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Early apoptosis in different models of cardiac hypertrophy induced by high renin-angiotensin system activity involves
J Omar Velez Rueda1, Julieta Palomeque, Alicia Mattiazzi
1Centro de Investigaciones Cardiovasculares, Consejo Nacional de Investigaciones Científicas y Técnicas-La Plata, Facultad de Medicina, Universidad Nacional de La Plata, La Plata, Argentina.
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.
Insights
Hyperactivity of the renin-angiotensin-aldosterone system (RAAS) causes heart cell death (apoptosis) in early cardiac disease, involving Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) and oxidative stress.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Biochemistry
Background:
- Hyperactivity of the renin-angiotensin-aldosterone system (RAAS) is implicated in cardiac disease progression.
- Calcium signaling and Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) play crucial roles in cardiac function and pathology.
- Oxidative stress is a known contributor to cardiovascular damage.
Purpose of the Study:
- To determine if RAAS hyperactivity induces apoptosis in early cardiac disease.
- To investigate the involvement of CaMKII in RAAS-induced cardiac apoptosis.
- To explore the relationship between RAAS, CaMKII, oxidative stress, and apoptosis in the heart.
Main Methods:
- Utilized spontaneously hypertensive rats (SHR) and isoproterenol-treated rats (Iso-rats) as models of early cardiac disease.
- Assessed cardiac hypertrophy, apoptosis markers (Bax/Bcl-2 ratio, TUNEL assay), RAAS activity (aldosterone), and CaMKII activity.
- Measured intracellular Ca(2+) handling, superoxide anion generation, and lipid peroxidation.
- Employed transgenic mice expressing CaMKII inhibitory or control peptides to elucidate CaMKII's role.
Main Results:
- SHR and Iso-rats exhibited elevated blood pressure, RAAS activity, cardiac hypertrophy, apoptosis, and enhanced CaMKII activity.
- Cardiac function remained unaltered, but oxidative stress markers (superoxide, lipid peroxidation) were increased.
- Enalapril treatment attenuated hypertrophy, apoptosis, and CaMKII activity.
- CaMKII activation was linked to oxidative stress, not intracellular Ca(2+) changes, and mediated apoptosis in vivo.
Conclusions:
- Endogenous RAAS hyperactivity directly induces oxidative stress and CaMKII-dependent apoptosis in early cardiac disease.
- CaMKII activation in this context is driven by oxidative stress rather than altered intracellular calcium handling.
- Targeting CaMKII or RAAS may offer therapeutic strategies for preventing apoptosis in early-stage cardiac conditions.
