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Endothelial and cardiomyocyte PI3Kβ divergently regulate cardiac remodelling in response to ischaemic injury

Chen, X; Zhabyeyev, P; Azad, AK; Wang, W; Minerath, RA; DesAulniers, J; Grueter, CE; ... Oudit, GY; + view all (2019) Endothelial and cardiomyocyte PI3Kβ divergently regulate cardiac remodelling in response to ischaemic injury. Cardiovascular Research , 115 (8) pp. 1343-1356. 10.1093/cvr/cvy298. Green open access

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Abstract

AIMS: Cardiac remodeling in the ischemic heart determines prognosis in patients with ischemic heart disease (IHD), while enhancement of angiogenesis and cell survival has shown great potential for IHD despite translational challenges. Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway plays a critical role in promoting angiogenesis and cell survival. However, the effect of PI3Kβ in the ischemic heart is poorly understood. This study investigates the role of endothelial and cardiomyocyte PI3Kβ in post-infarct cardiac remodeling. METHODS AND RESEARCH: PI3Kβ catalytic subunit-p110β level was increased in infarcted murine and human hearts. Using cell type-specific loss-of-function approaches, we reported novel and distinct actions of p110β in endothelial cells versus cardiomyocytes in response to myocardial ischemic injury. Inactivation of endothelial p110β resulted in marked resistance to infarction and adverse cardiac remodeling with decreased mortality, improved systolic function, preserved microvasculature, and enhanced Akt activation. Cultured endothelial cells with p110β knockout or inhibition displayed preferential PI3Kα/Akt/eNOS signaling that consequently promoted protective signaling and angiogenesis. In contrast, mice with cardiomyocyte p110β-deficiency exhibited adverse post-infarct ventricular remodeling with larger infarct size and deteriorated cardiac function, which was due to enhanced susceptibility of cardiomyocytes to ischemia-mediated cell death. Disruption of cardiomyocyte p110β signaling compromised nuclear p110β and phospho-Akt levels leading to perturbed gene expression and elevated pro-cell death protein levels, increasing the susceptibility to cardiomyocyte death. A similar divergent response of PI3Kβ endothelial and cardiomyocyte mutant mice was seen using a model of myocardial ischemia-reperfusion injury. CONCLUSIONS: These data demonstrate novel, differential, and cell-specific functions of PI3Kβ in the ischemic heart. While loss of endothelial PI3Kβ activity produces cardioprotective effects, cardiomyocyte PI3Kβ is protective against myocardial ischemic injury.

Type: Article
Title: Endothelial and cardiomyocyte PI3Kβ divergently regulate cardiac remodelling in response to ischaemic injury
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/cvr/cvy298
Publisher version: https://doi.org/10.1093/cvr/cvy298
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Myocardial infarction, PI3Kβ, Remodeling, Angiogenesis, Cardiomyocyte death
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10063314
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