Targeted deletion of angiotensin II type 2 receptor caused cardiac rupture after acute myocardial infarction.
BACKGROUND
Accumulating evidence has suggested that the cardiac renin-angiotensin system is activated during the remodeling process after myocardial infarction (MI). Although 2 types of angiotensin II receptors (AT(1) and AT(2)) are upregulated in the infarcted tissue, the contribution of AT(2) to the subsequent fibrogenetic phase of wound healing is less certain. This study was conducted to evaluate the role of AT(2) in wound healing after MI using an in vivo intervention study in mice with MI.


RESULTS
We examined myocardial hypertrophy, cardiac fibrosis, and morphological evidence of fibrillar collagen accumulation at the infarcted and noninfarcted regions in male mice lacking the AT(2) receptor (Agtr2-/Y) and age-matched wild-type (WT) animals. Of the Agtr2-/Y mice, 63.6% died of cardiac rupture, whereas 23.5% of the WT mice died of the same cause within 1 week. The extent of fibrosis and that of collagen gene expression in Agtr2-/Y mice were significantly reduced compared with WT mice at 1 week after coronary ligation. Furthermore, MI resulted in a marked increase in the prostaglandin E(2) (PGE(2)) level at 4 days after surgery in Agtr2-/Y mice. In WT mice, the PGE(2) level was also elevated after MI but to a significantly lesser extent than in Agtr2-/Y mice.


CONCLUSIONS
A chronic loss of AT(2) by gene targeting prevented the collagen deposition and caused cardiac rupture. The markedly elevated PGE(2) may be a mechanism that inhibits collagen synthesis in the infarcted region of Agtr2-/Y mice.
Ichihara
Sahoko
S
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tenn. 37232-0146, USA.
Senbonmatsu
Takaaki
T
Price
Edward
E
Ichiki
Toshihiro
T
Gaffney
F Andrew
FA
Inagami
Tadashi
T
D000818:Animals; D003094:Collagen / Q000032:analysis; D005355:Fibrosis; D017353:Gene Deletion; D018390:Gene Targeting; D006342:Heart Rupture, Post-Infarction / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D011453:Prostaglandins / Q000032:analysis; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics* / Q000502:physiology*; D015996:Survival Rate; D014463:Ultrasonography; D020257:Ventricular Remodeling
D011453:Prostaglandins; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D003094:Collagen