title: Early apoptosis in different models of cardiac hypertrophy induced by high renin-angiotensin system activity involves CaMKII.
abstract: The objective of this study was to establish whether 1) hyperactivity of renin-angiotensin-aldosterone system (RAAS) produces apoptosis in early stages of cardiac disease; and 2) Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is involved in these apoptotic events. Two models of hypertrophy were used at an early stage of cardiac disease: spontaneously hypertensive rats (SHR) and isoproterenol-treated rats (Iso-rats). At 4 mo, SHR showed blood pressure, aldosterone serum levels, used as RAAS activity index, and left ventricular mass index, used as hypertrophy index, above control values by 84.2 ± 2.6 mmHg, 211.2 ± 25.8%, and 8.6 ± 1.1 mg/mm, respectively. There was also an increase in apoptotis (Bax-to-Bcl-2 ratio and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling positive cells) associated with an enhancement of CaMKII activity with respect to age-matched controls (phosphorylated-CaMKII, 98.7 ± 14.1 above control). Similar results were observed in 4-mo-old Iso-rats. Cardiac function studied by echocardiography remained unaltered in all groups. Enalapril treatment significantly prevented hypertrophy, apoptosis, and CaMKII activity. Moreover, intracellular Ca(2+) handling in isolated myocytes was similar between SHR, Iso-rats, and their aged-matched controls. However, SHR and Iso-rats showed a significant increase in superoxide anion generation (lucigenin) and lipid peroxidation (thiobarbituric acid reactive substance). In transgenic mice with targeted cardiomyocyte expression of a CaMKII inhibitory peptide (AC3-I) or a scrambled control peptide (AC3-C), Iso treatment increased thiobarbituric acid reactive substance in both strains, whereas it increased CaMKII activity and apoptosis only in AC3-C mice. Endogenous increases in RAAS activity induce ROS and CaMKII-dependent apoptosis in vivo. CaMKII activation could not be associated with intracellular Ca(2+) increments and was directly related to the increase in oxidative stress.
authors.affiliation: Centro de Investigaciones Cardiovasculares, Consejo Nacional de Investigaciones Científicas y Técnicas-La Plata, Facultad de Medicina, Universidad Nacional de La Plata, La Plata, Argentina.
authors.forename: J Omar
authors.initials: JO
authors.lastname: Velez Rueda
authors.forename: Julieta
authors.initials: J
authors.lastname: Palomeque
authors.forename: Alicia
authors.initials: A
authors.lastname: Mattiazzi
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D004656:Enalapril / Q000494:pharmacology; D006321:Heart; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D010455:Peptides / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism
chemical_list: C527819:AC3-I peptide; D010455:Peptides; D017382:Reactive Oxygen Species; D013481:Superoxides; D000450:Aldosterone; D004656:Enalapril; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007545:Isoproterenol; D002118:Calcium