Effect of AT1 receptor blockade on cardiac collagen remodeling after myocardial infarction.
OBJECTIVE
Previous work has shown that cardiac fibrosis occurs after myocardial infarction (MI) in non-infarcted ventricular tissue and that this event is associated with abnormal cardiac function. Our aim was to investigate the effect of AT1 receptor blockade on cardiac collagen remodeling in post-MI rat heart remote from the infarct site by addressing collagen mRNA abundance, posttranslational hydroxylation of collagen monomers, and mature collagen deposition. Prolyl 4-hydroxylase (PH) mediates hydroxylation of procollagen alpha-chains in the endoplasmic reticulum of cardiac fibroblasts and thus regulates the downstream formation and secretion of helical procollagen molecules.


METHODS
The effects of losartan (15 mg/kg/day) on collagen deposition and mRNA abundance were monitored in viable left and right ventricles in sham-operated (control) and experimental groups in the presence or absence of losartan. Immunoreactive PH concentration in viable tissues as well as cardiac function in control and experimental groups was determined by ELISA.


RESULTS
Immunohistochemical staining and 4-hydroxyproline assays confirmed that losartan treatment attenuates fibrosis in experimental hearts. Northern analysis revealed that losartan treatment of 1, 2, or 4 week experimental groups had no effect on collagen mRNA abundance compared to untreated post-MI rats. On the other hand, immunoreactive PH concentration was significantly decreased in the post-MI group treated with losartan. Determination of cardiac mass and cardiac function revealed that losartan treatment was associated with attenuated cardiac hypertrophy and improved left ventricular (LV) function in experimental animals.


CONCLUSIONS
AT1 blockade is associated with a significant decrease in cardiac fibrosis in treated post-MI rats, and this trend is positively correlated to a significant decrease in immunoreactive PH compared to untreated experimental animals. The expression of cardiac PH may be regulated by angiotensin via AT1 receptor activation, and the suppression of PH with losartan treatment may be an important mechanism for modulation of collagen deposition in the post-MI rat heart.
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Molecular Cardiology Laboratory, St. Boniface General Hospital Research Centre, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Zhao
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Jassal
D S
DS
Dixon
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IM
D000804:Angiotensin II; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D015152:Blotting, Northern; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D006909:Hydroxyproline / Q000032:analysis; D007150:Immunohistochemistry; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D015415:Biomarkers; D012333:RNA, Messenger; D000804:Angiotensin II; D003094:Collagen; D019808:Losartan; D006909:Hydroxyproline