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Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers.

ABSTRACT: Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), (OEG₂)₂-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG₂)₂-IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG₂)₂-IP4 disrupts the nucleation and growth of pathological calcification.

SUBMITTER: Schantl AE

PROVIDER: S-EPMC7002685 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers.

Schantl Antonia E AE Verhulst Anja A Neven Ellen E Behets Geert J GJ D'Haese Patrick C PC Maillard Marc M Mordasini David D Phan Olivier O Burnier Michel M Spaggiari Dany D Decosterd Laurent A LA MacAskill Mark G MG Alcaide-Corral Carlos J CJ Tavares Adriana A S AAS Newby David E DE Beindl Victoria C VC Maj Roberto R Labarre Anne A Hegde Chrismita C Castagner Bastien B Ivarsson Mattias E ME Leroux Jean-Christophe JC

Nature communications 20200205 1

Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), (OEG<sub>2</sub>)<sub>2</sub>-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety p ...[more]

PMID: 32024848

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Project description:ObjectiveVascular calcification is a characteristic feature of atherosclerosis, diabetes mellitus, and end-stage renal disease. We have demonstrated that activation of protein kinase B (AKT) upregulates runt-related transcription factor 2 (Runx2), a key osteogenic transcription factor that is crucial for calcification of vascular smooth muscle cells (VSMC). Using mice with SMC-specific deletion of phosphatase and tensin homolog (PTEN), a major negative regulator of AKT, the present studies uncovered a novel molecular mechanism underlying PTEN/AKT/FOXO (forkhead box O)-mediated Runx2 upregulation and VSMC calcification.Approach and resultsSMC-specific PTEN deletion mice were generated by crossing PTEN floxed mice with SM22α-Cre transgenic mice. The PTEN deletion resulted in sustained activation of AKT that upregulated Runx2 and promoted VSMC calcification in vitro and arterial calcification ex vivo. Runx2 knockdown did not affect proliferation but blocked calcification of the PTEN-deficient VSMC, suggesting that PTEN deletion promotes Runx2-depedent VSMC calcification that is independent of proliferation. At the molecular level, PTEN deficiency increased the amount of Runx2 post-transcriptionally by inhibiting Runx2 ubiquitination. AKT activation increased phosphorylation of FOXO1/3 that led to nuclear exclusion of FOXO1/3. FOXO1/3 knockdown in VSMC phenocopied the PTEN deficiency, demonstrating a novel function of FOXO1/3, as a downstream signaling of PTEN/AKT, in regulating Runx2 ubiquitination and VSMC calcification. Using heterozygous SMC-specific PTEN-deficient mice and atherogenic ApoE(-/-) mice, we further demonstrated AKT activation, FOXO phosphorylation, and Runx2 ubiquitination in vascular calcification in vivo.ConclusionsOur studies have determined a new causative effect of SMC-specific PTEN deficiency on vascular calcification and demonstrated that FOXO1/3 plays a crucial role in PTEN/AKT-modulated Runx2 ubiquitination and VSMC calcification.

Dataset Information

Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers.

Publications

Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers.

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