β2-Adrenergic Receptor Overexpression Exacerbates Development of Heart Failure After Aortic Stenosis
To the Editor:
The recent article by Du et al1 shows that elevated cardiac β-adrenergic activity due to β2-adrenoceptor overexpression leads to functional deterioration after pressure overload. The authors had hypothesized that the enhanced myocardial contractility caused by β2-adrenoceptor overexpression would alleviate the onset of heart failure after pressure overload and that β2-adrenoceptors, therefore, represent a suitable target for gene therapy. The negative outcome of their study is in agreement with recently published data on isolated adult ventricular cardiomyocytes. These new data may, in fact, shed some light on the underlying cause for the negative outcome in Du et al’s1 study.
In vitro, selective stimulation of β2-adrenoceptors does not provoke hypertrophic growth.2 3 This observation is in line with the characteristics of transgenic mice overexpressing β2-adrenoceptors. On exposure to transforming growth factor (TGF)-β1, however, a hypertrophic responsiveness to β2-adrenoceptor stimulation can be induced in cardiomyocytes.4 The fact that cardiac fibrosis was found in the investigated animal model under pressure overload can be taken as a hint that the cardiac TGF-β system was activated in these animals. On the basis of these in vitro studies, one should expect a more pronounced hypertrophy of hearts expressing TGF-β and an enlarged number of functionally active β2-adrenoceptors (ie, in the transgenic animals compared with control animals under cardiac pressure overload conditions).
Du et al1 found that, normalized to the heart and left ventricular weight of sham-operated animals, the transgenic animals increased their heart and left ventricular weights by 101% and 89%, respectively, although in wild-type animals these parameters increased after aortic stenosis by only 56% and 56%, respectively. This indicates a positive relationship between β2-adrenoceptor expression and growth response under pressure overload. Because the overexpression of cardiac β2-adrenoceptors had no hypertrophic effect on its own but led to augmented hypertrophy in combination with pressure overload, this study is consistent with the in vitro data demonstrating that β2-adrenoceptors can couple with hypertrophic growth under specific circumstances, such as the presence of TGF-β. Additional data were generated from an examination of transgenic mice overexpressing TGF-β.4 The additional growth effect of β2-adrencoeptor stimulation may then lead to nonadapted hypertrophy and heart failure.
- Copyright © 2001 by American Heart Association
Du X-J, Autelitano DJ, Dilley RJ, et al. β2-Adrenergic receptor overexpression exacerbates development of heart failure after aortic stenosis. Circulation. 2000;101:71–77.
Zhou XJ, Schlüter K.-D, Piper HM. Hypertrophic responsiveness to β2-adrencoeptor stimulation on adult ventricular cardiomyocytes. Mol Cell Biochem. 1996;163/164:211–216.
Schlüter K-D, Zhou XJ, Piper HM. Induction of hypertrophic responsiveness to isoproterenol by TGF-β in adult rat cardiomyocytes. Am J Physiol. 1995;269:C1311–C1316.
The points raised by Dr Schlüter concerning the permissive effect of transforming growth factor-β (TGF-β) on β2-adrenergic receptor (β2-AR)–induced hypertrophy are intriguing and merit further investigation. However, in the in vivo thoracic aortic constriction (TAC) hypertrophic model, overexpression of β2-ARs did not cause an enhancement of hypertrophy per se; rather, it promoted the transition to heart failure.R1 The enhanced weight increase in transgenic mice, as calculated by Dr Schlüter, was mostly due to a slightly lower heart weight in sham-operated transgenic mice, together with increased atrial and right ventricular weights subsequent to failure. The lack of effect of β2-ARs on hypertrophy after TAC was further confirmed by a recent study in which hypertrophy, measured by left ventricle and total heart weights, was assessed in mice 1, 3, and 8 weeks after TAC. No exacerbating effect of β2-AR overexpression was observed at any of these time points.R2 Furthermore, in studies not yet published, we have found that β2-AR overexpression does not enhance hypertrophy after myocardial infarction. The finding of worsened heart failure without more extensive hypertrophy in β2-AR–overexpressing mice is in contrast to our findings with mice expressing constitutively active α1B-adrenergic receptors in the heart. After TAC, these mice showed enhanced hypertrophy by a number of indices,R3 but heart failure in this group, although more extensive than in wild-type mice, was less marked than in the β2-AR–expressing mice after TAC. Thus, there is a clear distinction between factors causing hypertrophy and those that predispose toward failure.
However, the permissive effect of TGF-β on β2-AR–mediated responses demonstrated by Schlüter et alR4 may be important in the very marked worsening of heart failure responses seen in β2-AR–expressing animals. These mice have more extensive fibrosis than wild-type, and TGF-β might well play an important role in this response. The availability of mice with TGF-β overexpression or TGF-β knockout provides the possibility to test this directly using cross-breading strategies.R5
Du XJ, Autelitano DJ, Dilley RJ, et al. β2-Adrenergic receptor overexpression exacerbates development of heart failure after aortic stenosis. Circulation. 2000;101:71–77.
Sheridan DJ, Autelitano DJ, Wang BH, et al. β2-Adrenergic receptor overexpression driven by an α-MHC promoter is downregulated in hypertrophied and failing myocardium. Cardiovasc Res. 2000;47:133–141.
Wang BH, Du X-J, Autelitano DJ, et al. Adverse effects of constitutively active α1B-adrenergic receptors following pressure overload in mouse heart. Am J Physiol.. 2000;279:H1079–H1086.
Schluter KD, Zhou XJ, Piper HM. Induction of hypertrophic responsiveness to isoproterenol by TGF-β in adult rat cardiomyocytes. Am J Physiol. 1995;269:C1311–1316.
Koglin J, Glysing-Jensen T, Raisanen-Sokolowski A, et al. Immune sources of transforming growth factor-β1 reduce transplant arteriosclerosis: insight derived from a knockout mouse model. Circ Res. 1998;83:652–660.