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(Circulation. 2007;115:763-772.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

An 1A-Adrenergic–Extracellular Signal-Regulated Kinase Survival Signaling Pathway in Cardiac Myocytes

Yuan Huang, MD; Casey D. Wright, PhD; Chastity L. Merkwan, BSc; Nichole L. Baye, BSc; Qiangrong Liang, MD, PhD; Paul C. Simpson, MD; Timothy D. O’Connell, PhD

From the Cardiovascular Research Institute at Sanford Research/USD and the Department of Medicine at The University of South Dakota School of Medicine, Sioux Falls, SD (Y.H., C.D.W., C.M., N.L.B., Q.L., T.D.O.), and the Cardiology Division, San Francisco Veterans Affairs Medical Center and the Cardiovascular Research Institute and Department of Medicine at The University of California at San Francisco, San Francisco (P.C.S.).

Correspondence to Timothy D. O’Connell, PhD, Cardiovascular Research Institute, Sanford Research/USD, Department of Medicine, The University of South Dakota, 1100 E 21st St, Suite 700, Sioux Falls, SD 57105. E-mail toconnel{at}usd.edu

Received September 15, 2006; accepted December 11, 2006.

Background— In 1-AR knockout (1ABKO) mice that lacked cardiac myocyte 1-adrenergic receptor (1-AR) binding, aortic constriction induced apoptosis, dilated cardiomyopathy, and death. However, it was unclear whether these effects were attributable to a lack of cardiac myocyte 1-ARs and whether the 1A, 1B, or both subtypes mediated protection. Therefore, we investigated 1A and 1B subtype–specific survival signaling in cultured cardiac myocytes to test for a direct protective effect of 1-ARs in cardiac myocytes.

Methods and Results— We cultured 1ABKO myocytes and reconstituted 1-AR signaling with adenoviruses expressing 1-GFP fusion proteins. Myocyte death was induced by norepinephrine, doxorubicin, or H₂O₂ and was measured by annexin V/propidium iodide staining. In 1ABKO myocytes, all 3 stimuli significantly increased apoptosis and necrosis. Reconstitution of the 1A subtype, but not the 1B, rescued 1ABKO myocytes from cell death induced by each stimulus. To address the mechanism, we examined 1-AR activation of extracellular signal-regulated kinase (ERK). In 1ABKO hearts, aortic constriction failed to activate ERK, and in 1ABKO myocytes, expression of a constitutively active MEK1 rescued 1ABKO myocytes from norepinephrine-induced death. In addition, only the 1A-AR activated ERK in 1ABKO myocytes, and expression of a dominant-negative MEK1 completely blocked 1A survival signaling in 1ABKO myocytes.

Conclusions— Our results demonstrate a direct protective effect of the 1A subtype in cardiac myocytes and define an 1A-ERK signaling pathway that is required for myocyte survival. Absence of the 1A-ERK pathway can explain the failure to activate ERK after aortic constriction in 1ABKO mice and can contribute to the development of apoptosis, dilated cardiomyopathy, and death.

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