The AP-1 Transcription Factor c-Jun Prevents Stress-Imposed Maladaptive Remodeling of the Heart

Abstract

Systemic hypertension increases cardiac workload and subsequently induces signaling networks in heart that underlie myocyte growth (hypertrophic response) through expansion of sarcomeres with the aim to increase contractility. However, conditions of increased workload can induce both adaptive and maladaptive growth of heart muscle. Previous studies implicate two members of the AP-1 transcription factor family, junD and fra-1, in regulation of heart growth during hypertrophic response. In this study, we investigate the function of the AP-1 transcription factors, c-jun and c-fos, in heart growth. Using pressure overload-induced cardiac hypertrophy in mice and targeted deletion of Jun or Fos in cardiomyocytes, we show that c-jun is required for adaptive cardiac hypertrophy, while c-fos is dispensable in this context. c-jun promotes expression of sarcomere proteins and suppresses expression of extracellular matrix proteins. Capacity of cardiac muscle to contract depends on organization of principal thick and thin filaments, myosin and actin, within the sarcomere. In line with decreased expression of sarcomere-associated proteins, Jun-deficient cardiomyocytes present disarrangement of filaments in sarcomeres and actin cytoskeleton disorganization. Moreover, Jun-deficient hearts subjected to pressure overload display pronounced fibrosis and increased myocyte apoptosis finally resulting in dilated cardiomyopathy. In conclusion, c-jun but not c-fos is required to induce a transcriptional program aimed at adapting heart growth upon increased workload.

ATF3-dependent cross-talk between cardiomyocytes and macrophages promotes cardiac maladaptive remodeling

“…On the other hand, JunD protects cardiomyocytes from undergoing apoptosis and hypertrophy by inhibiting AP-1 activity [14,15]. More recently, c-Jun was found to play a protective role in pressure overload maladaptive cardiac hypertrophy [16]. Collectively, these studies demonstrate that the AP-1 transcription factor targets gene programs that both induce and suppress apoptosis and hypertrophy, depending on AP-1 complex composition, expression level and the specific insult exerted.…”

Regulation of Hspb7 by MEF2 and AP-1: implications for Hspb7 in muscle atrophy

“…MEF2 has a well-established role in sarcomere organization, because it regulates key target genes associated with the costamere and sarcomeric proteins (Ewen et al, 2011;Hinits and Hughes, 2007;Potthoff et al, 2007). There are fewer studies that have investigated the role of AP-1 in sarcomere integrity; however, in cardiomyocytes c-Jun has been shown to have an important role in promoting sarcomere gene expression and sarcomere integrity (Windak et al, 2013). Interestingly, destabilization of the actin cytoskeleton triggers cJun activity in vitro and represses glucocorticoid receptor activity (Oren et al, 1999).…”

“…Additionally, although loss of MEF2 and AP-1 have been implicated in loss of sarcomere integrity during development and satellite cell-mediated muscle regeneration (Hinits and Hughes, 2007;Potthoff et al, 2007;Windak et al, 2013), the combined role of these factors in muscle atrophy has not been investigated. Here, we document that MEF2 and AP-1 regulate several genes associated with the actin cytoskeleton.…”

Role of the bradykinin B2 receptor in a rat model of local heart irradiation

“…1987). c-Jun has recently been shown to prevent myocardial fibrosis and cardiomyocyte apoptosis in cardiac adverse remodeling (Windak et al 2013). The kinases classically associated with c-Jun phosphorylation belong to the c-Jun N-terminal kinase (JNK) family, although c-Jun can also be phosphorylated through Erk 1/2 signaling (Leppä et al 1998).…”

“…Moreover, while in BN rats radiation induced phosphorylation of extracellular signal-regulated kinase (Erk) 1/2, a mitogen-activated protein kinase known for its beneficial effects in the heart (Das et al 2009), Erk 1/2 phosphorylation was not observed in BN/Ka animals. Similarly, kininogen-deficiency prevented radiation-induced phosphorylation of c-jun, a transcription factor that has recently been shown to reduce adverse cardiac remodeling (Windak et al 2013). Here, we investigate the role of the B2 receptor in signaling events and inflammatory infiltration leading up to adverse remodeling in the irradiated heart by blocking the receptor pharmacologically using the bradykinin analog, HOE-140 (icatibant), a B2 receptor-selective antagonist (Wirth et al 1991).…”