Extracellular Signal-Regulated Kinases 1 and 2 Regulate the Balance Between Eccentric and Concentric Cardiac Growth

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.
Circulation Research (Impact Factor: 11.02). 02/2011; 108(2):176-83. DOI: 10.1161/CIRCRESAHA.110.231514
Source: PubMed


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.
To determine the role of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in regulating the cardiac hypertrophic response.
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.
Taken together, these data demonstrate that the ERK1/2 signaling pathway uniquely regulates the balance between eccentric and concentric growth of the heart.

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    • "To further investigate the potential role of the ERK1/2 and AKT pathway in the hypertrophic-inhibiting effect of AT in TAC, we analyzed a typical downstream target, GATA4. GATA4 is a zinc finger, containing transcription factor that plays key roles in promoting heart growth and regulating cardiac hypertrophy [13, 14], and is associated with multiple hypertrophic signaling pathways, such as ERK1/2 [15], p38, Akt [16], and CnA/NFATc3 [17]. As shown in Figure 7, protein expression of GATA4 in the NS-TAC group was significantly increased compared with NS-SHAM group (P < 0.05), in consistence with literature [18, 19]. "
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