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ResearchIn-Press PreviewCardiologyVascular biology Open Access | 10.1172/jci.insight.165713

Insulin-like growth factor I reduces coronary atherosclerosis in pigs with familial hypercholesterolemia

Sergiy Sukhanov,1 Yusuke Higashi,1 Tadashi Yoshida,1 Svitlana Danchuk,1 Mitzi Alfortish,1 Traci Goodchild,2 Amy Scarborough,2 Thomas E. Sharp III,2 James S. Jenkins,3 Daniel Garcia,3 Jan Ivey,4 Darla L. Tharp,4 Jeffrey D. Schumacher,5 Zach Rozenbaum,6 Jay K Kolls,7 Douglas K. Bowles,8 David Lefer,2 and Patrice Delafontaine9

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Sukhanov, S. in: JCI | PubMed | Google Scholar |

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Higashi, Y. in: JCI | PubMed | Google Scholar

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Yoshida, T. in: JCI | PubMed | Google Scholar |

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Danchuk, S. in: JCI | PubMed | Google Scholar

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Alfortish, M. in: JCI | PubMed | Google Scholar

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Goodchild, T. in: JCI | PubMed | Google Scholar

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Scarborough, A. in: JCI | PubMed | Google Scholar

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Sharp III, T. in: JCI | PubMed | Google Scholar

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Jenkins, J. in: JCI | PubMed | Google Scholar

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Garcia, D. in: JCI | PubMed | Google Scholar

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Ivey, J. in: JCI | PubMed | Google Scholar

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Tharp, D. in: JCI | PubMed | Google Scholar

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Schumacher, J. in: JCI | PubMed | Google Scholar

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Rozenbaum, Z. in: JCI | PubMed | Google Scholar

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Kolls, J. in: JCI | PubMed | Google Scholar |

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Bowles, D. in: JCI | PubMed | Google Scholar

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Lefer, D. in: JCI | PubMed | Google Scholar

1Tulane University Heart & Vascular Institute, Tulane University School of Medicine, New Orleans, United States of America

2School of Medicine, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

3Department of Surgery, Ochsner Medical Center, New Orleans, United States of America

4School of Medicine, University of Missouri at Columbia, Columbia, United States of America

5Veterinary Sciences, Louisiana State University Cardiovascular Center of Excellence, New Orleans, United States of America

6Department of Cardiology, Tulane University School of Medicine, New Orleans, United States of America

7Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, United States of America

8University of Missouri at Columbia, Columbia, United States of America

9Department of Medicine, Tulane University School of Medicine, New Orleans, United States of America

Find articles by Delafontaine, P. in: JCI | PubMed | Google Scholar

Published January 5, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.165713.
Copyright © 2023, Sukhanov et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 5, 2023 - Version history
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Abstract

Although murine models of coronary atherosclerotic disease have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We administered human recombinant IGF-1 or saline (control) in atherosclerotic FH pigs for 6 months. IGF-1 decreased relative coronary atheroma in vivo (intravascular ultrasound) and reduced lesion cross-sectional area (postmortem histology). IGF-1 increased plaque’s fibrous cap thickness, and reduced necrotic core, macrophage content, and cell apoptosis consistent with promotion of a stable plaque phenotype. IGF-1 reduced circulating triglycerides, markers of systemic oxidative stress and CXCL12 chemokine levels. We used spatial transcriptomics (ST) to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects. ST analysis shows that IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1’s effect on atherosclerosis. Thus, IGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials.

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