Pathological hypertrophy reverses β2‐adrenergic receptor‐induced angiogenesis in mouse heart

Physiological Reports

Qi Xu¹  Nicole L. Jennings¹  Kenneth Sim¹  Lisa Chang¹  Xiao-Ming Gao¹  Helen Kiriazis¹  Ying Ying Lee¹  My-Nhan Nguyen¹  Elizabeth A. Woodcock¹  You-Yi Zhang²  Assam El-Osta¹  Anthony M. Dart¹ 

[1] Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia;Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing, China

关键词: Angiogenesis;    cAMP‐responsive‐element‐binding protein;    heart failure;    hypertrophy;    pressure overload;    β2‐adrenoceptor;   

DOI  :  10.14814/phy2.12340

来源: Wiley

【 摘 要 】

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 (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.

【 授权许可】

CC BY   
© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

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