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Caspase-1 Plays a Critical Role in Accelerating Chronic Kidney Disease-Promoted Neointimal Hyperplasia in the Carotid Artery

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Abstract

To determine whether caspase-1 is critical in chronic kidney disease (CKD)-mediated arterial neointimal hyperplasia (NH), we utilized caspase−/− mice and induced NH in carotid artery in a CKD environment, and uremic sera-stimulated human vascular smooth muscle cells (VSMC). We made the following findings: (1) Caspase-1 inhibition corrected uremic sera-mediated downregulation of VSMC contractile markers, (2) CKD-promoted NH was attenuated in caspase−/− mice, (3) CKD-mediated downregulation of contractile markers was rescued in caspase null mice, and (4) expression of VSMC migration molecule αvβ3 integrin was reduced in caspase−/− tissues. Our results suggested that caspase-1 pathway senses CKD metabolic danger signals. Further, CKD-mediated increase of contractile markers in VSMC and increased expression of VSMC migration molecule αvβ3 integrin in NH formation were caspase-1 dependent. Therefore, caspase-1 is a novel therapeutic target for the suppression of CKD-promoted NH.

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Abbreviations

CKD:

Chronic kidney disease

CVD:

Cardiovascular diseases

AVF:

Arteriovenous fistulas

NH:

Neointimal hyperplasia

VSMC:

Vascular smooth muscle cells

TLR:

Toll-like receptors

PAMP:

Pathogen-associated molecular patterns

DAMP:

Danger signal associated molecular patterns

NOD:

Nucleotide binding and oligomerization domain

NLR:

NOD-like receptors

HD:

Hemodialysis

HAVSMC:

Human aortic vascular smooth muscle cells

BUN:

Blood urea nitrogen

WT:

Wild type

VVG:

Verhoeff elastic-van Gieson stain

H & E:

Hematoxylin and eosin stain

ASC:

Apoptosis-associated speck-like protein containing caspase recruitment domain

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Acknowledgments

We thank Dr. R. Flavell from Yale University for generously providing caspase-1−/− mice.

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    Authors and Affiliations

    1. Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Lewis Katz School of Medicine, Temple University, 3500, North Broad Street, Philadelphia, PA, 19140, USA

      Lucas M. Ferrer, Alexandra M. Monroy, Jahaira Lopez-Pastrana, Gayani Nanayakkara, Ramon Cueto, Ya-feng Li, Xinyuan Li, Hong Wang, Xiao-feng Yang & Eric T. Choi

    2. Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA

      Hong Wang & Xiao-feng Yang

    3. Department of Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA

      Lucas M. Ferrer, Alexandra M. Monroy & Eric T. Choi

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    1. Lucas M. Ferrer
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    Correspondence to Xiao-feng Yang or Eric T. Choi.

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    Funding

    This work was supported by Temple University’s fund to ETC., the American Heart Association Postdoctoral Fellowship to YFL, and the National Institutes of Health Grants to ETC., XFY, and HW.

    Conflict of Interest

    The authors declare that they have no competing interests.

    Ethics Statement

    This study was conducted in accordance to the Helsinki declaration and with the ethical standards of the responsible committee on human experimentation (institutional and national). All participants provided written informed consent. All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the Institutional Animal Care and Use Committee of Temple University School of Medicine.

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    Associate Editor Jennifer L. Hall oversaw the review of this article

    Alexandra M. Monroy, Jahaira Lopez-Pastrana and Gayani Nanayakkara contributed equally to this work.

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    Ferrer, L.M., Monroy, A.M., Lopez-Pastrana, J. et al. Caspase-1 Plays a Critical Role in Accelerating Chronic Kidney Disease-Promoted Neointimal Hyperplasia in the Carotid Artery. J. of Cardiovasc. Trans. Res. 9, 135–144 (2016). https://doi.org/10.1007/s12265-016-9683-3

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