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Statins Impair Survival of Primary Human Mesenchymal Progenitor Cells via Mevalonate Depletion, NF-κB Signaling, and Bnip3

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Abstract

Circulating progenitor cells of bone marrow origin have been implicated in transplant cardiac allograft vasculopathy (CAV) and cardiac fibrosis. HMG-CoA reductase inhibitors, called “statins,” have been shown to impair the progression of CAV and improve patient survival. We examined the in vitro effects of three HMG-CoA reductase inhibitors atorvastatin, simvastatin, and pravastatin on the viability of MSCs and expression of nuclear factor kappa B (NF-κB). Mesenchymal stem cells (MSCs) isolated from human patients were treated with atorvastatin, simvastatin, and pravastatin at 0.1, 1.0, or 10 μM ± mevalonate. Human MSC treatment with 1 and 10 μM simvastatin or atorvastatin resulted in progressively reduced cell viability, which was associated with a decline in NF-κB p65. Viability was rescued by co-incubation with mevalonate or by pretreatment with Inhibitor of nuclear factor kappa-B kinase subunit beta (Iκκ-β). Pravastatin did not affect MSC viability or NF-κB expression. Mevalonate depletion through HMG-CoA reductase inhibition impairs the viability of primary human MSC through down-regulating NF-κB.

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Disclosures

Atorvastatin was provided by Pfizer. No other disclosures.

Informed Consent

This study utilized bone marrow obtained solely from informed patients who gave consent under ethics approved by the Bannatyne Campus Research Ethics Board of the University of Manitoba.

Animal Research

No animal studies were carried out by the authors for this article.

Sources of Funding

Funding was provided by the St. Boniface Hospital Foundation, Canadian Institutes of Health Research, and the University of Manitoba Department of Surgery. The experiments performed in this manuscript complied with the laws of Canada where the experiments were performed.

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Authors and Affiliations

  1. Institute of Cardiovascular Sciences, St. Boniface Research Centre, Department of Physiology, University of Manitoba, Winnipeg, MB, Canada

    Yun Li, Melanie A. Ngo, Kiranjit Sran, Daniel Bellan, Rakesh C. Arora, Lorrie A. Kirshenbaum & Darren H. Freed

  2. Mazankowski Research Centre, Department of Physiology, University of Alberta, Edmonton, AB, Canada

    Alison L. Müller & Darren H. Freed

  3. Department of Surgery, University of Manitoba, Winnipeg, MB, Canada

    Rakesh C. Arora & Darren H. Freed

  4. Department of Surgery, University of Alberta, Edmonton, AB, Canada

    Darren H. Freed

  5. University of Alberta Hospital, 2D4.34 WMC, 8440 112St, Edmonton, AB, T6G 2B7, USA

    Darren H. Freed

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  1. Yun Li
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  2. Alison L. Müller
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  3. Melanie A. Ngo
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  4. Kiranjit Sran
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  7. Lorrie A. Kirshenbaum
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Correspondence to Darren H. Freed.

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Editor-in-Chief Jennifer L. Hall oversaw the review of this article

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Li, Y., Müller, A.L., Ngo, M.A. et al. Statins Impair Survival of Primary Human Mesenchymal Progenitor Cells via Mevalonate Depletion, NF-κB Signaling, and Bnip3. J. of Cardiovasc. Trans. Res. 8, 96–105 (2015). https://doi.org/10.1007/s12265-014-9603-3

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