UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy

作者：Wang Li; Burmeister Brian T; Johnson Keven R; Baillie George S; Karginov Andrei V; Skidgel Randal A; O'Bryan John P^*; Carnegie Graeme K

来源：Cellular Signalling, 2015, 27(5): 908-922.

DOI：10.1016/j.cellsig.2015.02.003

• Phosphodiesterase 4 (PDE4) activation
• A-kinase anchoring protein (AKAP)
• Compartmentalized signaling
• 3 ',5 '-cyclic monophosphate (cAMP)
• protein kinase A (PKA)
• cardiomyocyte hypertrophy

Hypertrophy increases the risk of heart failure and arrhythmia. Prevention or reversal of the maladaptive hypertrophic phenotype has thus been proposed to treat heart failure. Chronic p-adrenergic receptor (beta-AR) stimulation induces cardiomyocyte hypertrophy by elevating 3',5'-cyclic adenosine monophosphate (cAMP) levels and activating downstream effectors such protein kinase A (PICA). Conversely, hydrolysis of cAMP by phosphodiesterases (PDEs) spatiotemporally restricts cAMP signaling. Here, we demonstrate that PDE4, but not PDE3, is critical in regulating cardiomyocyte hypertrophy, and may represent a potential target for preventing maladaptive hypertrophy. We identify a sequence within the upstream conserved region 1 of PDE4D, termed UCR1C, as a novel activator of PDE4 long isoforms. UCR1C activates PDE4 in complex with A-kinase anchoring protein (AKAP)-Lbc resulting in decreased PICA signaling facilitated by AKAP-Lbc. Expression of UCR1C in cardiomyocytes inhibits hypertrophy in response to chronic beta-AR stimulation. This effect is partially due to inhibition of nuclear PICA activity, which decreases phosphorylation of the transcription factor cAMP response element-binding protein (CREB). In conclusion, PDE4 activation by UCR1C attenuates cardiomyocyte hypertrophy by specifically inhibiting nuclear PICA activity. Published by Elsevier Inc.

• 出版日期2015-5