Interplay between the E2F pathway and b-adrenergic signaling in the pathological XXXX response of myocardium.

@entity35826 @entity851 @entity19 @entity384 @entity1184 @entity1919 @entity13436 @entity1994 @entity1379 @entity37447 @entity3044 @entity41716 @entity204 @entity4149
The E2F/Pocket protein (Rb) pathway regulates cell growth, differentiation, and @entity204 by modulating gene expression. We previously examined this pathway in the myocardium via manipulation of the unique E2F repressor, @entity35826 , which is believed to repress gene activity independently of Rb. @entity19 with targeted expression of @entity35826 in postnatal myocardium developed @entity384 ( @entity384 ) without @entity851 . We assessed the mechanisms of the apparent failure of compensatory @entity851 as well as their response to the b-adrenergic agonist @entity3044 . As early as 2weeks, @entity35826 transgenic (Tg) @entity19 present with dilated thinner left ventricles and significantly reduced ejection fraction and fractional shortening which persists at 6weeks of age, but with no apparent increase in left ventricle weight: body weight (LVW:BW). @entity35826 -Tg @entity19 treated with @entity3044 (6.1mg/kg/day) show double the increase in LVW:BW than their Wt counterparts (32% vs 16%, p-value: 0.007). Western blot analysis revealed the activation of the adrenergic pathway in Tg heart tissue under basal conditions with ~2-fold increase in the level of b2-adrenergic receptors (p-value: 8.9E-05), protein kinase A catalytic subunit (PKA-C) (p-value: 0.0176), activated c-Src @entity4149 -protein kinase (p-value: 0.0002), @entity13436 ( @entity13436 ) (p-value: 0.0005), and induction of the anti-apoptotic protein @entity1379 (p-value 0. 0.00001). In contrast, a ~60% decrease in the cardiac growth regulator: @entity1994 (p-value 0.0001) and a ~four fold increase in @entity1919 dependent @entity37447 ( @entity37447 ), the negative regulator of PKA activity, were evident in the myocardium of @entity35826 -Tg @entity19 . The expression of @entity41716 was down-regulated by @entity35826 , but was restored by @entity3044 . Further, Rb expression was down-regulated in Tg @entity19 in response to @entity3044 implying a net activation of the E2F pathway. Thus the unique regulation of E2F activity by @entity35826 renders the myocardium hypersensitive to adrenergic stimulus resulting in robust @entity851 . These data reveal a novel interplay between the E2F pathway, b2-adrenergic/PKA/ @entity37447 , and @entity13436 /c-Src axis in fine tuning the pathological @entity851 response. @entity35826 deregulates @entity41716 such that pro- @entity851 and survival are enhanced via b2-adrenergic signaling however this response is outweighed by the induction of anti- @entity1184 signals so that left ventricle dilation proceeds without any increase in muscle mass.
