title: Rho kinase activation and gene expression related to vascular remodeling in normotensive rats with high angiotensin I converting enzyme levels.
abstract: The RhoA/Rho kinase (ROCK) pathway is a new mechanism of remodeling and vasoconstriction. Few data are available regarding ROCK activation when angiotensin I-converting enzyme is high and blood pressure is normal. We hypothesized that ROCK is activated in the vascular wall in normotensive rats with genetically high angiotensin I-converting enzyme levels, and it causes increased vascular expression of genes promoting vascular remodeling and also oxidative stress. Aortic ROCK activation, mRNA and protein levels (of monocyte chemoattractant protein-1, transforming growth factor [TGF]-beta(1), and plasminogen activator inhibitor-1 [PAI-1]), NADPH oxidase activity, and O(2)(*-) production were measured in normotensive rats with genetically high (Brown Norway [BN]) and low (Lewis) angiotensin-I-converting enzyme levels and in BN rats treated with the ROCK antagonist fasudil (100 mg/kg per day) for 7 days. ROCK activation was 12-fold higher in BN versus Lewis rats (P<0.05) and was reduced with fasudil by 100% (P<0.05). Aortic TGF-beta1, PAI-1, and monocyte chemoattractant protein-1 mRNA levels were higher in BN versus Lewis rats by 300%, 180%, and 1000%, respectively (P<0.05). Aortic TGF-beta1, PAI-1, and monocyte chemoattractant protein-1 protein levels were higher in BN versus Lewis rats (P<0,05). Fasudil reduced TGF-beta1 and PAI-1 mRNA and TGF-beta1, PAI-1, and monocyte chemoattractant protein-1 protein aortic levels to those observed in Lewis rats. Aortic reduced nicotinamide-adenine dinucleotide phosphate oxidase activity and (*)O(2)(-) production were increased by 88% and 300%, respectively, in BN rats (P<0.05) and normalized by fasudil. In conclusion, ROCK is significantly activated in the aortic wall in normotensive rats with genetically high angiotensin-I-converting enzyme and angiotensin II, and it causes activation of genes that promote vascular remodeling and also increases vascular oxidative stress.
authors.affiliation: Department of Cardiovascular Diseases, Medical School, P. Universidad Católica de Chile, Santiago, Chile.
authors.forename: Paulina
authors.initials: P
authors.lastname: Rivera
authors.forename: María Paz
authors.initials: MP
authors.lastname: Ocaranza
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Jalil
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress / Q000502:physiology; D007703:Peptidyl-Dipeptidase A / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology*; D054460:rho-Associated Kinases