(Circulation. 2001;103:e11.)
© 2001 American Heart Association, Inc.
Correspondence |
ß2-Adrenergic Receptor Overexpression Exacerbates Development of Heart Failure After Aortic Stenosis
Physiologisches Institut, Giessen, Germany
To the Editor:
The recent article by Du et al1 shows that elevated cardiac ß-adrenergic activity due to ß2-adrenoceptor overexpression leads to functional deterioration after pressure overload. The authors had hypothesized that the enhanced myocardial contractility caused by ß2-adrenoceptor overexpression would alleviate the onset of heart failure after pressure overload and that ß2-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 ß2-adrenoceptors does not provoke hypertrophic growth.2 3 This observation is in line with the characteristics of transgenic mice overexpressing ß2-adrenoceptors. On exposure to transforming growth factor (TGF)-ß1, however, a hypertrophic responsiveness to ß2-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-ß 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-ß and an enlarged number of functionally active ß2-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 ß2-adrenoceptor expression and growth response under pressure overload. Because the overexpression of cardiac ß2-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 ß2-adrenoceptors can couple with hypertrophic growth under specific circumstances, such as the presence of TGF-ß. Additional data were generated from an examination of transgenic mice overexpressing TGF-ß.4 The additional growth effect of ß2-adrencoeptor stimulation may then lead to nonadapted hypertrophy and heart failure.
References
1.
Du X-J,
Autelitano DJ, Dilley RJ, et al.
ß2-Adrenergic receptor overexpression
exacerbates development of heart failure after aortic stenosis.
Circulation. 2000;101:71–77.
2. Zhou XJ, Schlüter K.-D, Piper HM. Hypertrophic responsiveness to ß2-adrencoeptor stimulation on adult ventricular cardiomyocytes. Mol Cell Biochem. 1996;163/164:211–216.
3.
Schlüter K-D,
Zhou XJ, Piper HM. Induction of hypertrophic responsiveness to
isoproterenol by TGF-ß in adult rat cardiomyocytes.
Am J Physiol. 1995;269:C1311–C1316.
4. Schlüter K-D, Frischkopf K, Flesch M, et al. Central role for ornithine carboxylase in ß-adrenoceptor mediated hypertrophy. Cardiovasc Res. 2000;45:410–417.[Medline] [Order article via Infotrieve]
Response
Baker Medical Research Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria, 8008, Australia
The points raised by Dr Schlüter concerning the
permissive effect of transforming growth factor-ß (TGF-ß) on
ß2-adrenergic receptor
(ß2-AR)–induced hypertrophy are intriguing
and merit further investigation. However, in the in vivo thoracic
aortic constriction (TAC) hypertrophic model, overexpression of
ß2-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 ß2-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
ß2-AR overexpression was observed at any of
these time points.R2
Furthermore, in studies not yet published, we have found that
ß2-AR overexpression does not enhance
hypertrophy after myocardial infarction. The finding of worsened heart
failure without more extensive hypertrophy in
ß2-AR–overexpressing mice is in contrast to
our findings with mice expressing constitutively active
1B-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 ß2-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-ß on ß2-AR–mediated responses demonstrated by Schlüter et alR4 may be important in the very marked worsening of heart failure responses seen in ß2-AR–expressing animals. These mice have more extensive fibrosis than wild-type, and TGF-ß might well play an important role in this response. The availability of mice with TGF-ß overexpression or TGF-ß knockout provides the possibility to test this directly using cross-breading strategies.R5
References
1. Du XJ, Autelitano DJ, Dilley RJ, et al. ß2-Adrenergic receptor overexpression exacerbates development of heart failure after aortic stenosis. Circulation. 2000;101:71–77.
2.
Sheridan DJ,
Autelitano DJ, Wang BH, et al. ß2-Adrenergic
receptor overexpression driven by an -MHC promoter is downregulated
in hypertrophied and failing myocardium.
Cardiovasc Res. 2000;47:133–141.
3.
Wang BH, Du X-J,
Autelitano DJ, et al. Adverse effects of constitutively active
1B-adrenergic receptors following pressure
overload in mouse heart. Am J
Physiol.. 2000;279:H1079–H1086.
4. Schluter KD, Zhou XJ, Piper HM. Induction of hypertrophic responsiveness to isoproterenol by TGF-ß in adult rat cardiomyocytes. Am J Physiol. 1995;269:C1311–1316.
5.
Koglin J,
Glysing-Jensen T, Raisanen-Sokolowski A, et al. Immune sources of
transforming growth factor-ß1 reduce
transplant arteriosclerosis: insight derived from a knockout mouse
model. Circ Res. 1998;83:652–660.
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