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Updated: Aug 16, 2026
Acute Myocardial Infarction in Rats
Published on: February 16, 2011
Postischemic apoptosis and functional recovery after angiotensin II type 1 receptor blockade in isolated working rat
Insights
Chronic angiotensin (AngII) type I receptor (AT1R) blockade reduced cardiomyocyte apoptosis after heart ischemia-reperfusion (IR). However, this reduction in apoptosis did not improve overall left ventricular (LV) functional recovery.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Ischemia-Reperfusion Injury
Background:
- Ischemia-reperfusion (IR) injury is a major cause of heart dysfunction.
- Cardiomyocyte (CM) apoptosis plays a critical role in the pathogenesis of IR injury.
- Angiotensin (AngII) type I receptor (AT1R) blockade is a potential therapeutic strategy.
Purpose of the Study:
- To investigate the effect of chronic AT1R blockade on CM apoptosis and left ventricular (LV) dysfunction post-IR.
- To assess the impact of AT1R blockade on key apoptotic markers in the heart.
Main Methods:
- Isolated working rat hearts subjected to IR (25 min global ischemia, 40 min reperfusion).
- Groups received chronic oral AT1R blockers (losartan or UP269-6) or no drug.
- Assessed LV developed pressure, apoptotic index (TUNEL assay), and apoptotic markers (Bcl-2, Bax, p53, caspase-3) via Western immunoblots.
Main Results:
- Losartan, but not UP269-6, preserved functional recovery in some groups.
- Both AT1R blockers reduced the apoptotic index and normalized changes in Bax, Bcl-2, p53, and caspase-3 expression post-IR.
- AT1R blockade altered the relationship between apoptosis and functional recovery.
Conclusions:
- IR induces LV dysfunction and CM apoptosis mediated by p53, caspase-3, and altered Bax/Bcl-2 ratio.
- Chronic AT1R blockade inhibits IR-induced apoptosis and marker changes.
- Reduced apoptosis does not necessarily equate to improved LV functional recovery after IR.
Objective:
To determine whether chronic angiotensin (AngII) type I receptor (AT1R) blockade inhibits cardiomyocyte (CM) apoptosis and attenuates left ventricular (LV) dysfunction after ischemia-reperfusion (IR) in the isolated working rat heart.
Methods:
Postischemic recovery of LV developed pressure, the apoptotic index (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP in situ nick end labeling or TUNEL assay), and changes in expression of apoptotic markers Bcl-2, Bax, p53 and caspase-3 (Western immunoblots) were measured after IR (50 min aerobic perfusion; 25 min global ischemia; 40 min reperfusion) in working rat hearts that were randomized to five groups of six each along 1 week or 3 week pretreatment arms: sham (no drug, no perfusion); no drug, aerobic perfusion; and oral AT1R blockers losartan (30 mg/kg per day) or UP269-6 (3 mg/kg per day), or no drug before IR.
Results:
Compared to the no drug group after IR, losartan (not UP269-6) preserved functional recovery in 1 and 3 week groups. However, both losartan and UP269-6 reduced the apoptotic index and normalized the increase in Bax, decrease in Bcl-2 and increase in p53 and caspase-3 after IR. A bell-shaped relation between apoptosis and functional recovery after IR was flattened by AT1R blockade.
Conclusion:
The results indicate that IR is associated with LV dysfunction and CM apoptosis involving activation of p53, caspase-3, and increased Bax/Bcl-2 ratio in the working rat heart. Importantly, chronic AT1R blockade inhibited the apoptosis and changes in expression of the markers without improving functional recovery, implying that decrease in apoptosis does not necessarily translate into decreased LV dysfunction.
