Project

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Protection from intimal hyperplasia by protein restriction: role of mTORC1 amino acid sensing and leptin

Applicant Longchamp Alban
Number 158895
Funding scheme Doc.Mobility
Research institution Harvard Medical School Brigham and Women's Hospital
Institution of higher education Institution abroad - IACH
Main discipline Cardiovascular Research
Start/End 01.12.2014 - 31.05.2016
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All Disciplines (2)

Discipline
Cardiovascular Research
Molecular Biology

Keywords (4)

Intimal hyperplasia; mTORC1; Leptin; Protein Restriction

Lay Summary (French)

Lead
Les pathologies artérielles occlusives représentent une des principale cause de mortalité dans le monde. Les traitements disponibles sont l’angioplastie, les stents, les endarterectomie, et les pontages chirurgicaux. Néanmoins, ces traitements souffrent d’un taux d échec élevé, principalement du au remodelage vasculaire ou hyperplasie intimale. La restriction alimentaire, définie comme une réduction des apports énergétiques/nutriments sans malnutrition augmente la résistance face aux stress, notamment le trauma chirurgical. Dans ce projet, nous proposons d’utiliser une restriction alimentaire de courte durée afin de prévenir l’hyperplasie intimale, et ainsi l’ischémie critique d’organe, la perte de membre, de fonction cérébrale ou vie.
Lay summary

Malgré des taux d’échecs élevés des interventions chirurgicales vasculaires, les stratégies afin de prévenir l’hyperplasie intimale sont manquantes. Ici, nous proposons de tester l’hypothèse que une intervention alimentaire brève (réduction de l apport protéique) diminue l hyperplasie intimale via une réduction de l’hormone pro-inflammatoire leptin, causée par l’inhibition du senseur protéique/énergétique mTORC1.

La première partie de ce projet a pour but d’établir le lien moléculaire entre la restriction alimentaire et la protection contre l’hyperplasie intimale. Nos données indiquent que la restriction alimentaire 1) diminue les taux de leptin et 2) diminue l’hyperplasie intimale. Etant donne que la leptin aggrave l’ l’hyperplasie intimale, nous proposons une relation causale entre la réduction des taux de leptin (après restriction alimentaire) et la prévention de l’hyperplasie intimale.

La deuxième partie vise à comprendre le lien entre le senseur de nutriment mTORC1 et la production de leptin. A la fin de ce projet, nous pourrons établir un lien entre la restriction alimentaire pré-chirurgicale, la sécrétion de leptin et le développent d’hyperplasie intimale. Ces données permettront une translation clinique afin de prévenir les pathologie artérielles occlusive, représentant un cout sociale et économique extrêmement élevé a l’heure actuelle. 

Direct link to Lay Summary Last update: 26.11.2014

Lay Summary (English)

Lead
Arterial occlusive disease is the leading cause of death in Western countries. Mainstays of contemporary therapies for this disease include angioplasties, stents, endarterectomies, and bypass surgery. However, these treatments suffer from high failure rates due to re-occlusive vascular wall adaptations, namely intimal hyperplasia. Dietary restriction, defined as reduced nutrient/energy intake without malnutrition, increases resistance to multiple forms of stress, including trauma incurred during major surgery. In this project, we propose to use short term dietary restriction to decrease intimal hyperplasia thus preventing recurrent end-organ ischemia, loss of limb, brain function, or life.
Lay summary

Despite high failure rates of vascular interventions, current strategies to mitigate incidence and/or severity of IH are lacking. Here, we propose to test the hypothesis that short-term protein restriction attenuates IH by reducing secretion of the proinflammatory adipokine leptin, via inhibition of the nutrient/energy sensor mTORC1 specifically in adipocytes.

The first part of this project will establish the molecular link between protein restriction and protection from IH. Our data indicate that protein restriction 1) reduces systemic leptin levels, and 2) reduces IH after carotid stenosis. Because leptin exacerbates IH we propose to test the hypothesis that there is a causal relationship between reduction of leptin levels upon protein restriction and prevention of IH. The second part aims to establish the link between the  nutrient/energy sensor, mTORC1 and leptin production in adipocytes. Leptin is a hormone produced primarily by adipocytes in response to nutrient/energy levels. mTORC1 integrates signals from amino acid, energy and growth factor availability to impact cellular decisions on anabolic and catabolic processes. We thus propose that the reduction in leptin observed upon short-term protein restriction depends on reduced mTORC1 signaling specifically in adipocytes.

Completion of this proposal will unravel novel mechanistic links between pre-operative protein restriction, leptin secretion, and the early establishment of IH. These data will have clear translational implications for the prevention of occlusive vascular adaptations, an enormous medical burden that currently lacks any mitigation strategy.

