(Circulation. 1999;99:3099-3102.)
© 1999 American Heart Association, Inc.
Brief Rapid Communications |
Cardiac-Directed Adenylyl Cyclase Expression Improves Heart Function in Murine Cardiomyopathy
From the Department of Medicine, VAMC-San Diego and University of California, San Diego (N.D., J.Z., H.K.H., D.E.); Department of Anesthesiology, VAMC-San Diego and University of California, San Diego (D.M.R.); and Collateral Therapeutics, Incorporated, San Diego, Calif (M.H.G., N.C.L., J.D., J.Y.Z., H.K.H.).
Correspondence to H. Kirk Hammond, MD (111-A), VAMC-San Diego, 3350 La Jolla Village Dr, San Diego, CA 92161. E-mail khammond{at}ucsd.edu
Background—We tested the hypothesis that increased cardiac myocyte adenylyl cyclase (AC) content increases cardiac function and response to catecholamines in cardiomyopathy.
Methods and Results—Transgenic mice with cardiac-directed expression of AC type VI (ACVI) were crossbred with mice with cardiomyopathy induced by cardiac-directed Gq expression. Gq mice had dilated left ventricles, reduced heart function, decreased cardiac responsiveness to catecholamine stimulation, and impaired ß-adrenergic receptor (ßAR)–dependent and AC-dependent cAMP production. Gq/AC mice showed improved basal cardiac function in vivo (P=0.01) and ex vivo (P<0.0005). When stimulated through the ßAR, cardiac responsiveness was increased (P=0.02), and cardiac myocytes showed increased cAMP production in response to isoproterenol (P=0.03) and forskolin (P<0.0001).
Conclusions—Increasing myocardial ACVI content in cardiomyopathy restores cAMP-generating capacity and improves cardiac function and responsiveness to ßAR stimulation.
Key Words: receptors, adrenergic, beta • gene therapy
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 O.-E. Brodde and M. C. Michel Adrenergic and Muscarinic Receptors in the Human Heart Pharmacol. Rev., December 1, 1999; 51(4): 651 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
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|
|
|
|
|
|
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|
|
|
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|
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