Norepinephrine-Induced Changes in Cardiac Transforming Growth Factor-β Isoform Expression Pattern of Female and Male Rats

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Abstract
Transforming growth factor-β (TGF-β) 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-β in the cardiac remodeling process induced by norepinephrine (NE), the expression of TGF-β1, TGF-β2, and TGF-β3 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 · h) and metoprolol (1 mg/kg · h) were used to block α- and β-adrenoceptors, respectively. After NE infusion, the three isoforms of TGF-β were differentially induced as far as the magnitude and the time course is concerned. The increased expression of TGF-β2 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-β2 after 1 day of NE-stimulation. The increase of TGF-β2 was significant only in the myocyte fraction obtained from female as well as from male hearts. The expression of the mRNA of all TGF-β isoforms of collagen type I and type III, and of the matrix metalloproteinase (MMP)-2 and its inhibitor TIMP-2 was reduced predominantly by α-adrenoceptor blockade with prazosin. The increase in TGF-β isoforms correlated with that of the mRNA expression of collagens, MMP-2 and TIMP-2.