Cardiomyocyte apoptosis and cardiac angiotensin-converting enzyme in spontaneously hypertensive rats
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J Díez1, A Panizo, M Hernández
1Vascular Pathophysiology Unit, School of Medicine, University of Navarra, Pamplona, Spain.
Insights
In spontaneously hypertensive rats, cardiac cell death (apoptosis) develops later than cell enlargement (hypertrophy) and is linked to angiotensin-converting enzyme (ACE) overactivity. ACE inhibition with quinapril normalized apoptosis, suggesting cell death dysregulation is a target for hypertension treatment.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Hypertension Research
Background:
- Spontaneous hypertension and cardiac hypertrophy are associated with increased cardiomyocyte apoptosis.
- The relationship between apoptosis, hypertrophy, blood pressure, and local angiotensin-converting enzyme (ACE) activity in spontaneously hypertensive rats (SHR) requires further investigation.
Purpose of the Study:
- To investigate the relationship between apoptosis and hypertrophy in cardiomyocytes of SHR.
- To evaluate the association of cardiomyocyte apoptosis with blood pressure and local ACE activity in SHR.
- To assess the effect of ACE inhibition on cardiomyocyte apoptosis and hypertrophy in SHR.
Main Methods:
- Study groups included 16-week-old SHR, 30-week-old untreated SHR, and 30-week-old SHR treated with quinapril.
- Cardiomyocyte apoptosis was assessed using DNA end labeling.
- Cardiomyocyte hypertrophy was evaluated by measuring nuclear polyploidization via DNA flow cytometry.
Main Results:
- Compared to Wistar-Kyoto rats, SHR exhibited increased blood pressure, cardiac hypertrophy (tetraploidy), and, at 30 weeks, increased ACE activity and apoptosis.
- A direct correlation was observed between ACE activity and the apoptotic index in untreated 30-week-old SHR.
- Long-term quinapril treatment normalized ACE activity and reduced apoptosis in treated SHR.
Conclusions:
- Cardiomyocyte hypertrophy appears earlier and in parallel with hypertension in SHR, while apoptosis develops later, associated with local ACE overactivity.
- Cell death dysregulation, specifically apoptosis, is linked to ACE activity in hypertension.
- Targeting ACE and the renin-angiotensin system may offer novel therapeutic strategies for managing cell death in hypertension.
Abstract:
Increased apoptosis has been reported in the heart of rats with spontaneous hypertension and cardiac hypertrophy. This study was designed to investigate the relationship between apoptosis and hypertrophy in cardiomyocytes from the left ventricle of spontaneously hypertensive rats (SHR). In addition, we evaluated whether the development of cardiomyocyte apoptosis is related to blood pressure or to the activity of the local angiotensin-converting enzyme (ACE) in SHR. The study was performed in 16-week-old SHR, 30-week-old untreated SHR, and 30-week-old SHR treated with quinapril (10 mg x kg[-1] x d[-1]) during 14 weeks before they were killed. Cardiomyocyte apoptosis was assessed by direct immunoperoxidase detection of digoxigenin-labeled 3'-hydroxyl ends of DNA. Nuclear polyploidization measured by DNA flow cytometry was used to assess cardiomyocyte hypertrophy. Compared with 16-week-old normotensive Wistar-Kyoto rats, 16-week-old SHR exhibited increased blood pressure (P<.001), increased rate of tetraploidy (P<.05), and similar levels of ACE activity and apoptosis. Compared with 30-week-old Wistar-Kyoto rats, 30-week-old SHR showed increased blood pressure (P<.001), increased ACE activity (P<.05), increased rate of tetraploidy (P<.01), and increased apoptosis (P<.01). Untreated 30-week-old SHR exhibited similar values of blood pressure and tetraploidy and higher ACE activity (P<.05) and apoptosis (P<.001) than 16-week-old SHR. A direct correlation (P<.01) was found between ACE activity and the apoptotic index in untreated 30-week-old SHR. The long-term administration of quinapril was associated with the normalization of ACE activity and apoptosis in treated SHR. These results suggest that the timing and mechanisms responsible for apoptosis and hypertrophy of cardiomyocytes are different in SHR. Whereas hypertrophy seems to be an earlier alteration that develops in parallel with hypertension, apoptosis develops later in association with overactivity of the local ACE. Our data suggest that cell death dysregulation may be a novel target for antihypertensive agents that interfere with the renin-angiotensin system in hypertension.