Team 2: Cellular and Molecular Cardiac Physiopathology
Aniella Abi-Gerges, PhD
Assistant Professor of Physiology
Gilbert and Rose-Marie Chagoury School of Medicine
Lebanese American University - Byblos Campus
Telephone: +961 9 547254; Ext. 2843
Research Topic Summary
Cardiovascular diseases (CVDs) are the leading cause of mortality in the world with an estimated 17.5 million deaths reported in 2012 - a number which is expected to grow to more than 23.6 million by 2030. Heart failure (HF), the last stage of most CVDs and a highly morbid and mortal condition, is characterized by a functional impairment of heart function. HF develops after chronic exposure of the myocardium to a constellation of risk factors, including uncontrolled hypertension, coronary artery disease, obesity and smoking. Despite continuous advances in treatment and prevention strategies, specific pharmacologic therapy reversing HF is not yet available.
Diabetes is universally deemed a traditional cardiovascular risk factor and diabetic cardiomyopathy has been initially defined as a common complication in diabetic patients characterized by the presence of myocardial and structural dysfunction. However, HF associated with diabetes has received little attention and the pathophysiology of diabetic cardiomyopathy is still not fully understood. Moreover, most common antidiabetic treatments have demonstrated negative or neutral effects on outcome in these settings.
In normal myocardium, cyclic adenosine 3’-5’ monophosphate (cAMP) modulates a myriad of processes, from short-term action in contraction/relaxation to long-term effects on growth/survival. cAMP elevation, particularly through β-adrenergic receptor (β-AR) stimulation, exerts inotropic and lusitropic effects by activating cAMP-dependent protein kinase A. In turn this kinase phosphorylates key proteins of cardiac excitation-contraction coupling and modulates their function. cAMP also binds and actives the exchange protein Epac which mediates pro-hypertrophic effects of β-AR stimulation.
Impairment of cAMP-mediated signaling is a molecular hallmark of cardiac hypertrophy and heart failure, attributed to chronic activation of the sympathetic nervous system.
The main focus of the team’s research is to examine specific changes affecting cAMP and calcium pathways in diabetic cardiomyopathy and evaluate their consequences for cardiac function. Delineation of these pathways and the related molecular mechanisms underlying diabetic cardiomyopathy would open the door to improving management of diabetic patients, and potentially preventing progression of cardiomyopathy to heart failure.
Pamela Abou Khalil
Senior Science Lab Technician
Gilbert and Rose-Marie Chagoury School of Medicine
Lebanese American University, Byblos Campus
Telephone: +961 9 547254, ext. 2993
Wared Nour-Eldine, Postdoctoral Fellow
Rita Hanna, Research Assistant
Dr. Gregoire Vandecasteele and Dr. Rodolphe Fischmeister: Laboratory of Excellence in Drug Discovery and Therapeutic Innovation (Labex LERMIT, Paris), University of Paris South, France.
Yassine Sassi, Aniella Abi-Gerges, Jeremy Fauconnier, Nathalie Mougenot, Steven Reiken, Kobra Haghighi, Evangelia G Kranias, Andrew R. Marks, Alain Lacampagne, Stefan Engelhardt, Stéphane N Hatem, Anne-Marie Lompré, Jean-Sébastien Hulot. Regulation of cAMP homeostasis by the efflux protein MRP4 in cardiac myocytes. Faseb Journal (2012) 26(3):1009-17.
Jérôme Leroy, Wito Richter, Delphine Mika, Liliana RV Castro, Aniella Abi-Gerges, Moses Xie, Colleen Scheitrum, Florence Lefebvre, Julia Schittl, Ruth Westenbroek, William A. Catterall, Flavien Charpentier, Marco Conti, Rodolphe Fischmeister, and Grégoire Vandecasteele. Phosphodiesterase 4B in the cardiac L-type Ca2+ channel complex regulates Ca2+ current and protects against ventricular arrhythmias in mice. Journal of Clinical Invesigation, (2011) 121(7):2651-2661.
Aniella Abi-Gerges, Wito Richter, Florence Lefebvre, Christophe Heymes, Jane-Lise Samuel, Claire Lugnier, Marco Conti, Rodolphe Fischmeister, and Grégoire Vandecasteele. Decreased expression and activity of cAMP phosphodiesterases in cardiac hypertrophy and its impact on β-adrenergic cAMP signals. Circulation Research, (2009) 105(8):784-92.
Jérôme Leroy, Aniella Abi-Gerges, Viacheslav O Nikolaev, Wito Richter, Jean-Luc Mazet, Marco Conti, Rodolphe Fischmeister, and Grégoire Vandecasteele. Spatiotemporal dynamics of β-adrenergic cAMP signals and L-type Ca2+ channel regulation in adult rat ventricular myocytes: Role of phosphodiesterases. Circulation Research (2008) 102: 1091-100.
Rochais, F., Abi-Gerges, A., Horner, K., Lefebvre, F., Cooper, M. F., Conti, M., Fischmeister, R. & Vandecasteele, G. A specific pattern of phosphodiesterases controls the cAMP signals generated by different Gs-coupled receptors in adult rat ventricular myocytes. Circulation Research (2006) 98, 1081-1088.
PHC CEDRE, 2019 -2021 : Rôle des régulateurs de la voie β-adrénergique dans la cardiomyopathie diabétique et les arythmies.
CNRS-LAU Joint Grant, 2018-2020: Characterization of cAMP signaling pathway in diabetic cardiomyopathy: Interplay between PDEs, MRP4 and Epac.
* Pathway in normal cardiac myocytes. Upon liberation of norepinephrine from the sympathetic nerve terminals, β1-adrenergic receptors activate cardiac adenylate cyclase (AC) isoforms (AC5 and AC6) via Gs protein hence leading to cAMP production. This latter activates PKA, HCN, and Epac. PKA phosphorylates the transcription factor CREB as well as the main actors involved in the excitation-contraction coupling (ECC) mainly L-Type calcium channels (LTCCs), ryanodine receptors (RyR2), phospholamban (PLB), and troponin I (TnI). Phosphorylation of LTCCs and RYR2 leads to an increased intracellular calcium levels hence enhancing the force of contraction. PLB phosphorylation leads to an increased sarcoplasmic Ca2+ uptake by SERCA2a and TnI phosphorylation to a reduction in Ca2+ sensitivity of the myoﬁlaments, both acting to accelerate contractile relaxation. These effects are antagonized by the liberation of acetylcholine from the parasympathetic nerve terminals, through the activation of the muscarinic M2 receptors coupled to Gi protein. Finally, cAMP level is a balance between its synthesis by AC, hydrolysis by phosphodiesterases (PDEs), and efﬂux through multidrug resistant protein (MRP). Adapted from Aniella Abi-Gerges et al., Real time monitoring of cyclic nucleotide changes in Living Cells. Encyclopedia of Biophysics (2019), Chapter 377.