Identification of Cell Cycle Regulatory and Inflammatory Genes As Predominant Targets of p38 Mitogen-Activated Protein Kinase in the Heart

Abstract

Abstract-Mitogen-activated protein kinases (MAPKs) regulate cardiomyocyte growth and apoptosis in response to extracellular stimulation, but the downstream effectors that mediate their pathophysiological effects remain poorly understood. We determined the targets and role of p38 MAPK in the heart in vivo by using local adenovirus-mediated gene transfer of constitutively active upstream kinase mitogen-activated protein kinase kinase 3b (MKK3bE) and wild-type p38␣ in rats. DNA microarray analysis of animals with cardiac-specific overexpression of p38 MAPK revealed that 264 genes were upregulated more than 2-fold including multiple genes controlling cell division, cell signaling, inflammation, adhesion, and transcription. A large number of previously unknown p38 target genes were found. Using gel mobility-shift assays we identified several cardiac transcription factors that were directly activated by p38 MAPK. Finally, we determined the functional significance of the altered cardiac gene-expression profile by histological analysis and echocardiographic measurements, which indicated that p38 MAPK overexpression-induced gene expression results in myocardial cell proliferation, inflammation, and fibrosis. In conclusion, we defined the novel target genes and transcription factors as well as the functional effects of p38 MAPK in the heart. Expression profiling of p38 MAPK overexpression identified cell cycle regulatory and inflammatory genes critical for pathological processes in the adult heart. (Circ Res. 2006;99:485-493.)

Extracellular superoxide dismutase protects the heart against oxidative stress and hypertrophy after myocardial infarction

“…Activation of p38 by TAK1 induced ventricular hypertrophy [41]. Tenhunen et al [42] injected adenovirus encoding wild-type p38-MAPKα together with a constitutively-activated upstream kinase into the hearts of rats; the hearts overexpressing p38 MAPK had increased expression of genes related to cell cycle progression and inflammation together with large areas of fibrosis. This observation, which is consistent with the established link between the p38 MAPK pathway and inflammatory responses in other organ systems, is similar to the findings in the peri-infarct region in the present study.…”

Mitogen-Activated Protein Kinases in Heart Development and Diseases

“…115 Other than fetal genes induction, several studies using gene expression profiling and detailed biochemical analysis implicated an induction of the inflammatory response and cell cycle regulation as a major consequence of constitutive p38 activation in the heart. 64,116 The induction of inflammatory cytokines can generate a positive feedback loop, leading to sustained p38 activation in the heart. 117 This observation is in agreement with the restrictive cardiomyopathy phenotype found in the p38-activated transgenic mouse heart, including extensive interstitial remodeling and stiffening of myocardium without chamber hypertrophy or dilatation.…”

Engineered Early Embryonic Cardiac Tissue Increases Cardiomyocyte Proliferation by Cyclic Mechanical Stretch via p38-MAP Kinase Phosphorylation

“…7,[18][19][20] Recent studies have also shown that p38MAPK plays a key role in CM proliferation in both developing fetal and postnatal myocardium. 19,[21][22][23] Therefore, the purpose of the present study was to elucidate the factors that regulate the proliferation activity of immature CMs within an in vitro-engineered cardiac tissue construct independent of the non-CM population proliferation activity. We tested the hypothesis that cyclic mechanical stretch increases specifically CM proliferation within EEECT and the inhibition of p38MAPK activity decreases CM proliferation.…”