Role of carnosine in peripheral arterial disease

Abstract Peripheral arterial disease is a serious manifestation of atherosclerosis in the lower extremities. Current interventions approved by FDA are either ineffective or have a modest effect. Surgical revascularization is the only viable option for PAD subjects; however, the stents can fail. Patients with PAD have marked defects in skeletal muscle metabolism, where the aerobic and anaerobic metabolism are uncoupled, increased acidification of the skeletal muscle and decreased ATP synthesis. In glycolytically active tissue, such as skeletal muscle, there are present histidyl dipeptides, such as carnosine which buffers intracellular pH, under ischemic conditions and facilitate the utilization of glucose during exercise and ischemia. Recent evidence from our laboratory shows that in addition to buffering, carnosine chelates first transition metals and improves angiogenesis, forms conjugates with reactive aldehydes derived from lipid peroxidation and regress atherosclerosis. Hence enhancing carnosine via supplementation, which easily permeates through the ischemic muscle, is easily could be a feasible therapeutic that can target the underlying pathophysiological associated with PAD and increase limb function. To achieve this goal, we will treat the PAD subjects with carnosine and examine whether the carnosine supplementation improves the lower extremity function. Second, we will perform extensive mechanistic studies to elucidate the mechanism by which carnosine improves the muscle function and finally we will follow these subjects and determine if carnosine has durable effects. Collectively, our pilot clinical trial will help us test the efficacy of carnosine as a low-cost therapeutic intervention for PAD patients and the data generated will serve as a strong rationale to design large definitive Phase III clinical trial for carnosine.