LDL receptor-null (LDLR 2/2 ) mice on a Western diet (WD) develop endothelial dysfunction and atherosclerosis, which are improved by the apolipoprotein A-I (apoA-I) mimetic peptide D-4F. Focusing on the kidney, LDLR 2/2 mice were fed a WD with D-4F or the inactive control peptide scrambled D-4F (ScD-4F) added to their drinking water. The control mice (ScD-4F) developed glomerular changes, increased immunostaining for MCP-1/CCL2 chemokine, increased macrophage CD68 and F4/80 antigens, and increased oxidized phospholipids recognized by the EO6 monoclonal antibody in both glomerular and tublointerstitial areas. All of these parameters were significantly reduced by D-4F treatment, approaching levels found in wildtype C57BL/6J or LDLR 2/2 mice fed a chow diet. Sterolregulatory element binding protein-1c (SREBP-1c) mRNA levels and triglyceride levels were elevated in the kidneys of the control mice (ScD-4F) fed the WD compared with C57BL/6J and LDLR 2/2 mice on chow (P , 0.001 and P , 0.001, respectively) and compared with D-4F-treated mice on the WD (P , 0.01). There was no significant difference in plasma lipids, lipoproteins, glucose, blood pressure, or renal apoB levels between D-4F-and ScD-4F-treated mice. We conclude that D-4F reduced renal oxidized phospholipids, resulting in lower expression of SREBP-1c, which, in turn, resulted in lower triglyceride content and reduced renal inflammation. ) mice has been shown to induce atherosclerosis, endothelial dysfunction, and inflammation of brain arterioles associated with cognitive dysfunction, all of which have been reported to be significantly ameliorated by treatment with the oral apolipoprotein A-I (apoA-I) mimetic peptide D-4F without a change in plasma lipid levels or blood pressure (1-3).In addition to hyperlipidemia, feeding a WD to LDLR 2/2 mice results in insulin resistance and elevated plasma glucose levels (4, 5). A major problem facing Western societies is an increase in chronic renal disease that appears to be associated with dyslipidemia and diabetes in addition to hypertension (6). Dyslipidemia has been emphasized as a factor that can exacerbate hypertension-induced renal damage as well as a factor that by itself may have adverse effects on the kidney (6). Diet-induced obesity in C57BL/6J mice has been reported to cause lipid accumulation in kidneys and glomerulosclerosis via a sterol-regulatory element binding protein 1c (SREBP-1c)-dependent pathway (7). Oxidized phospholipids have been identified as potent mediators of inflammation (8,9). Berliner and colleagues have reported that oxidized phospholipids induce cytokine production in endothelial cells through induction of SREBP (10) via an endothelial nitric oxide synthase (eNOS)-mediated mechanism (11).Pritchard and colleagues reported that the apoA-I mimetic peptide L-4F (identical to D-4F except that the peptide is synthesized from L-amino acids) restored the balance between nitric oxide and superoxide anion production by eNOS in LDL-treated endothelial cells in culture (12). Injection of ...

Background and Purpose-Hyperlipidemia is associated with platelet hyperreactivity. We hypothesized that L-4F, an apolipoprotein A-I mimetic peptide, would inhibit platelet aggregation in hyperlipidemic mice. Methods and Results-Injecting L-4F into apolipoprotein E (apoE)-null and low-density lipoprotein receptor-null mice resulted in a significant reduction in platelet aggregation in response to agonists; however, there was no reduction in platelet aggregation after injection of L-4F into wild-type (WT) mice. Consistent with these results, injection of L-4F into apoE-null mice prolonged bleeding time; the same result was not found in WT mice. Incubating L-4F in vitro with apoE-null platelet-rich plasma also resulted in decreased platelet aggregation. However, incubating washed platelets from either apoE-null or WT mice with L-4F did not alter aggregation.Compared with WT mice, unstimulated platelets from apoE-null mice contained significantly more 12-hydroxy 5,8,10,14-eicosatetraenoic acid, thromboxane A 2 , and prostaglandins D 2 and E 2 . In response to agonists, platelets from L-4F-treated apoE-null mice formed significantly less thromboxane A 2 , prostaglandins D 2 and E 2 , and 12-hydroxy 5,8,10,14-eicosatetraenoic acid. Conclusion-By

Atherosclerosis is an example of an inflammatory disorder. During the acute phase and under inflammatory conditions, high-density lipoprotein (HDL), which is normally anti-inflammatory, can become proinflammatory. Reactive oxygen species generated by several enzyme systems can modify phospholipids and sterols, producing oxidized phospholipids and oxidized sterols that reduce the capacity of HDL to protect against undesirable oxidative modifications of molecules. In animal models of dyslipidemia, diabetes, vascular inflammation, and chronic rejection, it is observed that reducing oxidative and inflammatory pressure will help HDL regain its protective role. One way to accomplish this is through the use of apolipoprotein A-I mimetic peptides, which remove oxidation products from lipoproteins and cell membranes, returning normal structure and function to low-density lipoprotein and HDL. These mimetic peptides markedly reduce atherosclerosis in animal models. Published studies of apolipoprotein mimetic peptides in models of inflammatory disorders other than atherosclerosis suggest that they have efficacy in a wide range of inflammatory conditions.