MOLECULAR TARGETING OF DILATED CARDIOMYOPATHY


Balwant S. Tuana, Ph.D., University of Ottawa Heart Institute, Ottawa, Canada

The E2F/Pocket protein pathway regulates cardiac growth, differentiation, and death. Modulating its activity presents intriguing possibilities for targeting cardiac disease. E2F activation leads to hypertrophy and apoptosis. We fine tuned modulation of E2F activity by suppression through E2F6. E2F6 transgenic (tg) mice develop dcm in the absence of hypertrophy. Modulation of the E2F pathway by E2F6 clearly impacted the phenotype and we investigated if and how the E2Fs may potentially integrate with beta adrenergic signals to define the hypertrophic response. Hypertrophy was induced in wt and E2F6 tg mice via delivery of isoproterenol (iso) at low or high dose. Mice were analyzed by echocardiography, and hearts were collected for biochemical and histological analysis. No difference in left ventricle (lv) mass: body weight were observed in wt and tg saline treated mice, but tg mice treated with the low dose of iso exhibited a 30% increase in lv mass while wt only display a 15% increase. Both wt and tg mice treated with the higher dose of iso exhibit 40% increases in lv mass. QPCR revealed wt mice treated with isop display an up-regulation of fetal gene program markers ANP, BNP, and &beta-MHC. Tg mice treated with saline only display an increase in fetal gene program markers, but display no further increase in response to iso. Western blot analysis revealed that beta-adrenergic receptors were decreased in wt mice treated with iso, but not in tgs. E2F6-tg mice develop dcm and heart failure in the absence of hypertrophy but are more sensitive to low dosage of iso than their wt counterparts. The increased sensitivity of tg mice to beta adrenergic stimulation may be linked to an inability to down-regulate beta receptor levels in response to iso. A unique role for E2Fs in beta adrenergic signaling is implied.