Göttingen pharmacologists led by DZHK - scientist Prof. Dr. Ali El - Armouche explore new therapy for heart failure: they activate the heart’s self-protection systems through targeted stimulation.
Currently, there is no therapy for myocardial weakness that can stop the progression of the disease or even reverse it. A research team lead by Prof. Dr. Ali El-Armouche from the Institute of Pharmacology at the University of Göttingen has now discovered that the enzyme PDE2 protects the heart from overload. The enzyme, however, forms only in later stages of heart failure and serves as the body's own braking system.
The tests were performed within the Europe-wide and from Göttingen coordinated project “EUGeneHeart” in joint collaboration with Prof. Dr. Rodolphe Fischmeister from the Faculté de Phamacie at the Université de Paris-Sud as well as with the support of the German Centre for Cardiovascular Research (DZHK) and Göttingen Collaborative Research Centre SFB 1002. The results are published in the online edition of the American journal "Journal of the American College of Cardiology." The researchers now want to find out how they can stimulate and control the heart’s self-protection in earlier stages of the disease. The findings may contribute to a new therapy for heart failure in which the pumping function of the heart is maintained.
Patients with heart failure are usually not very resilient. Provided that the heart is healthy it can be extremely powerful. In stressful situations it can, within seconds, increase fivefold its pumping function with increased cardiac force and heart rate by releasing adrenaline and noradrenaline. The sick heart however, is constantly exposed to extremely high stress hormone levels. In the course of the disease, these have no positive impact on the cardiac output. In fact, they damage the heart and promote the progression of the disease.
Under stress and after activation of outward-bound receptors, the two hormones adrenaline and noradrenaline increase the intracellular production of a key neurotransmitter, the so-called cyclic adenosine monophosphate (cAMP). This molecule relays strong stimulating effects on cardiac force and heart rate within the cell. However, the heart muscle cell has its own strong braking systems. They reduce an excessive cAMP rise and thus prevent an uncontrolled and toxic overstimulation. The enzymes functioning as braking systems belong to the family of so-called phosphodiesterases (PDEs).
Activating the body’s own protection
The working group led by professor El-Armouche has now shown that a specific subfamily of these enzymes, the PDE2, is increasingly formed in the diseased human heart. This increased production of PDE2 is an important protective mechanism in later stages of cardiomyopathy. Besides, the PDE2 has the unique property of being activated by the “positive” messenger cGMP and at the same time degrading the “negative” messenger cAMP. In earlier stages of the disease when the heart’s pumping function is still at a normal level, these enzymes are not yet increasingly formed. The heart is defenselessly exposed to the damaging stress hormones.
In experimental approaches with individual heart muscle cells, the Göttingen researchers showed for the first time that an artificial increase of PDE2 by virally implanted PDE2-genes protects against cardiomyopathy-promoting processes and events. Using cutting-edge technology such as the Förster resonance energy transfer (FRET) and in collaboration with Dr. Slava Nikolaev from the Department of Cardiology and Pneumology new fundamental insighst on functionality and the enzyme’s indirect target molecules could be obtained.
“The ailing heart muscle cell is basically smart and protects itself against permanent excessive attacks by stress hormones. It dramatically weakens the adrenaline and noradrenaline receptor and activates its own braking systems. Unfortunately, it seems to be not quick enough with the activation of the braking system and may not be effective enough. Only in later stages, massive over-stimulation will lead to an approximate doubling of the brake function. Our goal is to earlier and stronger activate the braking molecules in the diseased heart and thus ensure a better protection against the progression of the disease and life-threatening cardiac arrhythmia”, says Prof. El-Armouche.
To test the new method pharmacologically specific PDE2 activators as well as a gene therapeutic approach to cardiac-specific PDE2 overexpression are currently being developed and researched. The results will then be tested in animal models.