The apolipoprotein A-I mimetic peptide 4F prevents defects in vascular function in endotoxemic rats

Abstract

Sepsis is a major cause of death in hospitalized patients. Approximately 50% of patients in intensive care units develop sepsis, and the overall mortality rate is 29% ( 1 ). Mortality is due, in large part, to the cytotoxic actions of lipopolysaccharide (LPS), an endotoxic component of the outer membrane of Gram-negative bacteria. LPS is released from bacterial membranes and activates Toll-like receptors (TLR) on monocytes, neutrophils, and other target cells ( 2-5 ). TLRs transduce LPS action by activating nuclear factor (NF)-B-dependent signaling ( 4-6 ). By this mechanism, LPS stimulates the synthesis/release of infl ammatory cytokines, which play an important role in the innate immune response ( 7,8 ). Dysregulation of this infl ammatory response can lead to intravascular coagulation and multiple organ failure. LPS-induced cytokine production also increases expression of nitric oxide synthase 2 (NOS2) and cyclooxygenase 2 (COX-2), thus enhancing the synthesis of nitric oxide (NO) and arachidonic acidderived vasoactive prostanoids. These products have been implicated in hemodynamic disturbances in sepsis by reducing peripheral vascular resistance ( 9-14 ). Cardiovascular (CV) failure, characterized by severe hypotension and cardiac dysfunction, is linked to increased mortality in patients with severe sepsis ( 15-17 ).Lipoproteins are thought to play a role in the neutralization/detoxifi cation of endotoxin (18)(19)(20). Low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) bind to LPS and direct it to the liver for metabolism and excretion (18)(19)(20). HDL is most effective in clearing endotoxin, a property attributed to its relatively high phospholipid content compared with LDL and VLDL ( 18,21 ). With increasing Abstract High density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) reduce infl ammatory responses to lipopolysaccharide (LPS). We tested the hypothesis that the apoA-I mimetic peptide 4F prevents LPS-induced defects in blood pressure and vascular reactivity. Systolic blood pressure (SBP) was measured in rats at baseline and 6 h after injection of LPS (10 mg/kg) or saline vehicle. Subgroups of LPStreated rats also received 4F (10 mg/kg) or scrambled 4F (Sc-4F). LPS administration reduced SBP by 35% compared with baseline. 4F attenuated the reduction in SBP in LPStreated rats (17% reduction), while Sc-4F was without effect. Ex vivo studies showed a reduced contractile response to phenylephrine (PE) in aortae of LPS-treated rats (ED 50 = 459 ± 83 nM) compared with controls (ED 50 = 57 ± 6 nM). This was associated with nitric oxide synthase 2 (NOS2) upregulation. 4F administration improved vascular contractility (ED 50 = 60 ± 9 nM), reduced aortic NOS2 protein, normalized plasma levels of NO metabolites, and reduced mortality in LPS-treated rats. These changes were associated with a reduction in plasma endotoxin activity. In vivo administration of , , GM-082952 (C.R.W. and G.D.) and HL-85282 (H.G.) Abbreviations: apoA-I, apolipoprotein A-I; COX-2,...

HDL in Infectious Diseases and Sepsis

“…4F mimics also anti-inflammatory properties of HDL: in vitro, 4F inhibits the expression of pro-inflammatory mediators in LPS-treated cells by directly binding to LPS, thus resulting in the inhibition of LPS binding to LBP (Gupta et al 2005). In endotoxemic rats, the administration of 4F after LPS injection results in the attenuation of acute lung injury and increased survival, probably due to the preservation of circulating HDL-C and the downregulation of inflammatory pathways (Kwon et al 2012); 4F also prevents defects in vascular functions and is associated with a decrease in plasma endotoxin activity in rats (Dai et al 2010) and improved cardiac performance in LPS-treated rats (Datta et al 2011). These observations indicate that, by scavenging LPS, 4F may prevent LPS-induced release of pro-inflammatory cytokines and changes in HDL composition resulting in an effective reduction of clinical complications associated with sepsis.…”

Preservation of biological function despite oxidative modification of the apolipoprotein A-I mimetic peptide 4F

“…Similarly, 4F administration in vivo is associated with the rapid clearance of the peptide from the circulation and its incorporation in the vascular compartment ( 38 ). Because the apoA-I mimetic peptide 4F shares structural similarities with apoA-I, including the presence of redox-sensitive aromatic amino acids, we tested the hypothesis that the peptide serves as a reactive substrate for HOCl.…”

The Complexity of High-Density Lipoproteins

“…17 Also in vivo, administration of the apoA-I mimetic peptide 4F in lipopolysaccharide-treated rats promoted the transfer of lipopolysaccharide to HDL and improved survival. 18 Suzuki et al 2 did not determine whether oxidized lipids were present or were formed during the course of their experiments. Thus, their findings may not be related to the action of HDL on oxidized lipids.…”