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: J Omar Velez Rueda, Julieta Palomeque, Alicia Mattiazzi
• Journal: Journal of applied physiology (Bethesda, Md. : 1985) (J Appl Physiol (1985)) Vol. 112 Issue 12 Pg. 2110-20 (Jun 2012) ISSN: 1522-1601 [Electronic] United States
• PMID: 22492934 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AC3-I peptide
• Peptides
• Reactive Oxygen Species
• Superoxides
• Aldosterone
• Enalapril
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Isoproterenol
• Calcium

Topics

• Aldosterone (blood)
• Animals
• Apoptosis (physiology)
• Blood Pressure (physiology)
• Calcium (metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
• Enalapril (pharmacology)
• Heart
• Hypertrophy, Left Ventricular (metabolism, physiopathology)
• Isoproterenol (pharmacology)
• Lipid Peroxidation (physiology)
• Male
• Mice
• Mice, Transgenic
• Myocytes, Cardiac (metabolism, physiology)
• Oxidative Stress (physiology)
• Peptides (metabolism)
• Rats
• Rats, Inbred SHR
• Rats, Wistar
• Reactive Oxygen Species (metabolism)
• Renin-Angiotensin System (physiology)
• Superoxides (metabolism)