Pathological hypertrophy reverses beta(2)-adrenergic receptor-induced angiogenesis in mouse heart
AuthorXu, Q; Jennings, NL; Sim, K; Chang, L; Gao, X-M; Kiriazis, H; Lee, YY; Nguyen, M-N; Woodcock, EA; Zhang, Y-Y; ...
Source TitlePhysiological Reports
University of Melbourne Author/sEl-Osta, Assam
Document TypeJournal Article
CitationsXu, Q., Jennings, N. L., Sim, K., Chang, L., Gao, X. -M., Kiriazis, H., Lee, Y. Y., Nguyen, M. -N., Woodcock, E. A., Zhang, Y. -Y., El-Osta, A., Dart, A. M. & Du, X. -J. (2015). Pathological hypertrophy reverses beta(2)-adrenergic receptor-induced angiogenesis in mouse heart. PHYSIOLOGICAL REPORTS, 3 (3), https://doi.org/10.14814/phy2.12340.
Access StatusOpen Access
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.
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