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| ===Coronary Heart Disease===
| | {{ACM}} {{SemRikken}} |
| ====Cardio Protective Effect====
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| The mature spherical HDL particle is composed of enzymes, such as paraoxonase, platelet-activating factor acetylhydrolase (PAF-AH or Lp-PLA2), lecithin-cholesterol acyl transferase (LCAT), [[apolipoproteins]] (apoA-I and apoA-II), lipid molecules, such as [[triglyceride]], [[cholesterol]], [[phospholipids]] and bioactive lipid molecules, including sphingosine 1-phosphate (S1P) and related lysosphingolipids.<ref name="pmid18716026">{{cite journal| author=Scanu AM, Edelstein C| title=HDL: bridging past and present with a look at the future. | journal=FASEB J | year= 2008 | volume= 22 | issue= 12 | pages= 4044-54 | pmid=18716026 | doi=10.1096/fj.08-117150 | pmc=PMC2614615 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18716026 }} </ref> The antiatherogenic actions of HDL-C are complex and are mediated through the some of the aforementioned components. HDL-C plays a major role in reverse cholesterol transport, mobilizing cholesterol from the periphery to the liver. In addition, cardioprotective effects of HDL-C include endothelial protection, anti-inflammatory activity, as well as antioxidant and antithrombotic effects and maintenance of low blood viscosity through a permissive action on red cell deformability.
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| * Apo A-I :
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| **Several studies have shown that high-density lipoprotein (HDL)-cholesterol is antiatherogenic and serves a role in mediating cholesterol efflux from cells. Macrophage cholesterol efflux is a process whereby excess cholesterol in cells and in atherosclerotic plaques is removed. Current data indicate that the plasma HDL associated apolipoprotein M (apoM) levels modulate the ability of plasma to mobilize cellular cholesterol and protects against experimental atherosclerosis.<ref name="pmid24046869">{{cite journal| author=Elsøe S, Christoffersen C, Luchoomun J, Turner S, Nielsen LB| title=Apolipoprotein M promotes mobilization of cellular cholesterol in vivo. | journal=Biochim Biophys Acta | year= 2013 | volume= 1831 | issue= 7 | pages= 1287-92 | pmid=24046869 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24046869 }} </ref>
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| **Animal models have shown that the somatic gene transfer of human apo A-I can prevent the development of atherosclerosis or reverse preexisting atherosclerosis or its role in the anti-endotoxin function of HDL.<ref name="pmid9884386">{{cite journal| author=Benoit P, Emmanuel F, Caillaud JM, Bassinet L, Castro G, Gallix P et al.| title=Somatic gene transfer of human ApoA-I inhibits atherosclerosis progression in mouse models. | journal=Circulation | year= 1999 | volume= 99 | issue= 1 | pages= 105-10 | pmid=9884386 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9884386 }} </ref><ref name="pmid10534470">{{cite journal| author=Tangirala RK, Tsukamoto K, Chun SH, Usher D, Puré E, Rader DJ| title=Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. | journal=Circulation | year= 1999 | volume= 100 | issue= 17 | pages= 1816-22 | pmid=10534470 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10534470 }} </ref><ref name="pmid11804981">{{cite journal| author=Navab M, Anantharamaiah GM, Hama S, Garber DW, Chaddha M, Hough G et al.| title=Oral administration of an Apo A-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. | journal=Circulation | year= 2002 | volume= 105 | issue= 3 | pages= 290-2 | pmid=11804981 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11804981 }} </ref><ref name="pmid15188057">{{cite journal| author=Ma J, Liao XL, Lou B, Wu MP| title=Role of apolipoprotein A-I in protecting against endotoxin toxicity. | journal=Acta Biochim Biophys Sin (Shanghai) | year= 2004 | volume= 36 | issue= 6 | pages= 419-24 | pmid=15188057 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15188057 }} </ref>
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| **Current data suggest that, ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 in [[endothelial cells]], and the scavenger receptor B type 1 mediate multiple intracellular signaling pathways as well as the efflux of cholesterol and/or oxysterols in response to apoA-I/HDL.<ref name="pmid22488423">{{cite journal| author=Prosser HC, Ng MK, Bursill CA| title=The role of cholesterol efflux in mechanisms of endothelial protection by HDL. | journal=Curr Opin Lipidol | year= 2012 | volume= 23 | issue= 3 | pages= 182-9 | pmid=22488423 | doi=10.1097/MOL.0b013e328352c4dd | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22488423 }} </ref>
