Dietary intervention to protect against peripheral artery disease
Description: Atherosclerosis in peripheral arteries leads to peripheral artery disease (PAD), where reduced blow flow to the limbs causes ischemia, which may progress to critical limb threatening ischemia (CLTI) and associated risk of amputation. PAD patients also carry a high risk of cardiovascular event and death. Surgical revascularization is the only option for CLTI, but it is not always possible, nor effective. Moreover, even after successful revascularization, long-term patency is still plagued re-occlusion due to the pathologic process of intimal hyperplasia (IH). IH develops in response to vessel injury, leading to the formation of neointima layer, which progressively occludes the lumen of the vessel. IH results in complex recurrent end-organ ischemia, and often leads to loss of limb, brain function, or life. Despite decades of research, PAD and IH remain poorly understood and ill-treated. Dietary restriction (DR) has robust anti-aging effects and shows benefits against cardiovascular diseases. However, there is currently no clinical protocol leveraging the benefits of DR in patients undergoing vascular surgery. DR comes in many forms such as calorie restriction, time restricted feeding (TRF), or macronutrient (protein, carbohydrate or lipid) restriction. The pathways involved in the benefits of DR include amino acid sensing and mTOR, the GH-IGF-1 axis, the GCN2-eIF2a-ATF4 signalling module and increased production of hydrogen sulfide (H2S), a gasotransmitter derived from the cysteine metabolism with potent anti-inflammatory and antioxidant properties. The objective of this proposal is to test various forms of DR (protein restriction and TRF), or downstream effectors of DR such as H2S, to promote neovascularisation and protect against IH. The first aim is to test the metabolic and vascular benefits of a short-term ad libitum high carbohydrate/low protein diet. The second aim is to test the metabolic and vascular benefits of TRF using established mouse models of IH and neovascularization. This project will provide insightful knowledge about vascular pathologies and the biology and differences between of various DR interventions. The knowledge to be obtained through that proposal may provide the basis for new prospective clinical trials in PAD patients. In the long term, we foresee benefits for clinical practice and care, which will benefit multiple groups of our society.
Amount: CHF 840,000
Funding type: research
Funder scheme: Project funding
Start date: 2023-10-01
End date: 2027-09-30
Investigator: Allagnat, Florent
Institution: University of Lausanne – LA
Funded outputs count: 1
Funder award ID: 219997
OpenAlex ID: G8634583589