Functional significance of activation of calcium/calmodulin-dependent protein kinase II in angiotensin II--induced vascular hyperplasia and hypertension.

Abstract

We have reported that norepinephrine (NE) and angiotensin II (Ang II) increase CaM kinase II activity, which, in turn, activates cytosolic phospholipase A(2) (PLA(2)) and releases arachidonic acid. The products of arachidonic acid generated via cytochrome P-450 and lipoxygenase contribute to the development of hypertension and vascular smooth muscle cell (VSMC) hyperplasia. The purpose of this study was to investigate whether CaM kinase II contributes to VSMC proliferation elicited by NE and Ang II and to hypertension induced by Ang II. NE (1 micromol/L) and Ang II (1 micromol/L) increased proliferation of rabbit aortic VSMC as measured by increased [(3)H]-thymidine incorporation; this effect of NE and Ang II was attenuated 88 +/- 10% and 64 +/- 11% by the CaM kinase II inhibitor KN-93, respectively. Infusion of Ang II with miniosmotic pumps (350 ng/min for 6 days) in rats elevated mean arterial pressure (MABP), which was reduced by simultaneous infusion of KN-93 (578 ng/min, for 6 days) (Ang II alone: MABP =174 +/- 3 mm Hg, n=12 versus Ang II + KN-93: MABP 123 +/- 5 mm Hg, n=4, P<0.05). Administration of KN-93 as a single bolus injection (16 mg/Kg), but not its vehicle, in Ang II--infused hypertensive animals also decreased MABP from 179 +/- 9 mm Hg to 109 +/- 6 mm Hg (n=5, P<0.05). CaM kinase II activity was increased in the kidney of Ang II--infused hypertensive animals compared with normotensive controls. Treatment with KN-93 reduced CaM kinase II activity and ameliorated the intravascular injury in the kidneys of Ang II--infused hypertensive rats. Our data indicate that CaM kinase activation represents an important component of the mechanism(s) initiating VSMC proliferation and the development and maintenance of Ang II--induced hypertension in rat.

• Authors: Mubarack M Muthalif, Nour A Karzoun, Ibrahim F Benter, Lillian Gaber, Farid Ljuca, Mohammed R Uddin, Zinat Khandekar, Anne Estes, Kafait U Malik
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 39 Issue 2 Pt 2 Pg. 704-9 (Feb 2002) ISSN: 1524-4563 [Electronic] United States
• PMID: 11882635 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Angiotensin II
• DNA
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Calcium-Calmodulin-Dependent Protein Kinases
• Norepinephrine

Topics

• Angiotensin II (pharmacology)
• Animals
• Blood Vessels (pathology)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Calcium-Calmodulin-Dependent Protein Kinases (metabolism)
• Cell Cycle (drug effects)
• DNA (biosynthesis, drug effects)
• Disease Models, Animal
• Enzyme Activation
• Hyperplasia (chemically induced, enzymology)
• Hypertension (chemically induced, enzymology, pathology)
• Male
• Norepinephrine (pharmacology)
• Phosphorylation
• Rabbits
• Rats
• Rats, Sprague-Dawley