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Mitogen-activated protein kinase-activated protein kinase 2 in angiotensin II-induced inflammation and hypertension: regulation of oxidative stress.
- Source :
-
Hypertension (Dallas, Tex. : 1979) [Hypertension] 2011 Feb; Vol. 57 (2), pp. 245-54. Date of Electronic Publication: 2010 Dec 20. - Publication Year :
- 2011
-
Abstract
- Vascular oxidative stress and inflammation play an important role in angiotensin II-induced hypertension, and mitogen-activated protein kinases participate in these processes. We questioned whether mitogen-activated protein kinase-activated protein kinase 2 (MK2), a downstream target of p38 mitogen-activated protein kinase, is involved in angiotensin II-induced vascular responses. In vivo experiments were performed in wild-type and Mk2 knockout mice infused intravenously with angiotensin II. Angiotensin II induced a 30 mm Hg increase in mean blood pressure in wild-type that was delayed in Mk2 knockout mice. Angiotensin II increased superoxide production and vascular cell adhesion molecule-1 in blood vessels of wild-type but not in Mk2 knockout mice. Mk2 knockdown by small interfering RNA in mouse mesenteric vascular smooth muscle cells caused a 42% reduction in MK2 protein and blunted the angiotensin II-induced 40% increase of MK2 expression. Mk2 knockdown blunted angiotensin II-induced doubling of intracellular adhesion molecule-1 expression, 2.4-fold increase of nuclear p65, and 1.4-fold increase in Ets-1. Mk2 knockdown abrogated the angiotensin II-induced 4.7-fold and 1.3-fold increase of monocyte chemoattractant protein-1 mRNA and protein. Angiotensin II enhanced reactive oxygen species levels (by 29%) and nicotinamide adenine dinucleotide phosphate oxidase activity (by 48%), both abolished by Mk2 knockdown. Reduction of MK2 blocked angiotensin II-induced p47phox translocation to the membrane, associated with a 53% enhanced catalase expression. Angiotensin II-induced increase of MK2 was prevented by the nicotinamide adenine dinucleotide phosphate oxidase inhibitor Nox2ds-tat. Mk2 small interfering RNA prevented the angiotensin II-induced 30% increase of proliferation. In conclusion, MK2 plays a critical role in angiotensin II signaling, leading to hypertension, oxidative stress via activation of p47phox and inhibition of antioxidants, and vascular inflammation and proliferation.
- Subjects :
- Angiotensin II
Animals
Aorta metabolism
Aorta physiopathology
Blood Pressure genetics
Blood Pressure physiology
Blotting, Western
Cell Proliferation
Cells, Cultured
Chemokine CCL2 genetics
Chemokine CCL2 metabolism
Hypertension chemically induced
Hypertension physiopathology
Inflammation chemically induced
Inflammation physiopathology
Intracellular Signaling Peptides and Proteins genetics
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular cytology
Muscle, Smooth, Vascular metabolism
NADPH Oxidases metabolism
NF-kappa B metabolism
Protein Serine-Threonine Kinases genetics
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Superoxides metabolism
Vascular Cell Adhesion Molecule-1 metabolism
Hypertension metabolism
Inflammation metabolism
Intracellular Signaling Peptides and Proteins metabolism
Oxidative Stress
Protein Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4563
- Volume :
- 57
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Hypertension (Dallas, Tex. : 1979)
- Publication Type :
- Academic Journal
- Accession number :
- 21173344
- Full Text :
- https://doi.org/10.1161/HYPERTENSIONAHA.110.159889