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- Title
Pathological hypertrophy reverses β<sub>2</sub>-adrenergic receptor-induced angiogenesis in mouse heart.
- Authors
Xu, Qi; Jennings, Nicole L.; Sim, Kenneth; Chang, Lisa; Gao, Xiao‐Ming; Kiriazis, Helen; Lee, Ying Ying; Nguyen, My‐Nhan; Woodcock, Elizabeth A.; Zhang, You‐Yi; El‐Osta, Assam; Dart, Anthony M.; Du, Xiao‐Jun
- 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 (Ca MKIIδ) 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 (2 AR/ CREB/ VEGF signaling pathway. Pressure overload rapidly inhibited this signaling, likely as a consequence of activated Ca MKII and p53, leading to impaired angiogenesis and functional decompensation.
- Subjects
HYPERTROPHY; ADRENERGIC receptors; NEOVASCULARIZATION; VASCULAR endothelial cells; PHOSPHORYLATION; VASCULAR endothelial growth factors
- Publication
Physiological Reports, 2015, Vol 3, Issue 3, pn/a
- ISSN
2051-817X
- Publication type
Article
- DOI
10.14814/phy2.12340