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| * ApoA-I/SR-BI :
| | ''SANDBOX'' |
| **[[HDL]] also protects endothelial cells from apoptosis and promotes their growth and their migration via SR-BI-initiated signaling.<ref name="pmid20089950">{{cite journal| author=Saddar S, Mineo C, Shaul PW| title=Signaling by the high-affinity HDL receptor scavenger receptor B type I. | journal=Arterioscler Thromb Vasc Biol | year= 2010 | volume= 30 | issue= 2 | pages= 144-50 | pmid=20089950 | doi=10.1161/ATVBAHA.109.196170 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20089950 }} </ref> Recent studies have shown that SR-BI is also expressed in endothelial cells (ECs) and mediates HDL-associated apoA-I-induced stimulation of endothelial nitric oxide synthase (eNOS), inhibition of monocyte adhesion to endothelial cells, vasorelaxation, and re-endothelialization following perivascular electric injury.<ref name="pmid18753704">{{cite journal| author=Okajima F, Sato K, Kimura T| title=Anti-atherogenic actions of high-density lipoprotein through sphingosine 1-phosphate receptors and scavenger receptor class B type I. | journal=Endocr J | year= 2009 | volume= 56 | issue= 3 | pages= 317-34 | pmid=18753704 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18753704 }} </ref><ref name="pmid17574123">{{cite journal| author=Mineo C, Shaul PW| title=Role of high-density lipoprotein and scavenger receptor B type I in the promotion of endothelial repair. | journal=Trends Cardiovasc Med | year= 2007 | volume= 17 | issue= 5 | pages= 156-61 | pmid=17574123 | doi=10.1016/j.tcm.2007.03.005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17574123 }} </ref><ref name="pmid20105136">{{cite journal| author=Kimura T, Sato K, Tomura H, Okajima F| title=Cross-talk between exogenous statins and endogenous high-density lipoprotein in anti-inflammatory and anti-atherogenic actions. | journal=Endocr Metab Immune Disord Drug Targets | year= 2010 | volume= 10 | issue= 1 | pages= 8-15 | pmid=20105136 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20105136 }} </ref>
| | [[File:Captura de Pantalla 2024-05-18 a la(s) 9.33.11 p.m..png]] |
| **It is also proposed that the anti-apoptotic and proliferative effects of apoA-I are mediated through F1-ATPase-catalysed ADP production and subsequent P2Y13 receptor stimulation, thus contributing to the atheroprotective functions.<ref name="pmid19372457">{{cite journal| author=Radojkovic C, Genoux A, Pons V, Combes G, de Jonge H, Champagne E et al.| title=Stimulation of cell surface F1-ATPase activity by apolipoprotein A-I inhibits endothelial cell apoptosis and promotes proliferation. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 7 | pages= 1125-30 | pmid=19372457 | doi=10.1161/ATVBAHA.109.187997 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19372457 }} </ref>
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| ** HDL promotes the production of signaling molecule [[nitric oxide]] (NO) by upregulating endothelial NO synthase (eNOS) expression, by maintaining the lipid environment in caveolae where eNOS is colocalized with partner signaling molecules, and by stimulating eNOS as a result of kinase cascade activation by the high-affinity HDL receptor scavenger receptor class B type I (SR-BI). Studies have shown the ability of recombiant HDL (rHDL) or reconstituted apoA-I with phospholipids but without cholesterol to stimulate eNOS activation and to repair damaged endothelium and to enhance ischemia-induced angiogenesis through stimulation of endothelial progenitor cells (EPCs) in vivo.<ref name="pmid16528007">{{cite journal| author=Tso C, Martinic G, Fan WH, Rogers C, Rye KA, Barter PJ| title=High-density lipoproteins enhance progenitor-mediated endothelium repair in mice. | journal=Arterioscler Thromb Vasc Biol | year= 2006 | volume= 26 | issue= 5 | pages= 1144-9 | pmid=16528007 | doi=10.1161/01.ATV.0000216600.37436.cf | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16528007 }} </ref><ref name="pmid17272742">{{cite journal| author=Sumi M, Sata M, Miura S, Rye KA, Toya N, Kanaoka Y et al.| title=Reconstituted high-density lipoprotein stimulates differentiation of endothelial progenitor cells and enhances ischemia-induced angiogenesis. | journal=Arterioscler Thromb Vasc Biol | year= 2007 | volume= 27 | issue= 4 | pages= 813-8 | pmid=17272742 | doi=10.1161/01.ATV.0000259299.38843.64 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17272742 }} </ref> The enhancement of SR-BI expression by [[simvastatin]] results in enhancement of HDL- and rHDL-induced eNOS activation and subsequent inhibition of adhesion molecule expression, which supports the role of SR-BI in HDL-induced anti-inflammatory actions.