Distinct gene expression profiles in adult mouse heart following targeted MAP kinase activation

Abstract

Three major MAP kinase signaling cascades, ERK, p38, and JNK, play significant roles in the development of cardiac hypertrophy and heart failure in response to external stress and neural/hormonal stimuli. To study the specific function of each MAP kinase branch in adult heart, we have generated three transgenic mouse models with cardiac-specific and temporally regulated expression of activated mutants of Ras, MAP kinase kinase (MKK)3, and MKK7, which are selective upstream activators for ERK, p38, and JNK, respectively. Gene expression profiles in transgenic adult hearts were determined using cDNA microarrays at both early (4-7 days) and late (2-4 wk) time points following transgene induction. From this study, we revealed common changes in gene expression among the three models, particularly involving extracellular matrix remodeling. However, distinct expression patterns characteristic for each pathway were also identified in cell signaling, growth, and physiology. In addition, genes with dynamic expression differences between early vs. late stages illustrated primary vs. secondary changes on MAP kinase activation in adult hearts. These results provide an overview to both short-term and long-term effects of MAP kinase activation in heart and support some common as well as unique roles for each MAP kinase cascade in the development of heart failure.

MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1L613V mutation

“…HRas G12V display HCM associated with interstitial fibrosis and sudden death (20)(21)(22). Cardiac-specific Nf1-deleted mice develop marked cardiac hypertrophy, progressive cardiomyopathy, and fibrosis as adults (71).…”

“…Some data argue that excessive activity of this pathway causes HCM, whereas other evidence suggests involvement in physiological, but not pathological, hypertrophy (18,19). Transgenic mice with cardiac-specific expression of oncogenic HRas (G12V) display significant cardiac hypertrophy, decreased contractility, diastolic dysfunction associated with interstitial fibrosis, induction of cardiac fetal genes, and sudden death (20)(21)(22), all of which are consistent with HCM. In cultured cardiomyocytes, depletion of Erk1/2 with antisense oligonucleotides or pharmacological inhibition of Mek1/2 attenuates the hypertrophic response to agonist stimulation (23,24).…”

Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies

“…Gene expression profiling from temporally regulated V12H RAS transgenic hearts has suggested that induction of early response genes, loss of mitochondrial function and altered ionic channel proteins are the likely culprits of the pathological changes in extracellular matrix remodeling, cardiac output and electrophysiological parameters (96). Recent work has suggested that the selective induction of Gαi in the RAS transgenic heart contributes to impaired sarcoplasmic reticulum calcium cycling (97), and a number of other studies have led to descriptions of RAS-induced alterations in calcium transients (98)(99)(100).…”

What is hidden in the pannexin treasure trove: the sneak peek and the guesswork

“…Beside that, in mouse heart Panx1 expression significantly increases as result of the selective ERK, p38 and JNK activations [116]. These findings were obtained in the high-throughput study of adult mice expressing activated mutants of Ras, MKK3 and MKK7 in the cardiac specific and temporally regulated fashion.…”