α<inf>1</inf>-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload

O'Connell, TD; Swigart, PM; Rodrigo, MC; Ishizaka, S; Joho, S; Turnbull, L; Tecott, LH; Baker, AJ; Foster, E; Grossman, W; Simpson, PC

α<inf>1</inf>-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload

O'Connell, TD Swigart, PM Rodrigo, MC Ishizaka, S Joho, S Turnbull, L

Tecott, LH Baker, AJ Foster, E Grossman, W Simpson, PC

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Publication Type:: Journal Article
Citation:: Journal of Clinical Investigation, 2006, 116 (4), pp. 1005 - 1015
Issue Date:: 2006-04-01

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Field	Value	Language
dc.contributor.author	O'Connell, TD	en_US
dc.contributor.author	Swigart, PM	en_US
dc.contributor.author	Rodrigo, MC	en_US
dc.contributor.author	Ishizaka, S	en_US
dc.contributor.author	Joho, S	en_US
dc.contributor.author	Turnbull, L https://orcid.org/0000-0002-9255-9033	en_US
dc.contributor.author	Tecott, LH	en_US
dc.contributor.author	Baker, AJ	en_US
dc.contributor.author	Foster, E	en_US
dc.contributor.author	Grossman, W	en_US
dc.contributor.author	Simpson, PC	en_US
dc.date.available	2006-01-10	en_US
dc.date.issued	2006-04-01	en_US
dc.identifier.citation	Journal of Clinical Investigation, 2006, 116 (4), pp. 1005 - 1015	en_US
dc.identifier.issn	0021-9738	en_US
dc.identifier.uri	http://hdl.handle.net/10453/9639
dc.description.abstract	An α1-adrenergic receptor (α1-AR) antagonist increased heart failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), but it is unknown whether this adverse result was due to α1-AR inhibition or a nonspecific drug effect. We studied cardiac pressure overload in mice with double KO of the 2 main α1-AR subtypes in the heart, α1A (Adra1a) and α1B (Adra1b). At 2 weeks after transverse aortic constriction (TAC), KO mouse survival was only 60% of WT, and surviving KO mice had lower ejection fractions and larger end-diastolic volumes than WT mice. Mechanistically, final heart weight and myocyte cross-sectional area were the same after TAC in KO and WT mice. However, KO hearts after TAC had increased interstitial fibrosis, increased apoptosis, and failed induction of the fetal hypertrophic genes. Before TAC, isolated KO myocytes were more susceptible to apoptosis after oxidative and β-AR stimulation, and β-ARs were desensitized. Thus, α1-AR deletion worsens dilated cardiomyopathy after pressure overload, by multiple mechanisms, indicating that α1-signaling is required for cardiac adaptation. These results suggest that the adverse cardiac effects of α1-antagonists in clinical trials are due to loss of α1-signaling in myocytes, emphasizing concern about clinical use of α1-antagonists, and point to a revised perspective on sympathetic activation in heart failure.	en_US
dc.relation.ispartof	Journal of Clinical Investigation	en_US
dc.relation.isbasedon	10.1172/JCI22811	en_US
dc.subject.classification	Immunology	en_US
dc.subject.mesh	Myocardium	en_US
dc.subject.mesh	Cells, Cultured	en_US
dc.subject.mesh	Myocytes, Cardiac	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred Strains	en_US
dc.subject.mesh	Mice, Inbred C57BL	en_US
dc.subject.mesh	Mice, Knockout	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Cardiomyopathy, Dilated	en_US
dc.subject.mesh	Hypertension	en_US
dc.subject.mesh	Fibrosis	en_US
dc.subject.mesh	Receptors, Adrenergic, alpha-1	en_US
dc.subject.mesh	Signal Transduction	en_US
dc.subject.mesh	Apoptosis	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	Blood Pressure	en_US
dc.subject.mesh	Male	en_US
dc.title	α<inf>1</inf>-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload	en_US
dc.type	Journal Article
utslib.citation.volume	4	en_US
utslib.citation.volume	116	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	11 Medical and Health Sciences	en_US
dc.location.activity	ISI:000236556100022	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - ithree - Institute of Infection, Immunity and Innovation
utslib.copyright.status	closed_access
pubs.issue	4	en_US
pubs.publication-status	Published	en_US
pubs.volume	116	en_US

Abstract:

An α1-adrenergic receptor (α1-AR) antagonist increased heart failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), but it is unknown whether this adverse result was due to α1-AR inhibition or a nonspecific drug effect. We studied cardiac pressure overload in mice with double KO of the 2 main α1-AR subtypes in the heart, α1A (Adra1a) and α1B (Adra1b). At 2 weeks after transverse aortic constriction (TAC), KO mouse survival was only 60% of WT, and surviving KO mice had lower ejection fractions and larger end-diastolic volumes than WT mice. Mechanistically, final heart weight and myocyte cross-sectional area were the same after TAC in KO and WT mice. However, KO hearts after TAC had increased interstitial fibrosis, increased apoptosis, and failed induction of the fetal hypertrophic genes. Before TAC, isolated KO myocytes were more susceptible to apoptosis after oxidative and β-AR stimulation, and β-ARs were desensitized. Thus, α1-AR deletion worsens dilated cardiomyopathy after pressure overload, by multiple mechanisms, indicating that α1-signaling is required for cardiac adaptation. These results suggest that the adverse cardiac effects of α1-antagonists in clinical trials are due to loss of α1-signaling in myocytes, emphasizing concern about clinical use of α1-antagonists, and point to a revised perspective on sympathetic activation in heart failure.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/9639