<ref name="pmid18981156">{{cite journal| author=Kimura T, Mogi C, Tomura H, Kuwabara A, Im DS, Sato K et al.| title=Induction of scavenger receptor class B type I is critical for simvastatin enhancement of high-density lipoprotein-induced anti-inflammatory actions in endothelial cells. | journal=J Immunol | year= 2008 | volume= 181 | issue= 10 | pages= 7332-40 | pmid=18981156 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18981156 }} </ref>
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| * Sphingosine 1-phosphate (S1P) :
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| **Fractionation by density gradient centrifugation has shown that sphingosine 1-phosphate (S1P) is concentrated in the lipoprotein fraction with a rank order of [[HDL]] > [[LDL]] > [[VLDL]], and to a lesser extent, in the lipoprotein-deficient albumin fraction when expressed as pmol/mg protein. Thus, HDL-S1P has been proposed to mediate a variety of HDL-induced actions.<ref name="pmid11104690">{{cite journal| author=Murata N, Sato K, Kon J, Tomura H, Yanagita M, Kuwabara A et al.| title=Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions. | journal=Biochem J | year= 2000 | volume= 352 Pt 3 | issue= | pages= 809-15 | pmid=11104690 | doi= | pmc=PMC1221521 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11104690 }} </ref>
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| **S1P has been shown to improve ischemia/reperfusion-induced injury in vivo and in vitro with inhibition of inflammatory [[neutrophil]] recruitment and cardiomyocyte [[apoptosis]] in the infarcted area.<ref name="pmid12003800">{{cite journal| author=Jin ZQ, Zhou HZ, Zhu P, Honbo N, Mochly-Rosen D, Messing RO et al.| title=Cardioprotection mediated by sphingosine-1-phosphate and ganglioside GM-1 in wild-type and PKC epsilon knockout mouse hearts. | journal=Am J Physiol Heart Circ Physiol | year= 2002 | volume= 282 | issue= 6 | pages= H1970-7 | pmid=12003800 | doi=10.1152/ajpheart.01029.2001 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12003800 }} </ref><ref name="pmid19247197">{{cite journal| author=Karliner JS| title=Sphingosine kinase and sphingosine 1-phosphate in cardioprotection. | journal=J Cardiovasc Pharmacol | year= 2009 | volume= 53 | issue= 3 | pages= 189-97 | pmid=19247197 | doi=10.1097/FJC.0b013e3181926706 | pmc=PMC2835544 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19247197 }} </ref><ref name="pmid16982942">{{cite journal| author=Theilmeier G, Schmidt C, Herrmann J, Keul P, Schäfers M, Herrgott I et al.| title=High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1403-9 | pmid=16982942 | doi=10.1161/CIRCULATIONAHA.105.607135 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982942 }} </ref>
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| **The pro-atherogenic adhesion molecule expression elicited by S1P disappears in the presence of physiological concentrations of HDL in a manner sensitive to SR-BI.<ref name="pmid17046831">{{cite journal| author=Kimura T, Tomura H, Mogi C, Kuwabara A, Damirin A, Ishizuka T et al.| title=Role of scavenger receptor class B type I and sphingosine 1-phosphate receptors in high density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells. | journal=J Biol Chem | year= 2006 | volume= 281 | issue= 49 | pages= 37457-67 | pmid=17046831 | doi=10.1074/jbc.M605823200 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17046831 }} </ref>
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| * Paraoxonase 1 (PON1) :
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| ** Paraoxonase is an esterase enzyme that is synthesized by the [[liver]] and it is associated with HDL in the blood. There is considerable evidence to prove the fact that the antioxidant activity of HDL is largely due to the PON1 which is located on it.<ref name="pmid23908111">{{cite journal| author=Huang Y, Wu Z, Riwanto M, Gao S, Levison BS, Gu X et al.| title=Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex. | journal=J Clin Invest | year= 2013 | volume= 123 | issue= 9 | pages= 3815-28 | pmid=23908111 | doi=10.1172/JCI67478 | pmc=PMC3754253 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23908111 }} </ref> A atorvastatin study demonstrating HDL-related antioxidant activity as well as lipid-lowering properties proves PON1 action of prevents LDL oxidation and inactivates LDL-derived oxidized phospholipids.<ref name="pmid24024670">{{cite journal| author=Sozer V, Uzun H, Gelisgen R, Kaya M, Kalayci R, Tabak O et al.| title=The effects of atorvastatin on oxidative stress in L-NAME-treated rats. | journal=Scand J Clin Lab Invest | year= 2013 | volume= | issue= | pages= | pmid=24024670 | doi=10.3109/00365513.2013.828241 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24024670 }} </ref>
