AIMS: Cardiac dysfunction is a complication of sepsis and contributes to morbidity and mortality. Since raising plasma apolipoprotein (apo) A-I and high density lipoprotein (HDL) concentration reduces sepsis complications, we tested the hypothesis that the apoA-I mimetic peptide 4F confers similar protective effects in rats treated with lipopolysaccharide (LPS). METHODS AND RESULTS: Male Sprague-Dawley (SD) rats were randomized to receive saline vehicle (n=13), LPS (10 mg/kg: n=16) or LPS plus 4F (10 mg/kg each: n=13) by intraperitoneal injection. Plasma cytokine and chemokine levels were significantly elevated 24 hrs after LPS administration. Echocardiographic studies revealed changes in cardiac dimensions that resulted in a reduction in left ventricular end-diastolic volume (LVEDV), stroke volume (SV) and cardiac output (CO) 24 hrs after LPS administration. 4F treatment reduced plasma levels of inflammatory mediators and increased LV filling, resulting in improved cardiac performance. Chromatographic separation of lipoproteins from plasma of vehicle, LPS and LPS+4F rats revealed similar profiles. Further analyses showed that LPS treatment reduced the agarose electrophoretic mobility of isolated HDL fractions. HDL-associated proteins were characterized by SDSPAGE and mass spectrometry. ApoA-I and apoA-IV were reduced while apoE content was increased in LPStreated rats. 4F treatment in vivo attenuated changes in HDL-associated apolipoproteins and increased the electrophoretic mobility of the particle. CONCLUSIONS: The ability of 4F to reduce inflammation and improve cardiac performance in LPS-treated rats may be due to its capacity to neutralize endotoxin and prevent adverse changes in HDL composition and function.