ApoA-1 Mimetic Peptide Reverses Uremia-Induced Upregulation of Pro-Atherogenic Pathways in the Aorta

Abstract

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, NFĸB 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.

Targeting Immunity in End-Stage Renal Disease

“…Wistar rats treated with antioxidants such as L -arginine [69], tocotrienol, or α-tocopherol [70] showed a decrease in plasmatic concentrations of endothelial and cardiovascular stress markers including sICAM-1, TNF-α, NF-κB, VCAM-1, MCP-1, and TGF-β. Similar results have been obtained with LF-4 (an ApoA-1 mimetic peptide) [71], telmisartan [72], the oral sorbent AST-120, by improving the uremic milieu in ApoE-deficient mice [73]. However, the lack of reliable ESRD murine models makes these results difficult to interpret or translate to humans.…”

The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid

“…Studies support the notion that the COX-2/PGE2 axis has an important role in atherosclerosis. [28][29][30] In animal models of CKD, COX-2 is upregulated 31,32 and associated with a proinflammatory and prooxidant profile. 31,32 Serum from patients with CKD increases COX-2 expression in smooth muscle cells 33 and induces endothelial p38 MAPK and NF-kB activation.…”

“…[28][29][30] In animal models of CKD, COX-2 is upregulated 31,32 and associated with a proinflammatory and prooxidant profile. 31,32 Serum from patients with CKD increases COX-2 expression in smooth muscle cells 33 and induces endothelial p38 MAPK and NF-kB activation. 34 In our cultured endothelial cells, IAA increased COX-2 level and PGE2 production, induced NF-kB activation, and increased oxidative stress, mimicking the inflammatory and prooxidative profile found in CKD.…”

Role of dyslipidemia in impairment of energy metabolism, oxidative stress, inflammation and cardiovascular disease in chronic kidney disease

“…HDL cholesterol is reduced, maturation of CEpoor to CE-rich HDL-2 is impaired [8] and antioxidant, anti-inflammatory and reverse cholesterol transport activities of HDL are impaired in most ESRD patients [22,23]. These abnormalities are due to (a) reduced production and oxidative modification of ApoAI [8,24,25] which lead to HDL deficiency and impaired HDL binding to the gateway of cholesterol efflux (ATP binding cassette A1), (b) upregulation of acyl-CoA cholesterol acyltransferase (ACAT) [26][27][28][29] which limits release of intracellular cholesterol, (c) lecithin cholesterol acyltransferase (LCAT) deficiency [30] which impairs HDL maturation, and (d) paraoxonase and glutathione peroxidase deficiencies [28] which limit the ability of HDL to reduce oxidized LDL.…”