Abstract
Background and aims: Obesity and type 2 diabetes are significant risk factors for atherosclerotic cardiovascular disease (CVD) worldwide, but the underlying pathophysiological links are poorly understood. Neurotensin (NT), a 13-amino-acid hormone peptide, facilitates intestinal fat absorption and contributes to obesity in mice fed a high-fat diet. Elevated levels of pro-NT (a stable NT precursor produced in equimolar amounts relative to NT) are associated with obesity, type 2 diabetes, and CVD in humans. Whether NT is a causative factor in CVD is unknown. Methods: Nt+/+ and Nt–/– mice were either injected with adeno-associated virus encoding PCSK9 mutants or crossed with Ldlr–/– mice and fed a Western diet. Atherosclerotic plaques were analyzed by en face analysis, Oil Red O and CD68 staining. In humans, we evaluated the association between baseline pro-NT and growth of carotid bulb thickness after 16.4 years. Lipidomic profiles were analyzed. Results: Atherosclerotic plaque formation is attenuated in Nt-deficient mice through mechanisms that are independent of reductions in circulating cholesterol and triglycerides but associated with remodeling of the plasma triglyceride pool. An increasing plasma concentration of pro-NT predicts atherosclerotic events in coronary and cerebral arteries independent of all major traditional risk factors, indicating a strong link between NT and atherosclerosis. This plasma lipid profile analysis confirms the association of pro-NT with remodeling of the plasma triglyceride pool in atherosclerotic events. Conclusions: Our findings are the first to directly link NT to increased atherosclerosis and indicate the potential role for NT in preventive and therapeutic strategies for CVD.
| Original language | English |
|---|---|
| Article number | 117479 |
| Journal | Atherosclerosis |
| Volume | 392 |
| DOIs | |
| State | Published - May 2024 |
Bibliographical note
Publisher Copyright:© 2024 The Authors
Funding
We thank the Markey Cancer Center Research Communications Office for manuscript preparation, the Biospecimen Procurement and Translational Pathology Shared Resource Facility, and the Biostatistics and Bioinformatics Shared Resource Facility of the University of Kentucky Markey Cancer Center (supported by National Cancer Institute grant P30 CA177558 ). This study was supported by a National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases grant ( R01 DK112034 to B.M.E.) and a pilot award from the NIH National Center for Advancing Translational Sciences ( UL1TR001998 to B.M.E.), as well as the European Research Council ( AdG 2019-885003-PREVENT-2024 to O.M.), Swedish Research Council /Vetenskapsrådet (Dnr 2018-02760 to O.M.), grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (to O.M.) and the Swedish Heart and Lung Foundation /Hjärt-Lungfonden ( 2021-0253 to O.M.). The grants for our cardiovascular disease research are U.S. Department of Veterans Affairs (VA) grants I01CX001550 and BX004671 (to A.J.M.). The lipid measurements were performed in our VA lab using an instrument that was purchased with VA grant IS1BX003153 (to A.J.M. and S.S.). The NIH National Institute of General Medical Sciences COBRE grant that was used to support development of the lipid methods is P30 GM127211 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This study was supported by a National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases grant (R01 DK112034 to B.M.E.) and a pilot award from the NIH National Center for Advancing Translational Sciences (UL1TR001998 to B.M.E.), as well as the European Research Council (AdG 2019-885003-PREVENT-2024 to O.M.), Swedish Research Council/Vetenskapsrådet (Dnr 2018-02760 to O.M.), grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (to O.M.) and the Swedish Heart and Lung Foundation/Hjärt-Lungfonden (2021-0253 to O.M.). The grants for our cardiovascular disease research are U.S. Department of Veterans Affairs (VA) grants I01CX001550 and BX004671 (to A.J.M.). The lipid measurements were performed in our VA lab using an instrument that was purchased with VA grant IS1BX003153 (to A.J.M. and S.S.). The NIH National Institute of General Medical Sciences COBRE grant that was used to support development of the lipid methods is P30 GM127211. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.We thank the Markey Cancer Center Research Communications Office for manuscript preparation, the Biospecimen Procurement and Translational Pathology Shared Resource Facility, and the Biostatistics and Bioinformatics Shared Resource Facility of the University of Kentucky Markey Cancer Center (supported by National Cancer Institute grant P30 CA177558).
| Funders | Funder number |
|---|---|
| University of Kentucky Markey Comprehensive Cancer Center | |
| National Institutes of Health (NIH) | |
| The Markey Biostatistics and Bioinformatics Shared Resource Facility | |
| Swedish government | |
| Markey Cancer Center Research Communications Office | |
| U.S. Department of Veterans Affairs | I01CX001550, BX004671, IS1BX003153 |
| National Childhood Cancer Registry – National Cancer Institute | P30 CA177558 |
| National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences | P30 GM127211 |
| Hjärt-Lungfonden | 2021-0253 |
| Vetenskapsrådet | 2018-02760, Dnr 2018-02760 |
| H2020 European Research Council | AdG 2019-885003-PREVENT-2024 |
| National Institute of Diabetes and Digestive and Kidney Diseases | R01 DK112034 |
| National Center for Advancing Translational Sciences (NCATS) | UL1TR001998 |
Keywords
- Heart disease
- High-fat diet
- Neurotensin
- Obesity
- Small intestine
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
