ERK1/2 regulate the balance between eccentric and concentric growth of the heart

Izhak Kehat ¹ Jennifer Davis ² Malte Tiburcy ³ Federica Accornero ² John Lorenz ⁴ Wolfram H. Zimmermann ³ Sylvain Meloche ⁵ Jeffery D. Molkentin ^2,4

¹Physiology, Technion-Israel Institute of Technology, Haifa
²Division of Molecular Cardiovascular Biology, The Howard Hughes Medical Institute, Cincinnati, OH
³Department of Pharmacology and Heart Research Center, Georg-August-University Goettingen, Goettingen
⁴Physiology, University of Cincinnati, Cincinnati, OH
⁵Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Montréal

Introduction: The myocardium undergoes cellular and ventricular chamber remodeling and hypertrophy as a means of maintaining cardiac output in response to increased workload. An increase in cardiac afterload typically produces concentric hypertrophy characterized by an increase in cardiomyocyte width, while volume overload results in eccentric growth, characterized by cellular elongation and addition of sarcomeres in series. Concentric and eccentric growth likely result from orchestrated activation of specific intracellular signaling pathways, although the identity and mechanisms whereby these signaling pathways differentially regulate myocyte growth are not currently known.

Material and Methods: To determine the role of extracellular signal-regulated kinases 1/2 (ERK1/2) in regulating the cardiac hypertrophic response we used mice lacking all ERK1/2 protein in the heart by crossing Erk1^–/– mice with Erk2^fl/fl targeted mice and a cardiac Cre-recombinase expressing line (Erk1^–/–;Erk2^fl/fl-Cre). We also studied mice expressing activated MEK1 in the heart to induce ERK1/2 signaling and used mechanistic experiments in cultured myocytes to assess cellular growth characteristics associated with this signaling pathway.

Results: While loss of all ERK1/2 from the heart did not block the cardiac hypertrophic response per se, it did dramatically alter how the heart grew. For example, adult myocytes from hearts of Erk1^–/–;Erk2^fl/fl-Cre mice showed preferential eccentric growth (lengthening) while myocytes from MEK1 transgenic hearts showed concentric growth (width increase). Isolated adult myocytes acutely inhibited for ERK1/2 signaling by adenoviral gene transfer showed spontaneous lengthening while infection with an activated MEK1 adenovirus promoted constitutive ERK1/2 signaling and increased myocyte thickness.

Conclusions: Taken together these data demonstrate that the ERK1/2 signaling pathway uniquely regulates the balance between eccentric and concentric growth of the heart. Thus, the MEK1-ERK1/2 pathway may be the first identified signaling pathway capable of specifically directing the mode of cardiomyocyte hypertrophy.