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The α1A/C- and α1B-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse
Timothy D. O’Connell, … , Elyse Foster, Paul C. Simpson
Timothy D. O’Connell, … , Elyse Foster, Paul C. Simpson
Published June 1, 2003
Citation Information: J Clin Invest. 2003;111(11):1783-1791. https://doi.org/10.1172/JCI16100.
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Article Cardiology

The α1A/C- and α1B-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse

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Abstract

Catecholamines and α1-adrenergic receptors (α1-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.

Authors

Timothy D. O’Connell, Shinji Ishizaka, Akihiro Nakamura, Philip M. Swigart, M.C. Rodrigo, Gregory L. Simpson, Susanna Cotecchia, D. Gregg Rokosh, William Grossman, Elyse Foster, Paul C. Simpson

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Figure 6

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Response of the ABKO mice to stress. Ten- to twelve-week-old male ABKO a...
Response of the ABKO mice to stress. Ten- to twelve-week-old male ABKO and WT mice were used. (a) Exercise: free wheel running. Mice were given access to a running wheel for 12 hours on each of 30 consecutive nights, and distance, duration, and speed were recorded by a chronometer attached to the wheel (n = 4–5 mice each group). (b) Exercise: motorized treadmill. Mice were placed on a motorized treadmill set at the speed and for the duration indicated, and the number of times the motivational bar was touched, indicating failure to maintain treadmill speed, was recorded as breaks per minute. The left panel shows a single session (n = 8–9 mice per group), and the right panel shows 20 consecutive daily training sessions (n = 9–10). (c) TAC was done in congenic mice, and survival was recorded over 14 days.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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