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

Abstract

Rationale An increase in cardiac afterload typically produces concentric hypertrophy characterized by an increase in cardiomyocyte width, while 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 kinases 1/2 in regulating the cardiac hypertrophic response. Methods and results Here we used mice lacking all ERK1/2 protein in the heart (Erk1−/− Erk2fl/fl-Cre) and mice expressing activated Mek1 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. While 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 pathologic stress stimulation, it did dramatically alter how the heart grew. For example, adult myocytes from hearts of Erk1−/− Erk2fl/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. A similar effect was observed in engineered heart tissue under cyclical 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. Summary We studied mice lacking all ERK1/2 protein in the heart and mice expressing activated Mek1 in the heart to evaluate the role of the ERK 1/2 signaling cascade in regulating the cardiac hypertrophic response. While activation of the ERK pathway induced concentric hypertrophy, inhibition of this pathway resulted in eccentric hypertrophy. Using cardiomyocytes isolated from these mouse models, and using ex vivo culture models we show that these effects were mediated directly by ERK signaling. Greater ERK1/2 signaling directly programmed myocyte thickening while inhibition of ERK1/2 signaling promoted myocyte lengthening. Thus, this study sheds light on the molecular mechanisms that are partially responsible for the differential hypertrophic response of the heart to an increase in preload versus afterload.

Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events

“…Mitogen‐activated protein kinases (MAPKs) and, especially, extracellular signal‐regulated kinase (ERK), which is activated by virtually all hypertrophic stimuli in cardiomyocytes, represent the central pathway regulating transcription of ANP and BNP 17. Constitutive activation of MEK1 (upstream activator of ERK) in myocytes induces cardiac hypertrophy and NP expression,18 but loss of ERK from cardiomyocytes is not sufficient to block stress‐induced hypertrophic response 19. In addition to ERK, p38 MAPK has been shown to regulate NP expression in primary cardiomyocyte culture.…”

Growth Arrest–Specific 6 Exacerbates Pressure Overload–Induced Cardiac Hypertrophy

“…However, with increasing numbers of studies using genetic models, the effect of ERK1/2 in cardiac hypertrophy becomes complicated. Studies using overexpression 32 or knockout 33,34 animal model of MEK-ERK signaling both demonstrated deteriorative phenotype of cardiac hypertrophy, which suggested that excess ERK activation or complete deletion of ERK is both detrimental to cardiac hypertrophy. In consistent with this hypothesis, some recent studies have demonstrated that an excessive activation of ERK1/2 leads to more severe cardiac hypertrophy and function.…”

Systems Analysis of the Cardiac Myocyte Hypertrophy Signaling Network

“…Since eccentric hypertrophy has been linked to higher risk for systolic dysfunction and heart failure [31], [144], there has been great interest in learning about specific signaling pathways that regulate myocyte elongation [30], [145]. Increased CITED4 may therefore be beneficial to ~ 126 ~ the heart by preventing high levels of myocyte elongation in addition to its previously studied role in exercise induced myocyte proliferation.…”

“…Conversely, volume overload due to stimuli such as aortic regurgitation, arteriovenous fistulas, aerobic exercise, and pregnancy increases diastolic wall stress and results in eccentric hypertrophy, where the left ventricle dilates [29]. Little is known about the specific signaling pathways that determine myocyte elongation and eccentric hypertrophy versus increased myocyte thickness and concentric hypertrophy [30]. Since eccentric hypertrophy is a greater risk to patients than concentric ~ 10 ~ hypertrophy [31] , increased knowledge of the unique signaling pathways controlling these growth patterns will be vital in improving therapies for heart failure.…”

“…Previous work suggests that myocyte size is regulated by common signaling pathways and myocyte shape is regulated by distinct signaling pathways [37], [104]. But little is known about the specific signaling pathways that induce distinct characteristics of hypertrophy [18], [105].…”