Impact of phosphodiesterase 2 in diabetic cardiomyopathy
PhD Student: Eleder Cachorro Puente
Supervisor at TUD: Susanne Kämmerer, Ali El-Armouche,
Supervisor at KCL: Manuel Mayr
Start Date: 15.02.2020
Patients with type 1 or type 2 diabetes (DMT1, DMT2) suffer from comorbidities, like cardiovascular diseases being the most prevalent cause of mortality. Diabetes mellitus is associated with abnormal energy metabolism, oxidative stress, cardiac inflammation, fibrosis and altered Ca2+ signalling in the heart and leads to ventricular dysfunction, arrhythmia and sudden cardiac death (SCD). Phosphodiesterase 2 (PDE2) is a key node in cardiomyocytes, which is stimulated by cGMP leading to a remarkable cAMP degradation. In diabetic hearts, the cGMP signalling is depressed, displaying reduced cGMP levels and decreased cGMP activated protein kinase G activity. In contrast, the β-adrenergic-cAMP pathway is chronically activated in the diabetic hearts due to decreased energy supply and reduced cardiac function. Permanent activation of the cAMP signalling cascade leads to proarrhythmic remodeling of the calcium handling in diabetic cardiomyocytes. We hypothesize that PDE2 could compensate the imbalance of over-activated cAMP- and defective NP-cGMP signalling. Thus, PDE2 might play a cardioprotective and antiarrhythmic role via the mediated cGMP/cAMP cross-talk. The aim of the project is to study PDE2 functions during cardiac remodelling in established models of diabetic cardiomyopathy in terms of Ca2+ signalling, mitochondrial function/dynamics and cardiac inflammation.
Thereby, we will use the transgenic mice with cardiac specific PDE2 overexpression as well as the cardiac specific PDE2 knockout mice or human iPS-derived cardiomyocytes with PDE2 knockout. We will study the role of PDE2 in the development of cardiac arrhythmia after myocardial infarction in diabetic mouse models. Therefore, we will use perfused Langendorff hearts from PDE2A transgenic, knockout and control mice for assessing PDE2 functions in electrical activity upon β-adrenergic stimulation with the agonist isoprenaline. Preliminary results showed a concentration-dependent increase in heart rate upon isoprenaline in wild type mice. We will further establish the ex vivo model of myocardial ischemia-reperfusion injury by transient ligation of the coronary artery for 30 min in the Langendorff perfusion system. Preliminary data demonstrate the development of various arrhythmic events including ventricular extrasystole, bigeminy and ventricular tachycardia.
In conclusion, we suggest that PDE2 might serve as a new cardioprotective and antiarrhythmic target affecting altered Ca2+ signaling, oxidative stress and inflammatory processes in diabetic hearts.
Publications:
Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases. M.S. Sadek, E. Cachorro, A. El-Armouche, S. Kammerer. Int J Mol Sci. 2020;21:7462.
Cellular Mechanisms of the Anti-Arrhythmic Effect of Cardiac PDE2 Overexpression. M. Wagner, M.S. Sadek, N. Dybkova, F.E. Mason, J. Klehr, R. Firneburg, E. Cachorro, K. Richter, E. Klapproth, S.R. Kuenzel, K. Lorenz, J. Heijman, D. Dobrev, A. El-Armouche, S. Sossalla, S. Kämmerer. Int J Mol Sci. 2021;22(9):4816.