Journal article
Pharmacological and cell-specific genetic PI3Kα inhibition worsens cardiac remodeling after myocardial infarction
Journal of molecular and cellular cardiology, Vol.157, pp.17-30
08/2021
DOI: 10.1016/j.yjmcc.2021.04.004
PMID: 33887328
Abstract
PI3Kα (Phosphoinositide 3-kinase α) regulates multiple downstream signaling pathways controlling cell survival, growth, and proliferation and is an attractive therapeutic target in cancer and obesity. The clinically-approved PI3Kα inhibitor, BYL719, is in further clinical trials for cancer and overgrowth syndrome. However, the potential impact of PI3Kα inhibition on the heart and following myocardial infarction (MI) is unclear. We aim to determine whether PI3Kα inhibition affects cardiac physiology and post-MI remodeling and to elucidate the underlying molecular mechanisms.
Wildtype (WT) 12-wk old male mice receiving BYL719 (daily, p.o.) for 10 days showed reduction in left ventricular longitudinal strain with normal ejection fraction, weight loss, mild cardiac atrophy, body composition alteration, and prolonged QTC interval. RNASeq analysis showed gene expression changes in multiple pathways including extracellular matrix remodeling and signaling complexes. After MI, both p110α and phospho-Akt protein levels were increased in human and mouse hearts. Pharmacological PI3Kα inhibition aggravated cardiac dysfunction and resulted in adverse post-MI remodeling, with increased apoptosis, elevated inflammation, suppressed hypertrophy, decreased coronary blood vessel density, and inhibited Akt/GSK3β/eNOS signaling. Selective genetic ablation of PI3Kα in endothelial cells was associated with worsened post-MI cardiac function and reduced coronary blood vessel density. In vitro, BYL719 suppressed Akt/eNOS activation, cell viability, proliferation, and angiogenic sprouting in coronary and human umbilical vein endothelial cells. Cardiomyocyte-specific genetic PI3Kα ablation resulted in mild cardiac systolic dysfunction at baseline. After MI, cardiac function markedly deteriorated with increased mortality concordant with greater apoptosis and reduced hypertrophy. In isolated adult mouse cardiomyocytes, BYL719 decreased hypoxia-associated activation of Akt/GSK3β signaling and cell survival.
PI3Kα is required for cell survival (endothelial cells and cardiomyocytes) hypertrophic response, and angiogenesis to maintain cardiac function after MI. Therefore, PI3Kα inhibition that is used as anti-cancer treatment, can be cardiotoxic, especially after MI.
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•Inhibition of PI3Kα by BYL719 worsened cardiac remodeling post myocardial infarction.•Endothelial-specific ablation reduced coronary density.•Cardiomyocyte-specific ablation decreased cardiac function and increased mortality.•PI3Kα effects are mediated via Akt/GSK3β/eNOS signaling.
Details
- Title: Subtitle
- Pharmacological and cell-specific genetic PI3Kα inhibition worsens cardiac remodeling after myocardial infarction
- Creators
- Xueyi Chen - University of AlbertaPavel Zhabyeyev - University of AlbertaAbul K. Azad - University of AlbertaBart Vanhaesebroeck - University College LondonChad E. Grueter - University of IowaAllan G. Murray - University of AlbertaZamaneh Kassiri - University of AlbertaGavin Y. Oudit - University of Alberta
- Resource Type
- Journal article
- Publication Details
- Journal of molecular and cellular cardiology, Vol.157, pp.17-30
- DOI
- 10.1016/j.yjmcc.2021.04.004
- PMID
- 33887328
- NLM abbreviation
- J Mol Cell Cardiol
- ISSN
- 0022-2828
- eISSN
- 1095-8584
- Publisher
- Elsevier Ltd
- Grant note
- DOI: 10.13039/501100000024, name: Canadian Institutes of Health Research
- Language
- English
- Date published
- 08/2021
- Academic Unit
- Cardiovascular Medicine; Craniofacial Anomalies Research Center; Internal Medicine
- Record Identifier
- 9984360052502771
Metrics
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