Adipose Dependent Mechanisms of Dietary Protein Restriction Protective Effects on Vein Graft Adaptations

Brigham And Women'S Hospital, Boston MA

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Abstract

Therapies for occlusive arterial disease (vein and prosthetic bypasses, angioplasties, stents, endarterectomies, etc.) suffer from unacceptably high failure rates due to re-occlusive vascular wall adaptations, with intimal hyperplasia dominating most failures. Humans have evolved complex mechanisms to respond to and heal from stress such as vascular trauma. Dietary intake and patterns during these evolutionary pressures were quite different than the constant high protein intake of contemporary Western diets. Dietary restriction (reduced food intake without malnutrition) is known for extending longevity in multiple species. Recent published work by us and others has shown that brief dietary protein restriction (DPR) alone is also an approach to positively impact metabolic fitness and resistance to multiple forms of acute stress, including the vascular response to injury in arteries as well as vein grafts. We broadly theorize that adipose?a dominant, highly biologically active yet nimble tissue?can be pre-conditioned by short-term DPR to positively impact vein graft wall adaptations via specific signaling networks. Herein we test the hypothesis that short-term DPR attenuates vein graft intimal hyperplasia via the nutrient sensor molecule mTORC1 and leptin dependent mechanisms in the stromal vascular fraction of local adipose tissue. The project will complete three Specific Aims: 1) Delineate over time the impact of short-term DPR on specific compartments of adipose and vein graft wall intimal hyperplasia and remodeling. 2) Define adipose mTORC1 dependent mechanisms of DPR as they relate to vein graft wall intimal hyperplasia and wall remodeling 3) Determine the role of leptin signaling in DPR attenuation of the vein graft wall adaptations. This work builds on a foundation of multiple peer reviewed publications by the applicant, and established partnerships with experts in nutrition and vascular biology. Completion of these aims will uncover novel mechanistic links between pre-operative DPR, proinflammatory adipokine/cytokine secretion, the mTORC1 /leptin signaling pathways, and their links with early vein graft adaptations. These findings should be translatable to clinical practice as mechanistically informed, targeted adjunctive nutritional and medical therapies to prolong the durability of occlusive vascular disease interventions.