Extracellular signal-regulated kinases 1 and 2 regulate the balance between eccentric and concentric cardiac growth.
BACKGROUND
An increase in cardiac afterload typically produces concentric hypertrophy characterized by an increase in cardiomyocyte width, whereas volume overload or exercise results in eccentric growth characterized by cellular elongation and addition of sarcomeres in series. The signaling pathways that control eccentric versus concentric heart growth are not well understood.


OBJECTIVE
To determine the role of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in regulating the cardiac hypertrophic response.


RESULTS
Here, we used mice lacking all ERK1/2 protein in the heart (Erk1(-/-) Erk2(fl/fl-Cre)) and mice expressing activated mitogen-activated protein kinase kinase (Mek)1 in the heart to induce ERK1/2 signaling, as well as mechanistic experiments in cultured myocytes to assess cellular growth characteristics associated with this signaling pathway. Although genetic deletion of all ERK1/2 from the mouse heart did not block the cardiac hypertrophic response per se, meaning that the heart still increased in weight with both aging and pathological stress stimulation, 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), whereas 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, whereas infection with an activated Mek1 adenovirus promoted constitutive ERK1/2 signaling and increased myocyte thickness. A similar effect was observed in engineered heart tissue under cyclic stretching, where ERK1/2 inhibition led to preferential lengthening.


CONCLUSIONS
Taken together, these data demonstrate that the ERK1/2 signaling pathway uniquely regulates the balance between eccentric and concentric growth of the heart.
Department of Pediatrics, Division of Molecular Cardiovascular Biology, and Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH 45229-3039, USA.
Izhak
I
Kehat
Jennifer
J
Davis
Malte
M
Tiburcy
Federica
F
Accornero
Marc K
MK
Saba-El-Leil
Marjorie
M
Maillet
Allen J
AJ
York
John N
JN
Lorenz
Wolfram H
WH
Zimmermann
Sylvain
S
Meloche
Jeffery D
JD
Molkentin
D000818:Animals; D002478:Cells, Cultured; D006984:Hypertrophy; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology
D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1