Transitory reduction in angiotensin AT2 receptor expression levels in postinfarct remodelling in rat myocardium.
1. Myocardial infarction (MI) poses a significant risk for sudden cardiac death. The effectiveness of angiotensin-converting enzyme (ACE) inhibitors and AT1 receptor blockade in attenuating unfavourable post-MI outcomes indicates an important role for angiotensin (Ang) II signalling in the post-MI remodelling process. 2. AT1 and AT2 receptor expression is known to be altered during the early postinjury period and at the later failure stage in the infarcted heart. The aim of the present investigation was to characterize AngII receptor expression shifts in the intermediate, adaptive phases of post-MI hypertrophic remodelling. 3. The present study investigated relative cardiac AT1 and AT2 receptor expression levels using semiquantitative reverse transcription-polymerase chain reaction (GAPDH normalized) in rats at 4 and 20 weeks after ligation of the left anterior descending coronary artery. 4. Heart weight and normalized heart weight were significantly higher in the MI group than in the sham group 4 weeks post-MI, with significant hypertrophy of the left ventricle, left atrium and right ventricle in MI rats. At 20 weeks post-MI, left ventricular hypertrophy remained significant, whereas the mass of the other cardiac tissues was not different to that of sham controls. 5. AT2 receptor expression was markedly reduced in both the non-infarct and infarcted areas of the left ventricular wall in the MI group compared with the sham-operated group 4 weeks after surgery. Expression levels were reduced to 8 and 13% of sham values in the viable and scar tissue regions, respectively. By 20 weeks post-MI, there was no evidence of AT2 receptor expression suppression in the left ventricle. No significant relative changes in AT1 receptor mRNA levels were observed at either 4 or 20 weeks post-MI. 6. The present study demonstrates, for the first time, a selective downregulation of left ventricular AT2 receptor expression in the intermediate phase of post-MI ventricular remodelling in the rat. This downregulation may provide an enhanced AT1 receptor-mediated compensatory progrowth signal in the early adaptive post-MI growth phase. A more detailed understanding of the time-course of differential AT1 and AT2 receptor expression regulation post-MI may potentially identify an optimal window for targeted pharmacological intervention in the treatment of MI.
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
Clare J
CJ
Lax
Andrea A
AA
Domenighetti
Jillian M
JM
Pavia
Robert
R
Di Nicolantonio
Claire L
CL
Curl
Margaret J
MJ
Morris
Lea M D
LM
Delbridge
D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D015536:Down-Regulation / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D011184:Postoperative Period; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis* / Q000235:genetics; D013997:Time Factors; D020257:Ventricular Remodeling / Q000502:physiology
D057912:Angiotensin II Type 2 Receptor Blockers; D044139:Receptor, Angiotensin, Type 2