Conditional expression of a G(i)-coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy

Cardiomyopathy is a major cause of morbidity and mortality, Ventricular con duction delay, as shown by prolonged deflections in the electrocardiogram c aused by delayed ventricular contraction (wide QRS complex), is a common fe ature of cardiomyopathy and is associated with a poor prognosis. Although t he G(i)-signaling pathway is up-regulated in certain cardiomyopathies, prev ious studies suggested this up-regulation was compensatory rather than a po tential cause of the disease. Using the tetracycline transactivator system and a modified G(i)-coupled receptor (Ro1), we provide evidence that increa sed G(i) signaling in mice can result in a lethal cardiomyopathy associated with a wide QRS complex arrhythmia. Induced expression of Ro1 in adult mic e resulted in a >90% mortality rate at 16 wk, whereas suppression of Ro1 ex pression after 8 wk protected mice from further mortality and allowed parti al improvement in systolic function. Results of DNA-array analysis of over 6,000 genes from heath expressing Ro1 are consistent with hyperactive G(i) signaling. DNA-array analysis also identified known markers of cardiomyopat hy and hundreds of previously unknown potential diagnostic markers and ther apeutic targets for this syndrome. Our system allows cardiomyopathy to be i nduced and reversed in adult mice, providing an unprecedented opportunity t o dissect the role of G(i) signaling in causing cardiac pathology.