Protective Mechanisms by Protein Restriction in Intimal Hyperplasia
Description: Therapies for occlusive arterial disease (angioplasties, stents, endarterectomies, bypasses, 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 dietary patterns during the times of 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 work by us and others has shown that a brief period of protein restriction alone is an approach to positively impact metabolic fitness and resistance to multiple forms of acute stress, including the vascular response to injury. We broadly theorize that adipose'a dominant, highly biologically active yet nimble tissue'can be pre-conditioned by short-term protein restriction to positively impact the vascular response to trauma via specific nutrient sensitive signaling networks. For the current proposal we hypothesize that short-term protein restriction attenuates the arterial intimal hyperplastic response to injury via local adipose mTorC1 dependent mechanisms, which downstream increases local adiponectin and downregulates proinflammatory adipokines. This hypothesis will be tested using our validated murine models via the following Specific Aims: 1) Determine the impact of perivascular adipose phenotype on intimal hyperplasia 2) Define adipose mTORC1 and leptin dependent mechanisms in short-term pre-injury protein restriction as they relate to intimal hyperplasia. Completion of these Aims will unravel mechanistic ties between short-term protein restriction, adipose and associated mediator biology, and the earliest genesis of intimal hyperplasia, and point to clear translational strategies to prevent occlusive vascular adaptations associated with interventions.
Funder: American Heart Association
Amount: $198,000
Funding type: research
Funder scheme: Grant-in-Aid
Start date: 2016-01-01
End date: 2018-12-31
Investigators: C Keith OZAKI, C Keith OZAKI
Institution: Brigham and Women's Hospital, Inc.
Funded outputs count: 8
Funder award ID: 16GRNT27090006
OpenAlex ID: G563035108