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Published on: October 23, 2016
Persistent cardiac aldosterone synthesis in angiotensin II type 1A receptor-knockout mice after myocardial infarction
Jun Katada1, Tomomi Meguro, Hitomi Saito
1Pfizer-KEIO Research Laboratory, Tokyo, Japan. katada@kt.rim.or.jp
Insights
Even with angiotensin II (Ang II) receptor blockade, aldosterone contributes to heart remodeling after myocardial infarction (MI). Spironolactone treatment normalized cardiac remodeling and dysfunction in mice, suggesting its potential in combination therapy for MI patients.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Pharmacology
Background:
- The renin-angiotensin-aldosterone system (RAAS) is central to heart failure pathogenesis.
- Angiotensin II (Ang II) blockade reduces cardiovascular events post-myocardial infarction (MI) but doesn't fully prevent cardiac remodeling.
- The mechanisms of Ang II-independent cardiac remodeling remain unclear.
Purpose of the Study:
- To investigate the role of cardiac aldosterone in post-MI left ventricular (LV) remodeling.
- To evaluate the efficacy of spironolactone in mitigating Ang II-independent cardiac remodeling.
Main Methods:
- Myocardial infarction (MI) induced in wild-type (WT) and angiotensin II type 1A receptor-knockout (AT1A-KO) mice.
- Assessed LV geometry, hemodynamics, and cardiac gene expression at day 28 post-MI.
- Treated AT1A-KO mice with spironolactone and evaluated cardiac remodeling and dysfunction.
Main Results:
- Significant LV remodeling and dysfunction occurred in WT and AT1A-KO mice post-MI.
- Cardiac aldosterone synthase and aldosterone content were elevated in MI hearts, even in AT1A-KO mice.
- Spironolactone treatment in AT1A-KO mice nearly normalized LV remodeling, cardiac dysfunction, and cardiac gene expression.
Conclusions:
- Genetic blockade of AT1A signaling does not prevent aldosterone production in cardiac tissues post-MI.
- Cardiac aldosterone plays a crucial role in post-MI LV remodeling through Ang II-independent pathways.
- Spironolactone may be beneficial in MI patients, particularly when combined with RAAS blockade, to target aldosterone-mediated remodeling.
Background:
The renin-angiotensin-aldosterone system is implicated in the pathogenesis of heart failure. Pharmacological blockade of angiotensin II (Ang II)-dependent signaling is clinically effective in reducing cardiovascular events after myocardial infarction (MI) but still fails to completely prevent remodeling. The molecular basis underlying this Ang II-independent remodeling is unclear.
Methods And Results:
Acute MI was induced by coronary ligation in wild-type (WT) and angiotensin II type IA receptor-knockout (AT1A-KO) mice. Left ventricular (LV) geometry, hemodynamics, and cardiac gene expression were evaluated on day 28. Severe LV remodeling and resultant cardiac dysfunction were observed in WT mice, whereas less marked, but still significant, LV remodeling and cardiac dysfunction were induced in AT1A-KO mice. Gene expression levels of aldosterone synthase and the cardiac aldosterone content were both elevated in the MI hearts, even in AT1A-KO mice. In AT1A-KO mice treated with spironolactone (20 mg/kg per day), LV remodeling, cardiac dysfunction, and cardiac gene expression of collagens and natriuretic peptides were almost normalized.
Conclusions:
Our results indicate that genetic blockade of AT1A signaling fails to arrest aldosterone production in cardiac tissues and that cardiac aldosterone plays a critical role in post-MI LV remodeling. The results suggest that spironolactone could be potentially effective in patients with MI, when used in combination with renin-angiotensin system blockade, by blocking the actions of aldosterone produced by Ang II-independent mechanisms.
