title: 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.affiliation: Department of Pharmacology and Vascular Biology, Center of Excellence, College of Medicine, The University of Tennessee, Baptist Memorial Hospital, Memphis 38163, USA.
authors.forename: Mubarack M
authors.initials: MM
authors.lastname: Muthalif
authors.forename: Nour A
authors.initials: NA
authors.lastname: Karzoun
authors.forename: Ibrahim F
authors.initials: IF
authors.lastname: Benter
authors.forename: Lillian
authors.initials: L
authors.lastname: Gaber
authors.forename: Farid
authors.initials: F
authors.lastname: Ljuca
authors.forename: Mohammed R
authors.initials: MR
authors.lastname: Uddin
authors.forename: Zinat
authors.initials: Z
authors.lastname: Khandekar
authors.forename: Anne
authors.initials: A
authors.lastname: Estes
authors.forename: Kafait U
authors.initials: KU
authors.lastname: Malik
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001808:Blood Vessels / Q000473:pathology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006965:Hyperplasia / Q000139:chemically induced / Q000201:enzymology; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010766:Phosphorylation; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000804:Angiotensin II; D004247:DNA; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D009638:Norepinephrine