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This Article Full Text Full Text (PDF) All Versions of this Article: 294/1/H205    most recent 00829.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by McCloskey, D. T. Articles by Baker, A. J. Search for Related Content PubMed PubMed Citation Articles by McCloskey, D. T. Articles by Baker, A. J.

Expression of a G_i-coupled receptor in the heart causes impaired Ca²⁺ handling, myofilament injury, and dilated cardiomyopathy

Departments of Radiology and Medicine, University of California, and the Veterans Affairs Medical Center, San Francisco, California

Submitted 16 July 2007 ; accepted in final form 19 October 2007

Increased signaling by G_i-coupled receptors has been implicated in dilated cardiomyopathy. To investigate the mechanisms, we used transgenic mice that develop dilated cardiomyopathy after conditional expression of a cardiac-targeted G_i-coupled receptor (Ro1). Activation of G_i signaling by the Ro1 agonist spiradoline caused decreased cellular cAMP levels and bradycardia in Langendorff-perfused hearts. However, acute termination of Ro1 signaling with the antagonist nor-binaltorphimine did not reverse the Ro1-induced contractile dysfunction, indicating that Ro1 cardiomyopathy was not due to acute effects of receptor signaling. Early after initiation of Ro1 expression, there was a 40% reduction in the abundance of the sarcoplasmic reticulum Ca²⁺-ATPase (P < 0.05); thereafter, there was progressive impairment of both Ca²⁺ handling and force development assessed with ventricular trabeculae. Six weeks after initiation of Ro1 expression, systolic Ca²⁺ concentration was reduced to 0.61 ± 0.08 vs. 0.91 ± 0.07 µM for control (n = 6–8; P < 0.05), diastolic Ca²⁺ concentration was elevated to 0.41 ± 0.07 vs. 0.23 ± 0.06 µM for control (n = 6–8; P < 0.01), and the decline phase of the Ca²⁺ transient (time from peak to 50% decline) was slowed to 0.25 ± 0.02 s vs. 0.13 ± 0.02 s for control (n = 6–8; P < 0.01). Early after initiation of Ro1 expression, there was a ninefold elevation of matrix metalloproteinase-2 (P < 0.01), which is known to cause myofilament injury. Consistent with this, 6 wk after initiation of Ro1 expression, Ca²⁺-saturated myofilament force in skinned trabeculae was reduced to 21 ± 2 vs. 38 ± 0.1 mN/mm² for controls (n = 3; P < 0.01). Furthermore, electron micrographs revealed extensive myofilament damage. These findings may have implications for some forms of human heart failure in which increased activity of G_i-coupled receptors leads to impaired Ca²⁺ handling and myofilament injury, contributing to impaired ventricular pump function and heart failure.

matrix metalloproteinase-2; sarco(endo)plasmic reticulum Ca²⁺-ATPase; contraction; -opioid receptor; conditional expression