PI3K signaling in arterial diseases: Non redundant functions of the PI3K isoforms

Lupieri, Adrien; Smirnova, Natalia F.; Malet, Nicole; Gayral, Stéphanie; Laffargue, Muriel

doi:10.1016/j.jbior.2015.06.002

Cited by 20 publications

(11 citation statements)

References 164 publications

(190 reference statements)

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“…Endothelial cells have been shown to express the α, and γ isoforms of class I PI3Ks [34], and PCR analysis confirmed the presence of mRNA for these three isoforms in HUVECs (Fig. 4A).…”

Section: Resultsmentioning

confidence: 75%

“…PI3Kγ is a well-known mediator of inflammation in arterial walls through its roles in both immune cell signaling [63, 64] and in endothelial cells where it can modulate the E-selectin pathway necessary for leucocyte recruitment [65]. The identification of a beneficial role of PI3Kβ in endothelial cells confirms the specific role of these different PI3K isoforms in vascular diseases [34] and demonstrates that these two isoforms of PI3K may play opposite roles in a physiopathological context and especially in vascular diseases. PI3K is known to have an important role in platelet aggregation, and specific PI3Kβ inhibitors prevent the formation of stable α IIb β 3 integrin adhesion contacts, leading to defective platelet thrombus formation.…”

Section: Discussionmentioning

confidence: 94%

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PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors

Castaing-Berthou¹,

Malet²,

Radojkovic³

et al. 2017

Cell Physiol Biochem

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Background/Aims: High-density lipoproteins (HDL) exert multiple cardioprotective functions on the arterial wall, including the promotion of endothelial cell survival and proliferation. Among mechanism contributing to endothelial protection, it has been reported that apolipoprotein A-I (apoA-I), the major protein in HDL, binds and activates the endothelial ecto-F₁-ATPase receptor. This generates extracellular ADP, which in turn promotes endothelial cell survival. In this study we aimed to further investigate the signaling pathway involved downstream of apoA-I-induced ecto-F₁-ATPase activation. Methods: In human umbilical vein endothelial cells (HUVECs), pharmacological and gene silencing approaches were used to study pathways involved downstream ecto-F₁-ATPase activation by apoA-I. Results: ApoA-I and HDL both induced Akt phosphorylation. F₁-ATPase inhibitors such as inhibitory factor 1 and oligomycin completely blocked apoA-I-induced Akt phosphorylaton and significantly blocked HDL-induced phosphorylation, indicating that this signaling pathway is dependent on ecto-F₁-ATPase activation by apoA-I. Further, we were able to specify roles for the P2Y₁-ADPreceptor and the PI3Kβ isoform in this pathway since pharmacological inhibition and silencing of these proteins dramatically inhibited apoA-I-induced Akt phosphorylation and cell proliferation. Conclusion: Altogether, these data highlight a key role of the P2Y₁/PI3Kβ axis in endothelial cell proliferation downstream of ecto-F₁-ATPase activation by apoA-I. Pharmacological targeting of this pathway could represent a promising approach to enhance vascular endothelial protection.

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“…Endothelial cells have been shown to express the α, and γ isoforms of class I PI3Ks [34], and PCR analysis confirmed the presence of mRNA for these three isoforms in HUVECs (Fig. 4A).…”

Section: Resultsmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 94%

PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors

Castaing-Berthou¹,

Malet²,

Radojkovic³

et al. 2017

Cell Physiol Biochem

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“…111 This original expression pattern, different from other class of PI3K, places this protein as a good candidate for drug targeting in CVD. 109,112 In this context, our team has played a large part in determining the in vitro and in vivo immuno-modulatory functions of PI3Kg in arterial pathologies of atherosclerosis 113 and restenosis. 114 By driving the monocyte response to EDP, we recently identified that PI3Kg is a key signalling protein involved in EDP-induced atherosclerosis in vivo.…”

Section: Blocking Erc-mediated Signalling Pathwaysmentioning

confidence: 99%

Matrix ageing and vascular impacts: focus on elastin fragmentation

et al. 2016

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Cardiovascular diseases (CVDs) are the leading cause of death worldwide and represent a major problem of public health. Over the years, life expectancy has considerably increased throughout the world, and the prevalence of CVD is inevitably rising with the growing ageing of the population. The normal process of ageing is associated with progressive deterioration in structure and function of the vasculature, commonly called vascular ageing. At the vascular level, extracellular matrix (ECM) ageing leads to molecular alterations in long half-life proteins, such as elastin and collagen, and have critical effects on vascular diseases. This review highlights ECM alterations occurring during vascular ageing with a specific focus on elastin fragmentation and also the contribution of elastin-derived peptides (EDP) in age-related vascular complications. Moreover, current and new pharmacological strategies aiming at minimizing elastin degradation, EDP generation, and associated biological effects are discussed. These strategies may be of major relevance for preventing and/or delaying vascular ageing and its complications.

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“…The biological and biochemical effects of the Raf/MEK1/ERK, PI3K/PTEN/AKT/mTORC1/GSK-3 and TP53 pathways have been recently reviewed [ 1 – 7 ]. These signaling cascades are also important in cardiovascular diseases, diabetes, metabolism, neurological diseases, obesity and other maladies [ 8 – 10 ]. A key factor controlled by both pathways positively and negatively is the mTORC complex which is critical in regulating protein translation and is often dysregulated in various diseases [ 2 , 4 , 5 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Drug-resistance in doxorubicin-resistant FL5.12 hematopoietic cells: elevated MDR1, drug efflux and side-population positive and decreased BCL2-family member expression

et al. 2017

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Chemotherapeutic drug treatment can result in the emergence of drug-resistant cells. By culturing an interleukin-3 (IL-3)-dependent cell line, FL5.12 cells in the presence of the chemotherapeutic drug doxorubicin, we isolated FL/Doxo cells which are multi-drug resistant. Increased levels of drug efflux were detected in FL/Doxo cells which could be inhibited by the MDR1 inhibitor verapamil but not by the MRP1 inhibitor MK571. The effects of TP53 and MEK1 were examined by infection of FL/Doxo cells with retroviruses encoding either a dominant negative TP-53 gene (FL/Doxo+ TP53 (DN) or a constitutively-activated MEK-1 gene (FL/Doxo + MEK1 (CA). Elevated MDR1 but not MRP1 mRNA transcripts were detected by quantitative RT-PCR in the drug-resistant cells while transcripts encoding anti-apoptotic genes such as: BCL2, BCLXL and MCL1 were observed at higher levels in the drug-sensitive FL5.12 cells. The percentage of cells that were side-population positive was increased in the drug-resistant cells compared to the parental line. Drug-resistance and side-positive population cells have been associated with cancer stem cells (CSC). Our studies suggest mechanisms which could allow the targeting of these molecules to prevent drug-resistance.

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PI3K signaling in arterial diseases: Non redundant functions of the PI3K isoforms

Cited by 20 publications

References 164 publications

PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors

PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors

Matrix ageing and vascular impacts: focus on elastin fragmentation

Drug-resistance in doxorubicin-resistant FL5.12 hematopoietic cells: elevated MDR1, drug efflux and side-population positive and decreased BCL2-family member expression

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