Pathological hypertrophy reverses β2-adrenergic receptorinduced angiogenesis in mouse heart

Qi Xu, Nicole L. Jennings, Kenneth Sim, Lisa Chang, Xiao Ming Gao, Helen Kiriazis, Ying Ying Lee, My-Nhan Nguyen, Elizabeth A. Woodcock, You Yi Zhang, Assam El Osta, Anthony M. Dart, Xiao Jun Du

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2 Citations (Scopus)

Abstract

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 Ca2+/calmodulin-dependent kinase II (CaMKIId) and protein expression of p53, reduction in CREB phosphorylation, and reduced abundance of phospho-CREB, p300 and CBP recruited to the CREBresponsive 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.

Original languageEnglish
Article numbere12340
Number of pages16
JournalPhysiological Reports
Volume3
Issue number3
DOIs
Publication statusPublished - 2015

Keywords

  • Angiogenesis
  • cAMP-responsive-elementbinding protein
  • Heart failure
  • Hypertrophy
  • Pressure overload
  • β-adrenoceptor

Cite this

Xu, 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., Osta, A. E., Dart, A. M., & Du, X. J. (2015). Pathological hypertrophy reverses β2-adrenergic receptorinduced angiogenesis in mouse heart. Physiological Reports, 3(3), [e12340]. https://doi.org/10.14814/phy2.12340