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Calcineurin Blockade Prevents Cardiac Mitogen-activated Protein Kinase Activation and Hypertrophy in Renovascular Hypertension
- Source :
- Journal of Biological Chemistry. 275:40867-40873
- Publication Year :
- 2000
- Publisher :
- Elsevier BV, 2000.
-
Abstract
- Chronic stimulation of the renin-angiotensin system induces an elevation of blood pressure and the development of cardiac hypertrophy via the actions of its effector, angiotensin II. In cardiomyocytes, mitogen-activated protein kinases as well as protein kinase C isoforms have been shown to be important in the transduction of trophic signals. The Ca(2+)/calmodulin-dependent phosphatase calcineurin has also been suggested to play a role in cardiac growth. In the present report, we investigate possible cross-talks between calcineurin, protein kinase C, and mitogen-activated protein kinase pathways in controlling angiotensin II-induced hypertrophy. Angiotensin II-stimulated cardiomyocytes and mice with angiotensin II-dependent renovascular hypertension were treated with the calcineurin inhibitor cyclosporin A. Calcineurin, protein kinase C, and mitogen-activated protein kinase activations were determined. We show that cyclosporin A blocks angiotensin II-induced mitogen-activated protein kinase activation in cultured primary cardiomyocytes and in the heart of hypertensive mice. Cyclosporin A also inhibits specific protein kinase C isoforms. In vivo, cyclosporin A prevents the development of cardiac hypertrophy, and this effect appears to be independent of hemodynamic changes. These data suggest cross-talks between the calcineurin pathway, the protein kinase C, and the mitogen-activated protein kinase signaling cascades in transducing angiotensin II-mediated stimuli in cardiomyocytes and could provide the basis for an integrated model of cardiac hypertrophy.
- Subjects :
- Male
Angiotensin receptor
medicine.medical_specialty
Calcineurin Inhibitors
Cardiomegaly
Pharmacology
Mitogen-activated protein kinase kinase
Biochemistry
Mice
Internal medicine
Ca2+/calmodulin-dependent protein kinase
medicine
Animals
ASK1
Protein kinase A
Molecular Biology
Protein Kinase C
biology
MAP kinase kinase kinase
Chemistry
Angiotensin II
Calcineurin
Myocardium
Cyclin-dependent kinase 2
Cell Biology
Enzyme Activation
Mice, Inbred C57BL
Hypertension, Renovascular
Endocrinology
Cyclosporine
biology.protein
Mitogen-Activated Protein Kinases
cGMP-dependent protein kinase
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 275
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....1a010259e09c2a14b2cc43a4e8c61faa
- Full Text :
- https://doi.org/10.1074/jbc.m008071200