Abstract-Transforming growth factor-␤ (TGF-␤) 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-␤ in the cardiac remodeling process induced by norepinephrine (NE), the expression of TGF-␤1, TGF-␤2, and TGF-␤3 was studied and compared with the expression of collagen. NE (0.1 mg/kg ⅐ 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 ⅐ h) and metoprolol (1 mg/kg ⅐ h) were used to block ␣-and ␤-adrenoceptors, respectively. After NE infusion, the three isoforms of TGF-␤ were differentially induced as far as the magnitude and the time course is concerned. The increased expression of TGF-␤2 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-␤2 after 1 day of NE-stimulation. The increase of TGF-␤2 was significant only in the myocyte fraction obtained from female as well as from male hearts. The expression of the mRNA of all TGF-␤ isoforms of collagen type I and type III, and of the matrix metalloproteinase (MMP)-2 and its inhibitor TIMP-2 was reduced predominantly by ␣-adrenoceptor blockade with prazosin. The increase in TGF-␤ isoforms correlated with that of the mRNA expression of collagens, MMP-2 and TIMP-2.

Background: Elevated serum concentration of interleukin (IL)-6 is a predictor for poor prognosis in congestive heart failure. It was shown previously in rats, that IL-6 expression in the left ventricle (LV) was followed by LV hypertrophy. Methods: Using IL-6 deficient mice (IL-6^-/-), we studied the role of IL-6 in a model of norepinephrine (NE)-induced LV hypertrophy. Results: In wild type (WT) mice, IL-6 mRNA expression and its concentration in the serum were elevated after 4 h of NE-treatment (s.c. 0.25 mg/kg·h). Further, NE-induced LV hypertrophy was detected: LV weight/body weight (LVW/BW) ratio (+12.3±3%, p < 0.05) and mRNA expression of atrial natriuretic peptide (ANP) in WT mice (+120±25%, p < 0.05) after 3 days were increased. In contrast, NE did not induce elevation of LVW/BW ratio and ANP expression in IL-6^-/- mice. Replacement with recombinant IL-6 restored the hypertrophy-inducing effect of NE in IL-6^-/- mice. As to the extracellular matrix (ECM) proteins, NE increased collagen type I and III expression only in WT mice and not in IL-6^-/- mice. The addition of recombinant IL-6 elevated the expression of the ECM proteins to the WT level. Conclusion: IL-6 is a major player in the development of NE-induced LV hypertrophy in mice.

Background: Matrix metalloproteinases (MMPs) play an important role in myocardial remodeling. Their activity is regulated by the tissue inhibitors of metalloproteinases (TIMPs). The present study analyzed the contribution of changes in functional and molecular parameters to early cardiac remodeling in mice hearts. The role that TIMPs might play in this process was specially acknowledged. Methods: The remodeling was induced by norepinephrine (NE) given sc in balb/c mice. Varying concentrations, time and the addition of a neutralizing TIMP-1 antibody were evaluated. Results: High dose NE led to insufficiency of the left ventricle (LV) as evidenced by reduced NE-induced elevation of LV systolic pressure, contractility and relaxation. Further, signs of lung congestion were seen. NE induced a concentration-dependent increase of LV weight/body weight (LVW/BW) ratio and elevated mRNA expression of atrial natriuretic peptide (ANP). This was accompanied by induction of collagen type I and III, as well as TIMP-1 expression. Conclusions: The NE-induced increase of TIMP-1 expression may induce the elevation of the antihypertrophic cardiac factor ANP since NE-induced increase of ANP expression was abolished by neutralizing TIMP-1 antibody. Thus, TIMP-1 may mediate ANP-induced attenuation of NE-induced hypertrophy in the mouse heart.