Jan Magnus Aronsen has identified several new molecular mechanisms that cause chronic heart disease, and shown promising effects by blocking these mechanisms by novel drug candidates.
Small molecules that disrupt PDE3A from SERCA2 may offer effective treatment against cardiac arrhythmias and in heart failure.
Thesis: Molecular mediators of chronic heart disease – A search for novel, specific cardioprotective therapies
Candidate: Jan Magnus Aronsen
Time: March 8, 2018 at 13:15
Place: Oslo University Hospital, Rikshospitalet B: Blue auditorium (3)
Link to university website (in Norwegian)
(1/2) PhD candidate Jan Magnus Aronsen has contributed to several research articles the last decade, but in his PhD work he has investigated molecular mechanisms that can cause chronic heart disease. In the two first articles, new mechanisms for cardiac hypertrophy and remodelling have been identified. Furthermore, in animal models the researchers found that the pathological hypertrophy can be prevented with drugs that block these mechanisms.
(3) Low levels of potassium can lead to ventricular arrhythmias, and Aronsen and co-workers found 25 % reduced sodium-potassium pump activity in rat cardiomyocytes with low potassium levels. The pump pumps sodium out and potassium into the cell, and reduced activity leads to accumulation of sodium. This accumulation modulates the activity of the sodium-calcium exchanger and leads to increased calcium levels, uncontrolled contractions and eventually arrhythmias.
(4) SERCA2 is responsible for calisum transport into the sarcoplasmatic reticulum within cardiomyocytes, and reduced SERCA2 activity increases the risk of arrhythmias in heart patients. Aronsen and co-workers show that the enzyme PDE3A binds directly to SERCA2, and SERCA2 activity increases when this binding is disrupted by a new drug candidate.
(3) Aronsen, J. M., Skogestad, J., Lewalle, A., Louch, W. E., Hougen, K., Stokke, M. K., Swift, F., Niederer, S., Smith, N. P., Sejersted, O., & Sjaastad, I. (2015). Hypokalaemia induces Ca2+ overload and Ca2+ waves in ventricular myocytes by reducing Na+, K+‐ATPase α2 activity. The Journal of physiology, 593(6), 1509-1521.
(4) Skogestad, J., Aronsen, J. M., Hougen, K., Lunde, M., Lothe, G. B., Albert, I., Børstad, M., Marshall, S., Calejo, A. I. C., Lunde, P. K., Morth, J. P., Tasken, K., Carlson, C. R., & Sjaastad, I. (2017). PDE3A Binds Directly to and Inhibits SERCA2 Activity Independently of its Catalytic Activity.
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