Key result
Infection with an adenovirus expressing a dominant-negative killer CREB mutant reduced AngII-induced smooth muscle cell proliferation by 90% and prevented angioplasty-induced neointimal hyperplasia.
Why the study?
Does inhibition of CREB reduce AngII-induced smooth muscle cell proliferation and neointimal hyperplasia in porcine models?
Does inhibition of CREB reduce AngII-induced smooth muscle cell proliferation and neointimal hyperplasia in porcine models?
Inhibition of CREB via a dominant-negative mutant significantly reduces AngII-induced smooth muscle cell proliferation and prevents neointimal hyperplasia in a porcine model.
Answers are grounded in this paper and cite their sources.
CREB may mediate AngII-driven neointimal hyperplasia; leaves open its therapeutic targeting in atherosclerosis and restenosis.
The cAMP response element-binding protein (CREB) is a transcription factor that mediates the cellular response to metabolic and mitogenic signals. Whether CREB contributes to vascular function has received little attention, especially in relation to the processes associated with atherosclerotic disease progression and restenosis. This study examined the involvement of CREB in the mitogenic actions of angiotensin II (AngII), a growth factor that promotes neointimal hyperplasia in response to vascular injury. Treatments were performed on quiescent vascular smooth muscle cells (VSMCs) obtained from a porcine explant model. Organ culture was performed on porcine hearts subjected to angioplasty ex vivo. Stimulation of VSMCs with AngII resulted in transient CREB phosphorylation. Proliferation of smooth muscle cells in response to AngII was reduced by 90 % after infection with adenovirus expressing dominant-negative killer CREB (kCREB) mutant. Likewise, expression of kCREB prevented angioplasty-induced neointimal hyperplasia. AngII-induced CREB phosphorylation was independent of cAMP activation. Examination of putative CREB kinases revealed that MSK was responsible for phosphorylating CREB. In addition, inhibition of PKC revealed that this kinase operates upstream and activates MSK. These results indicate that activation of CREB via PKC and MSK is essential for SMC proliferation in response to AngII.
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Molnár et al. (2013) studied Neointimal hyperplasia. Adenovirus expressing dominant-negative killer CREB (kCREB) mutant vs. Control / AngII alone was evaluated on Proliferation of smooth muscle cells in response to AngII (90% reduction). Infection with an adenovirus expressing a dominant-negative killer CREB mutant reduced AngII-induced smooth muscle cell proliferation by 90% and prevented angioplasty-induced neointimal hyperplasia.
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