Direct link to Lay Summary Last update: 26.11.2014

Responsible applicant and co-applicants

Publications

Publication
Local perivascular adiponectin associates with lower extremity vascular operative wound complications.
Sharma Gaurav, Kulkarni Rohan, Shah Samir K, King William W, Longchamp Alban, Tao Ming, Ding Kui, Ozaki C Keith (2016), Local perivascular adiponectin associates with lower extremity vascular operative wound complications., in Surgery, 160(1), 204-10.
Nitric Oxide Deficit Drives Intimal Hyperplasia in Mouse Models of Hypertension.
Allagnat F, Haefliger J-A, Lambelet M, Longchamp A, Bérard X, Mazzolai L, Corpataux J-M, Déglise S (2016), Nitric Oxide Deficit Drives Intimal Hyperplasia in Mouse Models of Hypertension., in European journal of vascular and endovascular surgery : the official journal of the European Society, 51(5), 733-42.
Connexin43 Inhibition Prevents Human Vein Grafts Intimal Hyperplasia.
Longchamp Alban, Allagnat Florent, Alonso Floriant, Kuppler Christopher, Dubuis Celine, Ozaki C. Keith, Mitchell James R., Bercelli Scott, Corpataux Jean-Marc, Deglise Sebastien, Haefliger Jacques-Antoine (2015), Connexin43 Inhibition Prevents Human Vein Grafts Intimal Hyperplasia., in Plos One, e0138847.
Perivascular adipose adiponectin correlates with symptom status of patients undergoing carotid endarterectomy.
Sharma Gaurav, Tao Ming, Ding Kui, Yu David, King William, Deyneko Galina, Wang Xiaosong, Longchamp Alban, Schoen Frederick J, Ozaki C Keith, Semel Marcus E (2015), Perivascular adipose adiponectin correlates with symptom status of patients undergoing carotid endarterectomy., in Stroke; a journal of cerebral circulation, 46(6), 1696-9.
Surgical injury induces local and distant adipose tissue browning
Longchamp Alban, Tao Ming, Bartelt Alexander, Ding Kui, Lynch Lydia, Hine Christopher, Corpataux Jean-Marc, Kristal Bruce S., Mitchell James R., Ozaki C. Keith (2015), Surgical injury induces local and distant adipose tissue browning, in Adipocyte, 163-174.

Collaboration

Group / person Country
Types of collaboration
Dr. Indranil Sinha/Harvard University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Christopher Chen/ Boston University United States of America (North America)
- Publication
Prof. Xavier Berard/Bordeaux University Hospital France (Europe)
- Publication
Prof. A. Yaël Nossent/Leiden University Medical Center Netherlands (Europe)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Arteriosclerosis, Thrombosis and Vascular Biology / Peripheral Vascular Disease Talk given at a conference Nutrient Restriction Triggers Angiogenesis via GCN2/ATF4-Dependent H2S Production 05.05.2016 Nashville, TN, United States of America Longchamp Alban;
ANNUAL OBESITY RESEARCH INCUBATOR SESSION Talk given at a conference Dietary Regulation of Hydrogen Sulfide Production: Implications for Stress Resistance, Energy Metabolism and Angiogenesis 04.03.2016 Boston, MA, United States of America Longchamp Alban;
CVDM - FRONTIERS IN BIOMEDICAL SCIENCE SEMINAR SERIES Talk given at a conference Stimulation of endogenous hydrogen sulfide production by diet: implications during angiogenesis 18.12.2015 Boston, United States of America Longchamp Alban;
Arteriosclerosis, Thrombosis and Vascular Biology Peripheral Vascular Disease Poster Surgical Injury Induces Local and Distant Adipose Tissue Browning 07.05.2015 San Francisco, CA, United States of America Longchamp Alban;
International Gap Junction Conference Talk given at a conference Cx43 Inhibition Prevents Human Vein Intimal Hyperplasia 28.03.2015 Valparaiso, Chile Longchamp Alban;


Knowledge transfer events



Self-organised

Title Date Place

Awards

Title Year
Brigham Research Institute 2016
Prix du Docteur Cesar Roux 2015

Abstract

In this proposal, we propose to test the hypothesis that short-term protein restriction attenuates IH by reducing secretion of the proinflammatory adipokine leptin, via inhibition of the nutrient/energy sensor mTORC1 specifically in adipocytes. This proposal builds on my mentors established murine model of IH (carotid artery focal stenosis), published expertise in vascular biology, protein/amino acid sensing and dietary interventions. This hypothesis will be tested via the following Specific Aims:Aim 1. Establish leptin as the molecular link between protein restriction and protection from IH. Our data indicate that protein restriction 1) reduces systemic leptin levels, and 2) reduces IH after carotid stenosis. Because leptin exacerbates IH, we propose to test the hypothesis that there is a causal relationship between reduction of leptin levels upon protein restriction and prevention of IH. To this end, we will use our validated murine carotid stenosis model, in mice preconditioned on a protein-restricted diet with or without addition of exogenous leptin. We predict protein restriction-mediated protection from IH will be lost upon exogenous leptin administration.Aim 2. Establish the nutrient/energy sensor, mTORC1, as the key positive regulator of leptin production in adipocytes. Leptin is a hormone produced primarily by adipocytes in response to nutrient/energy levels. mTORC1 integrates signals from amino acid, energy and growth factor availability to impact cellular decisions on anabolic and catabolic processes. We propose that the reduction in leptin observed upon short-term protein restriction depends on reduced mTORC1 signaling specifically in adipocytes. We will test this in differentiated adipocytes in vitro using short hairpin RNA targeting a negative regulator of mTORC1 (Tsc1), and in vivo using a genetic mouse model in which Tsc1 is ablated specifically in adipocytes (ATsc1KO) resulting in mTORC1 overactivation. We predict that upon adipose mTORC1 overactivation 1) leptin levels will be increased independently of food intake and 2) mice on a protein-restricted diet will loose protection against IH.
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