Conditional expression of a Gi-coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy

Conditional expression of a G_i-coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy

^*Gladstone Institute of Cardiovascular Disease and Gladstone Institute of Neurological Disease, and Departments of ^†Medicine and ^‖Radiology, University of California, San Francisco, CA 94141-9100; ^‡Stanford University School of Medicine, Department of Pediatrics, Stanford, CA 94305; ^§Affymetrix, Inc., Santa Clara, CA 94086; and ^¶Mt. Sinai School of Medicine, Departments of Medicine and Physiology and Biophysics, New York, NY 10029-6574

Edited by Eva J. Neer^††, Harvard Medical School, Boston, MA, and approved February 15, 2000 (received for review September 16, 1999)

Abstract

Cardiomyopathy is a major cause of morbidity and mortality. Ventricular conduction delay, as shown by prolonged deflections in the electrocardiogram caused by delayed ventricular contraction (wide QRS complex), is a common feature of cardiomyopathy and is associated with a poor prognosis. Although the G_i-signaling pathway is up-regulated in certain cardiomyopathies, previous studies suggested this up-regulation was compensatory rather than a potential cause of the disease. Using the tetracycline transactivator system and a modified G_i-coupled receptor (Ro1), we provide evidence that increased G_i signaling in mice can result in a lethal cardiomyopathy associated with a wide QRS complex arrhythmia. Induced expression of Ro1 in adult mice resulted in a >90% mortality rate at 16 wk, whereas suppression of Ro1 expression after 8 wk protected mice from further mortality and allowed partial improvement in systolic function. Results of DNA-array analysis of over 6,000 genes from hearts expressing Ro1 are consistent with hyperactive G_i signaling. DNA-array analysis also identified known markers of cardiomyopathy and hundreds of previously unknown potential diagnostic markers and therapeutic targets for this syndrome. Our system allows cardiomyopathy to be induced and reversed in adult mice, providing an unprecedented opportunity to dissect the role of G_i signaling in causing cardiac pathology.

Footnotes

↵ ** To whom reprint requests should be addressed at: Gladstone Institute of Cardiovascular Disease, P.O. Box 419100, San Francisco, CA 94141-9100. E-mail: bconklin{at}gladstone.ucsf.edu.
This paper was submitted directly (Track II) to the PNAS office.
‡‡ Deceased February 20, 2000.
Abbreviations:

IDC,

idiopathic dilated cardiomyopathy;

RASSL,

receptor activated solely by a synthetic ligand;

Ro1,

RASSL, opioid 1;

tTA,

tetracycline transactivator;

αMHC,

α myosin heavy chain;

GPCRs,

G protein-coupled receptors;

IKACh,

potassium-selective ion channel;

LV,

left ventricle or ventricular;

LVFS,

LV fractional shortening;

PTX,

pertussis toxin;

GenMAPP,

Gene MicroArray Pathway Profiler