers in Immunology10.

(2) Mariero, L. H., Torp, M. K., Heiestad, C. M., Baysa, A., Li, Y., Valen, G., Vaage, J., & Stensløkken, K. O. (2019). Inhibiting nucleolin reduce inflammation induced by mitochondrial DNA in cardiomyocytes exposed to hypoxia and reoxygenation. British journal of pharmacology.

(3) Torp, M. K., Ranheim, T., Flatebø, T., Heiestad, C., Yndestad, A., & Stensløkken, K. O. (2018). Mitochondrial DAMPs in ex vivo ischemia-reperfusion injury in mouse heartsJournal of Molecular and Cellular Cardiology120, 5.

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