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Plasma Levels of Endothelial Microparticles Bearing Monomeric C-reactive Protein are Increased in Peripheral Artery Disease

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Abstract

C-reactive protein (CRP) as an indicator of cardiovascular disease (CVD) has shown limited sensitivity. We demonstrate that two isoforms of CRP (pentameric, pCRP and monomeric, mCRP) present in soluble form or on microparticles (MPs) have different biological effects and are not all measured by clinical CRP assays. The high-sensitivity CRP assay (hsCRP) did not measure pCRP or mCRP on MPs, whereas flow cytometry did. MPs derived from endothelial cells, particularly those bearing mCRP, were elevated in peripheral artery disease (PAD) patients compared to controls. The numbers of mCRP+ endothelial MPs did not correlate with hsCRP measurements of soluble pCRP, indicating their independent modulation. In controls, statins lowered mCRP+ endothelial MPs. In a model of vascular inflammation, mCRP induced endothelial shedding of MPs and was proinflammatory, while pCRP was anti-inflammatory. mCRP on endothelial MPs may be both an unmeasured indicator of, and an amplifier of, vascular disease, and its detection might improve risk sensitivity.

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Abbreviations

CRP:

C-reactive protein

hsCRP:

high-sensitivity CRP assay

mCRP:

monomeric CRP

MNL:

mononuclear leukocyte

MP:

microparticle

PAD:

peripheral artery disease

pCRP:

pentameric CRP

TEM:

transendothelial migration

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Acknowledgments

We are grateful for the CRP antibody donation of Dr. Larry Potempa (Roosevelt University, Chicago, Illinois). We would like to thank all subjects who participated in the study, Tenille Epperson and Joe L. Raya for their technical assistance and the MD Anderson Cancer Center Flow Cytometry Core for their assistance with the Amnis cytometer.

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Authors and Affiliations

  1. The Division of Cardiovascular Sciences and the DeBakey Heart Center, Department of Medicine, Baylor College of Medicine and Houston Methodist Hospital, One Baylor Plaza, M.S. BCM620, Houston, TX, 77030, USA

    Jeffrey R. Crawford, JoAnn Trial, George E. Taffet & Mark L. Entman

  2. The Division of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA

    Vijay Nambi

  3. The Division of Atherosclerosis and Vascular Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Vijay Nambi & Ron C. Hoogeveen

  4. Center for Cardiovascular Prevention, Methodist DeBakey Heart and Vascular Center, 6565 Fannin St., Houston, TX, 77030, USA

    Vijay Nambi

Authors
  1. Jeffrey R. Crawford
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  2. JoAnn Trial
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  3. Vijay Nambi
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  4. Ron C. Hoogeveen
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Corresponding author

Correspondence to JoAnn Trial.

Ethics declarations

Compliance with Ethical Standards

The study was conducted in accordance with the ethical standards of the Helsinki declaration and its later amendments and with the ethical standards and approval of the Institutional Review Board of Baylor College of Medicine. Informed consent was obtained from all individual participants included in the study. No animal studies were carried out by the authors for this article.

Sources of Funding

This work was supported by the National Institutes of Health [T32AI053831-10 to J.R.C., RO1 HL-089792 to M.L.E.], Bethesda, Maryland; the Hankamer Foundation, Houston, Texas; the Vivian L. Smith Foundation, Houston, Texas; and The Medallion Foundation, Houston, Texas.

Conflict of Interest

V.N. and R.C.H. are co-investigators on a provisional patent filed by Roche for use of biomarkers in heart failure prediction. The other authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. V.N. has indicated that he has served on the regional advisory board (once) for Sanofi-Regeneron.

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Associate Editor Enrique Lara-Pezzi oversaw the review of this article

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Crawford, J.R., Trial, J., Nambi, V. et al. Plasma Levels of Endothelial Microparticles Bearing Monomeric C-reactive Protein are Increased in Peripheral Artery Disease. J. of Cardiovasc. Trans. Res. 9, 184–193 (2016). https://doi.org/10.1007/s12265-016-9678-0

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