Myeloperoxidase and serum amyloid A contribute to impaired in vivo reverse cholesterol transport during the acute phase response but not group IIA secretory phospholipase A2

Abstract

Atherosclerosis is linked to inflammation. HDL protects against atherosclerotic cardiovascular disease, mainly by mediating cholesterol efflux and reverse cholesterol transport (RCT). The present study aimed to test the impact of acute inflammation as well as selected acute phase proteins on RCT with a macrophage-to-feces in vivo RCT assay using intraperitoneal administration of [3H]cholesterol-labeled macrophage foam cells. In patients with acute sepsis, cholesterol efflux toward plasma and HDL were significantly decreased (P < 0.001). In mice, acute inflammation (75 µg/mouse lipopolysaccharide) decreased [3H]cholesterol appearance in plasma (P < 0.05) and tracer excretion into feces both within bile acids (−84%) and neutral sterols (−79%, each P < 0.001). In the absence of systemic inflammation, overexpression of serum amyloid A (SAA, adenovirus) reduced overall RCT (P < 0.05), whereas secretory phospholipase A2 (sPLA2, transgenic mice) had no effect. Myeloperoxidase injection reduced tracer appearance in plasma (P < 0.05) as well as RCT (−36%, P < 0.05). Hepatic expression of bile acid synthesis genes (P < 0.01) and transporters mediating biliary sterol excretion (P < 0.01) was decreased by inflammation. In conclusion, our data demonstrate that acute inflammation impairs cholesterol efflux in patients and macrophage-to-feces RCT in vivo in mice. Myeloperoxidase and SAA contribute to a certain extent to reduced RCT during inflammation but not sPLA2. However, reduced bile acid formation and decreased biliary sterol excretion might represent major contributing factors to decreased RCT in inflammation. Atherosclerosis is linked to inflammation. HDL protects against atherosclerotic cardiovascular disease, mainly by mediating cholesterol efflux and reverse cholesterol transport (RCT). The present study aimed to test the impact of acute inflammation as well as selected acute phase proteins on RCT with a macrophage-to-feces in vivo RCT assay using intraperitoneal administration of [3H]cholesterol-labeled macrophage foam cells. In patients with acute sepsis, cholesterol efflux toward plasma and HDL were significantly decreased (P < 0.001). In mice, acute inflammation (75 µg/mouse lipopolysaccharide) decreased [3H]cholesterol appearance in plasma (P < 0.05) and tracer excretion into feces both within bile acids (−84%) and neutral sterols (−79%, each P < 0.001). In the absence of systemic inflammation, overexpression of serum amyloid A (SAA, adenovirus) reduced overall RCT (P < 0.05), whereas secretory phospholipase A2 (sPLA2, transgenic mice) had no effect. Myeloperoxidase injection reduced tracer appearance in plasma (P < 0.05) as well as RCT (−36%, P < 0.05). Hepatic expression of bile acid synthesis genes (P < 0.01) and transporters mediating biliary sterol excretion (P < 0.01) was decreased by inflammation. In conclusion, our data demonstrate that acute inflammation impairs cholesterol efflux in patients and macrophage-to-feces RCT in vivo in mice. Myeloperoxidase and SAA contribute to a certain extent to reduced RCT during inflammation but not sPLA2. However, reduced bile acid formation and decreased biliary sterol excretion might represent major contributing factors to decreased RCT in inflammation. Epidemiological studies established a strong inverse association between plasma HDL cholesterol levels and the risk of atherosclerotic cardiovascular disease (CVD) (1Assmann G. Gotto Jr, A.M. HDL cholesterol and protective factors in atherosclerosis.Circulation. 2004; 109: III8-III14Crossref PubMed Google Scholar, 2Linsel-Nitschke P. Tall A.R. HDL as a target in the treatment of atherosclerotic cardiovascular disease.Nat. Rev. Drug Discov. 2005; 4: 193-205Crossref PubMed Scopus (407) Google Scholar). A major anti-atherogenic activity of HDL is regarded to be reverse cholesterol transport (RCT), a process comprising removal of excess cholesterol from peripheral cells, most importantly macrophage foam cells in atherosclerotic lesions, and transport back to the liver for subsequent excretion into bile and feces (2Linsel-Nitschke P. Tall A.R. HDL as a target in the treatment of atherosclerotic cardiovascular disease.Nat. Rev. Drug Discov. 2005; 4: 193-205Crossref PubMed Scopus (407) Google Scholar, 3Rader D.J. Alexander E.T. Weibel G.L. Billheimer J. Rothblat G.H. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis.J. Lipid Res. 2009; 50: S189-S194Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar). Understanding the pathophysiological factors regulating RCT is therefore of prime importance. Inflammation is strongly linked to atherosclerosis (4Libby P. Inflammation in atherosclerosis.Nature. 2002; 420: 868-874Crossref PubMed Scopus (6840) Google Scholar, 5Ross R. Atherosclerosis–an inflammatory disease.N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (18952) Google Scholar, 6Rader D.J. Daugherty A. Translating molecular discoveries into new therapies for atherosclerosis.Nature. 2008; 451: 904-913Crossref PubMed Scopus (386) Google Scholar). The atherosclerotic plaque itself is increasingly considered a site of chronic inflammation within the vessel wall (5Ross R. Atherosclerosis–an inflammatory disease.N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (18952) Google Scholar, 7Steinberg D. Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime.Nat. Med. 2002; 8: 1211-1217Crossref PubMed Scopus (583) Google Scholar). In addition, markers of inflammation are elevated in plasma of patients with established atherosclerotic CVD, and circulating levels of several acute phase proteins (APPs) have been shown to possess a predictive value for future cardiovascular events (8Tsimikas S. Willerson J.T. Ridker P.M. C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients.J. Am. Coll. Cardiol. 2006; 47: C19-C31Crossref PubMed Scopus (279) Google Scholar, 9Rader D.J. Inflammatory markers of coronary risk.N. Engl. J. Med. 2000; 343: 1179-1182Crossref PubMed Scopus (227) Google Scholar). Recently, it was also demonstrated that eliminating a large part of the hepatic acute phase response (APR) by knocking out the gp130 receptor on hepatocytes confers significant protection from that might contribute to the atherosclerotic process R. of inflammation gp130 atherosclerosis in and Med. PubMed Scopus Google Scholar). inflammation on HDL in HDL and of the HDL D.J. inflammation of HDL into of J. PubMed Scopus Google Scholar, of and inflammation on and and to the Lipid Res. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, HDL cholesterol transport during PubMed Scopus Google it that might into in vivo the of the present study was to of the in vivo RCT and to out the role of that have been established to HDL during inflammatory data demonstrate that acute inflammation cholesterol efflux to plasma in patients with and impairs macrophage-to-feces RCT in vivo in mice. secretory phospholipase A2 and but not serum amyloid A contribute to reduced cholesterol efflux toward However, expression of in the absence of inflammation not macrophage-to-feces SAA overexpression and decreased in vivo RCT patients with acute to the in were established for of of for and and for the of therapies in Med. 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