Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling

Abstract

The MAPKs are important transducers of growth and stress stimuli in virtually all eukaryotic cell types. In the mammalian heart, MAPK signaling pathways have been hypothesized to regulate myocyte growth in response to developmental signals or physiologic and pathologic stimuli. Here we generated cardiac-specific transgenic mice expressing dominant-negative mutants of p38α, MKK3, or MKK6. Remarkably, attenuation of cardiac p38 activity produced a progressive growth response and myopathy in the heart that correlated with the degree of enzymatic inhibition. Moreover, dominant-negative p38α, MKK3, and MKK6 transgenic mice each showed enhanced cardiac hypertrophy following aortic banding, Ang II infusion, isoproterenol infusion, or phenylephrine infusion for 14 days. A mechanism underlying this enhanced-growth profile was suggested by the observation that dominant-negative p38α directly augmented nuclear factor of activated T cells (NFAT) transcriptional activity and its nuclear translocation. In vivo, NFAT-dependent luciferase reporter transgenic mice showed enhanced activation in the presence of the dominant-negative p38α transgene before and after the onset of cardiac hypertrophy. More significantly, genetic disruption of the calcineurin Aβ gene rescued hypertrophic cardiomyopathy and depressed functional capacity observed in p38-inhibited mice. Collectively, these observations indicate that reduced p38 signaling in the heart promotes myocyte growth through a mechanism involving enhanced calcineurin-NFAT signaling

Protein Kinase Cε-Calcineurin Cosignaling Downstream of Toll-Like Receptor 4 Downregulates Fibrosis and Induces Wound Healing Gene Expression in Cardiac Myofibroblasts

“…PKCε was confirmed to activate an AP-1.luc reporter construct in these cells. Furthermore, potentiation of CN-dependent activation of an NFAT.luc reporter by PKCε suggests that mechanisms independent of AP-1 may also operate, such as direct posttranslational modification of NFAT itself (68,69). Both LPS and AngII activated pGL3.rCOX2.luc and NFAT.luc reporters as expected.…”

In vivo functions of mitogen-activated protein kinases: conclusions from knock-in and knock-out mice

“…In another study, 8-10 week old heterozygous p38a and p38b mice were used. In contrast to p38b mice, but similar to the former study, p38a mice showed an increased survival and resistance to myocardial infarction with no further abnormalities in body and heart weight, heart architecture, dia-and systolic blood pressure and LV pressures Braz et al 2003). The role of p38a in hypertrophy and fibrosis as a response to cardiac ischemia was addressed by construction of cardiac-specific p38a D40-83 floxed mice in C57BL/6 background.…”

“…Additionally, some researchers noted defects in T-cell function and cytokine production Kaiser et al 2004). Cardiac-specific TG mice expressing dnMEK3 displayed enhanced cardiac hypertrophy following aortic banding, angiotensin II infusion and phenilephrine infusion for 14 days (Braz et al 2003).…”

“…Skeletal preparations of TG mice that express a constitutively active MEK6 revealed a shortened axial and appendicular skeleton, which resulted in a dwarf phenotype (Zhang et al 2006). TG mice with cardiacspecific dnMEK6 showed features similar to dnMEK3 mutants and enhanced cardiac hypertrophy (Braz et al 2003). Double KO of MEK3 -/-and MEK6 -/-mice resulted in embryonic lethality due to placental and vascular defects (Brancho et al 2003;Adams et al 2000;Beardmore et al 2005).…”

Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response to Beta-Adrenergic Stimulation

“…At cellular and molecular levels, cardiac hypertrophy is characterized by increased myocyte size, sarcomerogenesis, and reexpression of a set of fetal genes, such as the atrial natriuretic factor, B-type natriuretic peptide, and ␤-myosin heavy chain genes, which are coordinately controlled by a subset of hypertrophy-responsive transcription factors, including myocyte enhancer factor 2 (MEF2), nuclear factor of activated T cells (NFAT), and GATA4 (2, 3) (4). Depending on the upstream hypertrophic stimuli, these transcriptional regulators can be directly phosphorylated or dephosphorylated by protein kinases, such as mitogen-activated protein (MAP) kinase and protein kinases A and C, as well as the calcium-activated phosphatase calcineurin, to facilitate hypertrophic gene expression (5)(6)(7)(8)(9). Disruption and/or attenuation of the activities of these transcription factors could serve as a potential therapeutic approach in terms of inhibiting the hypertrophic responses in the heart (10)(11)(12).…”