title: The alpha(1A/C)- and alpha(1B)-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse.
abstract: Catecholamines and alpha(1)-adrenergic receptors (alpha(1)-ARs) cause cardiac hypertrophy in cultured myocytes and transgenic mice, but heart size is normal in single KOs of the main alpha(1)-AR subtypes, alpha(1A/C) and alpha(1B). Here we tested whether alpha(1)-ARs are required for developmental cardiac hypertrophy by generating alpha(1A/C) and alpha(1B) double KO (ABKO) mice, which had no cardiac alpha(1)-AR binding. In male ABKO mice, heart growth after weaning was 40% less than in WT, and the smaller heart was due to smaller myocytes. Body and other organ weights were unchanged, indicating a specific effect on the heart. Blood pressure in ABKO mice was the same as in WT, showing that the smaller heart was not due to decreased load. Contractile function was normal by echocardiography in awake mice, but the smaller heart and a slower heart rate reduced cardiac output. alpha(1)-AR stimulation did not activate extracellular signal-regulated kinase (Erk) and downstream kinases in ABKO myocytes, and basal Erk activity was lower in the intact ABKO heart. In female ABKO mice, heart size was normal, even after ovariectomy. Male ABKO mice had reduced exercise capacity and increased mortality with pressure overload. Thus, alpha(1)-ARs in male mice are required for the physiological hypertrophy of normal postnatal cardiac development and for an adaptive response to cardiac stress.
authors.affiliation: San Francisco Veterans Affairs Medical Center, Department of Medicine, University of California San Francisco (UCSF), San Francisco, California 94121, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: O'Connell
authors.forename: Shinji
authors.initials: S
authors.lastname: Ishizaka
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nakamura
authors.forename: Philip M
authors.initials: PM
authors.lastname: Swigart
authors.forename: M C
authors.initials: MC
authors.lastname: Rodrigo
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Simpson
authors.forename: Susanna
authors.initials: S
authors.lastname: Cotecchia
authors.forename: D Gregg
authors.initials: DG
authors.lastname: Rokosh
authors.forename: William
authors.initials: W
authors.lastname: Grossman
authors.forename: Elyse
authors.initials: E
authors.lastname: Foster
authors.forename: Paul C
authors.initials: PC
authors.lastname: Simpson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D005260:Female; D005838:Genotype; D006321:Heart / Q000502:physiology; D006984:Hypertrophy / Q000235:genetics*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032342:Muscle Cells / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D009929:Organ Size; D010805:Physical Conditioning, Animal; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000502:physiology*; D012260:Ribonucleases / Q000378:metabolism; D012737:Sex Factors; D013997:Time Factors
chemical_list: C547714:Adra1a protein, mouse; C547717:Adra1b protein, mouse; D018340:Receptors, Adrenergic, alpha-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D012260:Ribonucleases