Abstract 18285: Carnosine Supplementation Improves Metabolic Syndrome and Revascularization After Hindlimb Ischemia in Diet-Induced Obese Mice

Abstract

Critical limb ischemia (CLI) affects more than 10 million people in U.S. as a result of peripheral arterial disease. It is an important clinical condition that leads to claudication, increased risk of peripheral limb infection, gangrene and amputation. Although surgical revascularization can facilitate blood flow, obese and type 2 diabetic (T2D) CLI patients are poor candidates for revascularization surgery, and thus, we investigated a potential alternative therapy. Carnosine is an endogenous histidyl dipeptide present in high concentrations in skeletal muscle (1-20 mM). Previous studies of T2D patients showed that carnosine level is reduced in the gastrocnemius muscle. Similarly, 12 weeks high fat diet (HFD; 60% kcal fat) fed mice had significantly lower carnosine level in the gastrocnemius muscle (1.2±0.1nmol/mg tissue) than low fat fed (LFD; 2.8±0.5 nmol/mg tissue; n=6; P<0.05) as measured by LC-MS/ESI. To better understand the consequences of carnosine deficiency in obesity, we tested whether chronic supplementation of carnosine alters metabolic stress in HFD fed C57BL/6 mice. Carnosine supplementation (3g/l drinking water) for 6 weeks significantly attenuated body weight (43±1gm) and glucose tolerance in obese mice compared with untreated obese mice (49±2gm; n=12; P<0.05). Because carnosine quenches reactive oxygen and carbonyl species that can limit ischemic injury we also tested if carnosine supplementation could attenuate CLI in obese mice. Doppler perfusion imaging 14 days after femoral artery ligation in obese mice showed that carnosine (1gm/l) pretreatment (1 week and continued after ligation) significantly increased hindlimb (HL) blood flow recovery in treated mice to 56±3% of the non-ischemic control limb compared to untreated mice (34±3%;n=4;P<0.05).Similarly, in non-obese mice carnosine treatment also significantly increased HL blood flow recovery to (63±6%) of the non-ischemic control limb compared to untreated mice (19±3%;n=6; P<0.05).These findings show that carnosine mitigates effects of diet-induced metabolic syndrome, and improves angiogenesis and thus may be a potential inexpensive and safe therapeutic for attenuating metabolic syndrome and increasing revascularization in obese patients suffering CLI.