title: Arginine uptake is attenuated, through post-translational regulation of cationic amino acid transporter-1, in hyperlipidemic rats.
abstract: Endothelial cell dysfunction (ECD) is a common feature of hypercholesterolemia. Defective nitric oxide (NO) generation due to decreased endothelial nitric oxide synthase (eNOS) activity is a crucial parameter characterizing ECD. L-arginine is the sole precursor for NO biosynthesis. Among several transporters that mediate L-arginine uptake, cationic amino acid transporter-1 (CAT-1) acts as a specific arginine transporter for eNOS. Our hypothesis implies that CAT-1 is a major determinant of eNOS activity in hypercholesterolemia. We studied aortic arginine uptake, CAT-1 and CAT-2 mRNA expression, and CAT-1, and PKC alpha protein in: (a) control, untreated animals (CTL), (b) rats fed with 4% cholesterol+1% cholate and 2% corn oil for 6 weeks (CHOL) and (c) rats with hypercholesterolemia treated orally with either atorvastatin (CHOL+ATORVA, 20mg/kg BW/day) or arginine 1% (CHOL+ARG) in the drinking water (modalities which have been shown to enhance CAT-1 activity and improve endothelial function). Serum cholesterol levels significantly increased in cholesterol fed animals, an increase which was blocked by atorvastatin (CTL: 66.8+/-15, CHOL: 133.9+/-22, CHOL+ARG: 128.2+/-20, CHOL+ATORVA: 77+/-15 mg/dl). Arginine transport was significantly decreased in CHOL. Treatment with neither arginine nor atorvastatin had an effect. Using RT-PCR, we found no change in aortic CAT-1 and CAT-2 mRNA expression in CHOL as well as following arginine or atorvastatin administration. The abundance of CAT-1 protein was significantly augmented in cholesterol fed rats and was not affected by arginine or atorvastatin. PKC alpha protein content, which was previously shown to regulate CAT-1 activity, increased significantly in CHOL and was neither affected by atorvastatin nor arginine. In conclusion, aortic arginine uptake is attenuated in hypercholesterolemia, through post-translational modulation of CAT-1 protein, possibly via upregulation of PKC alpha.
authors.affiliation: Department of Nephrology, Tel Aviv Sourasky Medical Center, Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel. dorons@tasmc.health.gov.il
authors.forename: Idit F
authors.initials: IF
authors.lastname: Schwartz
authors.forename: Meirav
authors.initials: M
authors.lastname: Ingbir
authors.forename: Tamara
authors.initials: T
authors.lastname: Chernichovski
authors.forename: Ran
authors.initials: R
authors.lastname: Reshef
authors.forename: Gil
authors.initials: G
authors.lastname: Chernin
authors.forename: Alex
authors.initials: A
authors.lastname: Litvak
authors.forename: Talia
authors.initials: T
authors.lastname: Weinstein
authors.forename: Yoram
authors.initials: Y
authors.lastname: Levo
authors.forename: Doron
authors.initials: D
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000503:physiopathology; D001120:Arginine / Q000378:metabolism*; D027201:Cationic Amino Acid Transporter 1 / Q000235:genetics / Q000378:metabolism*; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004727:Endothelium / Q000201:enzymology* / Q000503:physiopathology; D005786:Gene Expression Regulation; D006937:Hypercholesterolemia / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D019001:Nitric Oxide Synthase / Q000502:physiology; D011499:Protein Processing, Post-Translational; D051381:Rats; D017208:Rats, Wistar
chemical_list: D027201:Cationic Amino Acid Transporter 1; D001120:Arginine; D019001:Nitric Oxide Synthase