Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy

Abstract

Mitogen-activated protein kinase (MAPK) pathways couple intrinsic and extrinsic signals to hypertrophic growth of cardiomyocytes. The MAPK kinase MEK5 activates the MAPK ERK5. To investigate the potential involvement of MEK5±ERK5 in cardiac hypertrophy, we expressed constitutively active and dominant-negative forms of MEK5 in cardiomyocytes in vitro. MEK5 induced a form of hypertrophy in which cardiomyocytes acquired an elongated morphology and sarcomeres were assembled in a serial manner. The cytokine leukemia inhibitory factor (LIF), which stimulates MEK5 activity, evoked a similar response. Moreover, a dominant-negative MEK5 mutant speci®cally blocked LIF-induced elongation of cardiomyocytes and reduced expression of fetal cardiac genes without blocking other aspects of LIFinduced hypertrophy. Consistent with the ability of MEK5 to induce serial assembly of sarcomeres in vitro, cardiac-speci®c expression of activated MEK5 in transgenic mice resulted in eccentric cardiac hypertrophy that progressed to dilated cardiomyopathy and sudden death. These ®ndings reveal a speci®c role for MEK5±ERK5 in the induction of eccentric cardiac hypertrophy and in transduction of cytokine signals that regulate serial sarcomere assembly. Keywords: dilated cardiomyopathy/heart/leukemia inhibitory factor/mitogen-activated protein kinase IntroductionCardiac cells do not divide after birth, so both normal growth of the myocardium and stress-induced myocardial remodeling must take place through hypertrophic growth without cell division (MacLellan and Schneider, 2000). Cardiac hypertrophy can occur by an increase in width of myo®brils, resulting in a thickening of the myocardial wall or`concentric hypertrophy', or by an increase in myo®bril length, producing chamber dilation or`eccentric hypertrophy'. These contrasting forms of hypertrophy are coupled to parallel versus serial assembly of sarcomeres, respectively. In the case of normal physiological growth or exercise-induced hypertrophy, concentric and eccentric hypertrophy occur simultaneously and in a balanced manner, enabling the heart to increase pumping capacity in response to increased demand. Disease states that put stress on the heart can also induce hypertrophy; however, depending on the stimulus, either concentric or eccentric hypertrophy may predominate. Although hypertrophy may compensate initially for the additional demands placed on the heart by disease, continued stress almost inevitably results in decompensation and the development of hypertrophic or dilated cardiomyopathy. In order for any form of hypertrophic remodeling to occur, stress stimuli must activate signaling pathways that regulate protein synthesis, sarcomeric assembly and organization, and gene expression (Sugden and Clerk, 1998;Chien, 1999;Nicol et al., 2000).Mitogen-activated protein kinase (MAPK) pathways provide an important connection between external stimuli that activate a wide variety of cell signaling systems and the nucleus. At the core of each MAPK cascade is a threekinase module in which the m...

Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure

“…The adoption of an elongated cardiomyocyte morphology in eccentric hypertrophy models precedes the development of cardiac dysfunction (19), suggesting this pattern of cardiomyocyte hypertrophy is not a simple epiphenomenon of heart failure. Rather, eccentric hypertrophy results from the activation of specific signaling pathways, such as the mitogen-activated protein kinase 5 (Erk5) pathway (20). We found that Erk5 activity was increased by pressure overload (Fig.…”

MAP3Ks as central regulators of cell fate during development

“…In addition, fibroblasts from MEK5-deficient embryos fail to induce Myocyte enhancing factor 2 (MEF2) activity, which is a downstream mediator of ERK5. Importantly, overexpression of MEK5 to the heart in mice leads to hypertrophy and eventually dilated cardiomyopathy (Nicol et al, 2001). Activation of p38, JNK, ERK1/2, and NF B signaling pathways are necessary for epithelial to mesenchymal transition (EMT) with each having an effect during mesenchyme production (Compton et al, 2006;Rivera-Feliciano et al, 2006;Santibanez, 2006;Grund et al, 2008).…”

The mAKAP signalosome and cardiac myocyte hypertrophy

“…Chronic b-adrenergic stimulation in vivo results in the secretion of IL-6 type cytokines such as leukemia inhibitory factor by both cardiac fibroblasts and myocytes (31). Cytokine and catecholaminergic stimulation of myocyte gp130/LIF and a-adrenergic receptors, respectively, will activate the ERK5 MAPK pathway (32), resulting in synergistic PKA activity, through PDE4D3 inhibition. Epac1 is activated by a one-hundred fold higher concentration of cAMP than PKA (K act, Epac1 ¼ 10 75 710 74 M) (29).…”

“…The mAKAPb signalosome includes ERK5 and calcineurin Ab, two enzymes that can induce myocyte hypertrophy (32,40). We have tested whether mAKAPb expression is required for myocyte hypertrophy.…”