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

Research output: Contribution to journalArticleResearchpeer-review

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, 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 ; Osta, Assam El ; Dart, Anthony M. ; Du, Xiao Jun. / Pathological hypertrophy reverses β2-adrenergic receptorinduced angiogenesis in mouse heart. In: Physiological Reports. 2015 ; Vol. 3, No. 3.
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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.",
keywords = "Angiogenesis, cAMP-responsive-elementbinding protein, Heart failure, Hypertrophy, Pressure overload, β-adrenoceptor",
author = "Qi Xu and Jennings, {Nicole L.} and Kenneth Sim and Lisa Chang and Gao, {Xiao Ming} and Helen Kiriazis and Lee, {Ying Ying} and My-Nhan Nguyen and Woodcock, {Elizabeth A.} and Zhang, {You Yi} and Osta, {Assam El} and Dart, {Anthony M.} and Du, {Xiao Jun}",
year = "2015",
doi = "10.14814/phy2.12340",
language = "English",
volume = "3",
journal = "Physiological Reports",
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Xu, Q, Jennings, NL, Sim, K, Chang, L, Gao, XM, Kiriazis, H, Lee, YY, Nguyen, M-N, Woodcock, EA, Zhang, YY, Osta, AE, Dart, AM & Du, XJ 2015, 'Pathological hypertrophy reverses β2-adrenergic receptorinduced angiogenesis in mouse heart' Physiological Reports, vol. 3, no. 3, e12340. https://doi.org/10.14814/phy2.12340

Pathological hypertrophy reverses β2-adrenergic receptorinduced angiogenesis in mouse heart. / 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; Osta, Assam El; Dart, Anthony M.; Du, Xiao Jun.

In: Physiological Reports, Vol. 3, No. 3, e12340, 2015.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Pathological hypertrophy reverses β2-adrenergic receptorinduced angiogenesis in mouse heart

AU - Xu, Qi

AU - Jennings, Nicole L.

AU - Sim, Kenneth

AU - Chang, Lisa

AU - Gao, Xiao Ming

AU - Kiriazis, Helen

AU - Lee, Ying Ying

AU - Nguyen, My-Nhan

AU - Woodcock, Elizabeth A.

AU - Zhang, You Yi

AU - Osta, Assam El

AU - Dart, Anthony M.

AU - Du, Xiao Jun

PY - 2015

Y1 - 2015

N2 - 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.

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 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.

KW - Angiogenesis

KW - cAMP-responsive-elementbinding protein

KW - Heart failure

KW - Hypertrophy

KW - Pressure overload

KW - β-adrenoceptor

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DO - 10.14814/phy2.12340

M3 - Article

VL - 3

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