title: Persistent cardiac aldosterone synthesis in angiotensin II type 1A receptor-knockout mice after myocardial infarction.
abstract: 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.
  
  
  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.
authors.affiliation: Pfizer-KEIO Research Laboratory, Tokyo, Japan. katada@kt.rim.or.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Katada
authors.forename: Tomomi
authors.initials: T
authors.lastname: Meguro
authors.forename: Hitomi
authors.initials: H
authors.lastname: Saito
authors.forename: Akira
authors.initials: A
authors.lastname: Ohashi
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Anzai
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000450:Aldosterone / Q000096:biosynthesis* / Q000502:physiology; D000818:Animals; D019405:Cytochrome P-450 CYP11B2 / Q000096:biosynthesis; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000235:genetics; D013148:Spironolactone / Q000494:pharmacology / Q000627:therapeutic use; D020257:Ventricular Remodeling
chemical_list: D044140:Receptor, Angiotensin, Type 1; D013148:Spironolactone; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2