Norepinephrine-induced changes in cardiac transforming growth factor-beta isoform expression pattern of female and male rats.
Transforming growth factor-beta (TGF-beta) is a ubiquitous growth-regulating protein with an essential role in tissue repair and formation of extracellular matrix (ECM). To better understand the role of different isoforms of TGF-beta in the cardiac remodeling process induced by norepinephrine (NE), the expression of TGF-beta1, TGF-beta2, and TGF-beta3 was studied and compared with the expression of collagen. NE (0.1 mg/kg. h) was intravenously infused in female and male Sprague-Dawley rats for several time periods, and freshly obtained ventricular myocardium after 1 day was dissociated into myocyte and nonmyocyte fractions. Prazosin (0.1 mg/kg x h) and metoprolol (1 mg/kg. h) were used to block alpha- and beta-adrenoceptors, respectively. After NE infusion, the three isoforms of TGF-beta were differentially induced as far as the magnitude and the time course is concerned. The increased expression of TGF-beta2 started earlier with a maximum after 12 hours and was more pronounced (10-fold elevation) than that of the other two isoforms, with a clear specificity for the left ventricle in female hearts. This specificity was also seen in male rats with 16-fold elevation of TGF-beta2 after 1 day of NE-stimulation. The increase of TGF-beta2 was significant only in the myocyte fraction obtained from female as well as from male hearts. The expression of the mRNA of all TGF-beta isoforms of collagen type I and type III, and of the matrix metalloproteinase (MMP)-2 and its inhibitor TIMP-2 was reduced predominantly by alpha-adrenoceptor blockade with prazosin. The increase in TGF-beta isoforms correlated with that of the mRNA expression of collagens, MMP-2 and TIMP-2.
Carl-Ludwig-Institute of Physiology, University of Leipzig, Liebigstr. 27, D-04103 Leipzig, Germany. briestw@medizin.uni-leipzig.de
Wilfried
W
Briest
Lars
L
Homagk
Beate
B
Rassler
Barbara
B
Ziegelhöffer-Mihalovicová
Henning
H
Meier
Andrea
A
Tannapfel
Sabine
S
Leiblein
Anja
A
Saalbach
Alexander
A
Deten
Heinz-Gerd
HG
Zimmer
D018674:Adrenergic Antagonists / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D018674:Adrenergic Antagonists; D000316:Adrenergic alpha-Agonists; D020033:Protein Isoforms; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D009638:Norepinephrine