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| ** Studies have suggested that serum antioxidant activity of PON1 was an important factor which provided protection from oxidative stress and lipid peroxidation in [[CAD]].<ref name="pmid23998046">{{cite journal| author=Shekhanawar M, Shekhanawar SM, Krisnaswamy D, Indumati V, Satishkumar D, Vijay V et al.| title=The role of 'paraoxonase-1 activity' as an antioxidant in coronary artery diseases. | journal=J Clin Diagn Res | year= 2013 | volume= 7 | issue= 7 | pages= 1284-7 | pmid=23998046 | doi=10.7860/JCDR/2013/5144.3118 | pmc=PMC3749616 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23998046 }} </ref> Thus, evaluating the effects of PON 1 for CAD patients may be promising in the treatment and prognosis of CAD.
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| ** Studies have shown pomegranate to be a potent anti-atherogenic agent because of its antioxidants which have the ability to increase the activity of the HDL-associated paraoxonase 1 (PON1), which breaks down harmful oxidized lipids in lipoproteins, in macrophages, and in atherosclerotic plaques.<ref name="pmid23908863">{{cite journal| author=Aviram M, Rosenblat M| title=Pomegranate for your cardiovascular health. | journal=Rambam Maimonides Med J | year= 2013 | volume= 4 | issue= 2 | pages= e0013 | pmid=23908863 | doi=10.5041/RMMJ.10113 | pmc=PMC3678830 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23908863 }} </ref>
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| * Indirect cardioprotective actions :
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| ** It includes, HDL capacities to promote pancreatic β-cell [[insulin]] secretion, to protect pancreatic β cells from apoptosis, and to enhance [[glucose]] uptake by skeletal muscle myocytes. Studies have shown that inhibition of insulin-stimulated glucose uptake in primary human skeletal myotubes by conditioned media from macrophages pre-incubated with LDL was restored by co-treatment with HDL.<ref name="pmid23437184">{{cite journal| author=Carey AL, Siebel AL, Reddy-Luthmoodoo M, Natoli AK, D'Souza W, Meikle PJ et al.| title=Skeletal muscle insulin resistance associated with cholesterol-induced activation of macrophages is prevented by high density lipoprotein. | journal=PLoS One | year= 2013 | volume= 8 | issue= 2 | pages= e56601 | pmid=23437184 | doi=10.1371/journal.pone.0056601 | pmc=PMC3578940 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23437184 }} </ref>
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| ** In vascular smooth muscles, HDL tempers proinflammatory, promigratory, and degradative processes, and through actions on endothelium and [[platelets]] HDL is antithrombotic. The antithrombotic properties may also be related to the abilities of HDL to attenuate the expression of tissue factor and selectins, to downregulate thrombin generation via the protein C pathway, and to directly and indirectly blunt platelet activation. Thus, in addition to its cholesterol-transporting properties, HDL favorably regulates endothelial cell phenotype and reduces the risk of [[thrombosis]].<ref name="pmid16763172">{{cite journal| author=Mineo C, Deguchi H, Griffin JH, Shaul PW| title=Endothelial and antithrombotic actions of HDL. | journal=Circ Res | year= 2006 | volume= 98 | issue= 11 | pages= 1352-64 | pmid=16763172 | doi=10.1161/01.RES.0000225982.01988.93 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16763172 }} </ref>
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| ** Furthermore, HDL decreases white adipose tissue mass, increases energy expenditure, and promotes the production of adipose-derived cytokine adiponectin that has its own vascular-protective properties.<ref name="pmid23023510">{{cite journal| author=Mineo C, Shaul PW| title=Novel biological functions of high-density lipoprotein cholesterol. | journal=Circ Res | year= 2012 | volume= 111 | issue= 8 | pages= 1079-90 | pmid=23023510 | doi=10.1161/CIRCRESAHA.111.258673 | pmc=PMC3500606 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23023510 }} </ref>
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