TY - JOUR
T1 - The α1A/C- and α1B-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse
AU - O'Connell, Timothy D.
AU - Ishizaka, Shinji
AU - Nakamura, Akihiro
AU - Swigart, Philip M.
AU - Rodrigo, M. C.
AU - Simpson, Gregory L.
AU - Cotecchia, Susanna
AU - Rokosh, D. Gregg
AU - Grossman, William
AU - Foster, Elyse
AU - Simpson, Paul C.
PY - 2003/6
Y1 - 2003/6
N2 - Catecholamines and α1-adrenergic receptors (α 1-ARs) cause cardiac hypertrophy in cultured myocytes and transgenic mice, but heart size is normal in single KOs of the main α1-AR subtypes, α1A/C and α1B. Here we tested whether α1-ARs are required for developmental cardiac hypertrophy by generating α1A/C and α1B double KO (ABKO) mice, which had no cardiac α1-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. α1-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, α1-ARs in male mice are required for the physiological hypertrophy of normal postnatal cardiac development-and for an adaptive response to cardiac stress.
AB - Catecholamines and α1-adrenergic receptors (α 1-ARs) cause cardiac hypertrophy in cultured myocytes and transgenic mice, but heart size is normal in single KOs of the main α1-AR subtypes, α1A/C and α1B. Here we tested whether α1-ARs are required for developmental cardiac hypertrophy by generating α1A/C and α1B double KO (ABKO) mice, which had no cardiac α1-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. α1-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, α1-ARs in male mice are required for the physiological hypertrophy of normal postnatal cardiac development-and for an adaptive response to cardiac stress.
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U2 - 10.1172/JCI200316100
DO - 10.1172/JCI200316100
M3 - Article
C2 - 12782680
AN - SCOPUS:0038142299
SN - 0021-9738
VL - 111
SP - 1783
EP - 1791
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -