ApoA-1 mimetic peptide reverses uremia-induced upregulation of pro-atherogenic pathways in the aorta.
BACKGROUND
Chronic kidney disease (CKD) results in accelerated atherosclerosis and cardiovascular disease. This is primarily mediated by oxidative stress, inflammation and dyslipidemia. By mediating reverse cholesterol transport and exerting antioxidant/anti-inflammatory actions, high-density lipoprotein (HDL) and ApoA-1 protect against atherosclerosis. Plasma Apo-1, HDL cholesterol and HDL antioxidant/anti-inflammatory activities are reduced in CKD. ApoA-1 mimetic peptides associate with and enhance antioxidant/anti-inflammatory properties of HDL. We hypothesized that long-term administration of ApoA-1 mimetic peptide, L4F, may ameliorate inflammation and oxidative stress in the conduit arteries in experimental CKD.


METHODS
After 5/6 nephrectomy, rats were randomized to L4F (5 mg/kg s.c. 3 times weekly for 4 weeks) and placebo-treated groups. Sham-operated rats served as controls.


RESULTS
The untreated CKD group exhibited marked lipid accumulation and upregulations of NAD(P)H oxidase subunits (gp91(phox), p22(phox), and p47(phox)), COX-2, 12-lipoxygenase, MCP-1, PAI-1, myeloperoxidase and iNOS, NFκB activation and nitrotyrosine accumulation in the thoracic aorta. L4F administration reversed or attenuated these abnormalities without altering renal function or plasma lipids.


CONCLUSIONS
CKD leads to lipid accumulation and upregulation of pro-atherogenic pathways in the artery wall. These abnormalities are attenuated by ApoA-1 mimetic peptide, pointing to its protective effect in CKD. Future studies are needed to explore the effect of these peptides in CKD patients.
Vaziri
Nosratola D
ND
Bai
Yongli
Y
Yuan
Jun
J
Said
Hannah L
HL
Sigala
Whitney
W
Ni
Zhemin
Z
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000494:pharmacology* / Q000502:physiology; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001167:Arteritis / Q000378:metabolism* / Q000517:prevention & control; D050197:Atherosclerosis / Q000378:metabolism* / Q000517:prevention & control; D018932:Chemokine CCL2 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000503:physiopathology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation; D014511:Uremia / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D016632:Apolipoprotein A-I; D001092:Arachidonate 12-Lipoxygenase; D018932:Chemokine CCL2; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases; D052247:Nitric Oxide Synthase Type II; D010455:Peptides; D009195:Peroxidase; D017395:Plasminogen Activator Inhibitor 1; D017346:Protein Serine-Threonine Kinases; D014443:Tyrosine; D000097782:NF-kappaB-Inducing Kinase; C491766:Ccl2 protein, rat; C002744:3-nitrotyrosine; C496318:Nos2 protein, rat