Biological determinants of aldosterone-induced cardiac fibrosis in rats.
To determine the events leading to cardiac fibrosis in aldosterone-salt hypertensive rats, we studied protein and mRNA accumulation of procollagens I and III for 60 days. After 3 and 7 days of treatment systolic pressure was normal, and no histological or biochemical changes were seen in rat hearts. At day 15 arterial pressure was raised (+40%) and left ventricular hypertrophy was +15%. Cardiac examination after hemalun-eosin staining and immunolabeling with anticollagen I and III antibodies showed no structural alterations, but an 83% increase in right ventricular type III procollagen mRNA levels was found. At 30 and 60 days we found progressive cardiac fibrosis, with inflammatory cells, myocyte necrosis, and elevation of both types I and III procollagen mRNA levels in both ventricles. To determine whether aldosterone had effects on Na,K-ATPase that might lead to ionic disturbances and induce myocyte necrosis, we studied the major cardiac Na,K-ATPase isoform genes. Although Na,K-ATPase alpha 1- and beta 1-subunit mRNA levels were elevated in kidney at day 1, neither of these cardiac transcripts nor the specific alpha 2 isoform was altered between 1 and 15 days. These results show that accumulation of procollagen mRNAs occurs before collagen deposition. Cardiac alterations are late and not preceded by changes in Na,K-ATPase cardiac gene expression, precluding a direct modulation of cardiac collagen synthesis and Na,K-ATPase by aldosterone.
D000450:Aldosterone / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D015152:Blotting, Northern; D003094:Collagen / Q000096:biosynthesis / Q000378:metabolism; D005355:Fibrosis; D006321:Heart / Q000187:drug effects*; D006651:Histocytochemistry; D006973:Hypertension / Q000150:complications* / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000473:pathology; D007668:Kidney / Q000201:enzymology; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D009336:Necrosis; D009693:Nucleic Acid Hybridization; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000008:administration & dosage; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D013974:Thyroxine / Q000097:blood; D013997:Time Factors; D014158:Transcription, Genetic
D011347:Procollagen; D012333:RNA, Messenger; D012965:Sodium Chloride; D000450:Aldosterone; D003094:Collagen; D000254:Sodium-Potassium-Exchanging ATPase; D013974:Thyroxine