TY  - JOUR
AU  - Xu, Q
AU  - Jennings, NL
AU  - Sim, K
AU  - Chang, L
AU  - Gao, X-M
AU  - Kiriazis, H
AU  - Lee, YY
AU  - Nguyen, M-N
AU  - Woodcock, EA
AU  - Zhang, Y-Y
AU  - El-Osta, A
AU  - Dart, AM
AU  - Du, X-J
Y2  - 2020/12/18
Y1  - 2015/03/01
SN  - 2051-817X
UR  - http://hdl.handle.net/11343/255654
AB  - β-adrenergic activation and angiogenesis are pivotal for myocardial function but the link between both events remains unclear. The aim of this study was to explore the cardiac angiogenesis profile in a mouse model with cardiomyocyte-restricted overexpression of β2-adrenoceptors (β2-TG), and the effect of cardiac pressure overload. β2-TG mice had heightened cardiac angiogenesis, which was essential for maintenance of the hypercontractile phenotype seen in this model. Relative to controls, cardiomyocytes of β2-TGs showed upregulated expression of vascular endothelial growth factor (VEGF), heightened phosphorylation of cAMP-responsive-element-binding protein (CREB), and increased recruitment of phospho-CREB, CREB-binding protein (CBP), and p300 to the VEGF promoter. However, when hearts were subjected to pressure overload by transverse aortic constriction (TAC), angiogenic signaling in β2-TGs was inhibited within 1 week after TAC. β2-TG hearts, but not controls, exposed to pressure overload for 1-2 weeks showed significant increases from baseline in phosphorylation of Ca(2+)/calmodulin-dependent kinase II (CaMKIIδ) and protein expression of p53, reduction in CREB phosphorylation, and reduced abundance of phospho-CREB, p300 and CBP recruited to the CREB-responsive element (CRE) site of VEGF promoter. These changes were associated with reduction in both VEGF expression and capillary density. While non-TG mice with TAC developed compensatory hypertrophy, (2-TGs exhibited exaggerated hypertrophic growth at week-1 post-TAC, followed by LV dilatation and reduced fractional shortening measured by serial echocardiography. In conclusion, angiogenesis was enhanced by the cardiomyocyte (2AR/CREB/VEGF signaling pathway. Pressure overload rapidly inhibited this signaling, likely as a consequence of activated CaMKII and p53, leading to impaired angiogenesis and functional decompensation.
LA  - English
PB  - WILEY
T1  - Pathological hypertrophy reverses beta(2)-adrenergic receptor-induced angiogenesis in mouse heart
DO  - 10.14814/phy2.12340
IS  - Physiological Reports
VL  - 3
IS  - 3
L1  - /bitstream/handle/11343/255654/PMC4393171.pdf?sequence=1&isAllowed=y
ER  -