Developing a new drug to reduce ischemia-reperfusion injury

Targeting the AKAP18γ/δ-PLB interaction could reduce ischemia-reperfusion injury caused by revascularization after myocardial infarction, according to Ellen Østensen‘s PhD thesis.


MAIN RESULTS:

  1. New information on the structure of AKAP18γ/δ was found.
  2. Molecules that target the AKAP18γ/δ-PLB interaction in cardiomyocates were developed.
  3. In an animal study, treatment with the new molecules before opening the occluded coronary artery reduced ischemia-reperfusion injury by up to 40 %.

THESIS DEFENCE:

Thesis: Adrenergic regulation of the Ca2+ homeostasis in the heart – Cardioprotective effects in ischemia-reperfusion injury of targeting the AKAP18γ/δ-PLB interaction
Candidate: Ellen Østensen
Time: December 5, 2017 at 13:15
Place: Oslo University Hospital, Rikshospitalet: Red Auditorium
Link to university website (in Norwegian)


SUMMARY:

A-kinase anchoring protein 18γ/δ (AKAP18γ/δ) is found in complex with phosfolamban (PLB) within cardiomyocytes. Their interaction is important for calcium release and re-uptake in the cytoplasm of the cardiomyocytes. Targeting the AKAP18γ/δ-PLB interaction could be a way to reduce the ischemia-reperfusion injury frequently seen following a myocardial infarction. Ellen Østensen and co-workers have synthesied molecules to target this interaction and tested the effect in an animal study. Treatment before opening the occluded coronary artery reduced infarct size by up to 40 %. The work could lead to the development of small molecules that could be excellent drug canditates in cardiovascular disease.


REFERENCES:

(1) Bjerregaard-Andersen, K., Østensen, E., Scott, J. D., Tasken, K., & Morth, J. P. (2016). Malonate in the nucleotide-binding site traps human AKAP18γ/δ in a novel conformational stateActa Crystallographica Section F: Structural Biology Communications72(8), 591-597.