Mitogen-activated protein kinases and transcription factors during increased cardiac workload and remodelling
Tenhunen, Olli (2006-09-12)
Cardiac hypertrophy and remodelling are mechanisms of adaptation to increased workload and acute injuries of the heart. In the long-term, these initially beneficial mechanisms become detrimental and ultimately lead to the development of heart failure. The molecular determinant of myocardial remodelling and heart failure is altered intracellular signal transduction and a modified gene expression pattern in the individual cardiomyocyte. This study was aimed at characterising the changes in mitogen-activated protein kinases (MAPKs) and their nuclear effector, GATA-4, and their functional significance and interaction in experimental models of increased cardiac workload and remodelling.
To study the effects of increased cardiac workload on MAPKs and GATA-4, isolated perfused rat hearts were subjected to increased left ventricular wall stress and their activities were determined using western blot and gel mobility shift assays. Left ventricular wall stress rapidly activated the DNA binding of GATA-4, and this activation was abolished in the presence of endothelin-1 (ET-1) and angiotensin II receptor antagonists. Furthermore, the activation of GATA-4 DNA binding was significantly attenuated by p38 MAPK and extracellular signal regulated kinase (ERK) inhibition. To gain further insights into the role of p38 MAPK as a regulator of cardiac transcription factors, gene expression and remodelling, a gene transfer protocol of increased p38 MAPK activity was established. Direct adenovirus-mediated gene transfer of wild-type p38α and constitutively active upstream kinase mitogen-activated kinase kinase 3b (MKK3b) selectively increased p38 MAPK activity in the left ventricle, which was followed by up-regulation of cardiac gene expression, myocardial inflammation and fibrosis. Using a DNA microarray approach, the cardiac target genes of p38 MAPK were identified, including several cell division, inflammation and signal transduction-associated genes. Furthermore, p38 MAPK over-expression was found to increase the DNA binding activities of several transcription factors, including GATA-4. Finally, the functional role of p38 MAPK was determined using adenovirus-mediated gene transfer in an experimental model of myocardial infarction. Post-infarction remodelling was characterised by a sustained down-regulation of p38 MAPK, while rescue of p38 MAPK activity attenuated post-infarction remodelling through anti-apoptotic and angiogenic mechanisms.
These results indicate that p38 MAPK is a key regulator of GATA-4 transcription factor and cardiac gene expression during left ventricular wall stress and remodelling. They demonstrate that p38 MAPK, being cardioprotective in the infarcted heart but promoting inflammation and fibrosis in the normal heart, has a unique dual role in the myocardium.
- Avoin saatavuus