Prevention of oxLDL uptake leads to decreased atherosclerosis in hematopoietic NPC1-deficient Ldlr-/-mice.
Atherosclerosis is a chronic inflammatory disease of medium and large vessels and is typically characterized by the predominant accumulation of low-density lipoprotein (LDL)-cholesterol inside macrophages that reside in the vessel walls. Previous studies clearly demonstrated an association specifically between the oxidized type of LDL (oxLDL) and atherosclerotic lesion formation. Further observations revealed that these atherosclerotic lesions displayed enlarged, lipid-loaded lysosomes. By increasing natural antibodies against oxLDL, pneumococcal vaccination has been shown to reduce atherosclerosis in LDL receptor knockout (Ldlr-/-) mice. Relevantly, loss of the lysosomal membrane protein Niemann-Pick Type C1 (NPC1) led to lysosomal accumulation of various lipids and promoted atherosclerosis. Yet, the importance of lysosomal oxLDL accumulation inside macrophages, compared to non-modified LDL, in atherosclerosis has never been established.



By transplanting NPC1 bone marrow into lethally irradiated Ldlr-/-mice, a hematopoietic mouse model for lysosomal cholesterol accumulation was created. Through injections with heat-inactivated pneumococci, we aimed to demonstrate the specific contribution of lysosomal oxLDL accumulation inside macrophages in atherosclerosis development.



While there were no differences in plaque morphology, a reduction in plaque size and plaque inflammation was found in immunized NPC1mut-transplanted mice, compared to non-immunized NPC1mut-transplanted mice.



Lysosomal oxLDL accumulation within macrophages contributes to murine atherosclerosis. Future intervention strategies should focus specifically on preventing oxLDL, unlike non-modified LDL, from being internalized into lysosomes. Such an intervention can have an additive effect to current existing treatments against atherosclerosis.
Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands.
Mike L J
MLJ
Jeurissen
Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands.
Sofie M A
SMA
Walenbergh
Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands.
Tom
T
Houben
Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands; Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Marion J J
MJJ
Gijbels
Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands.
Jieyi
J
Li
Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands.
Tim
T
Hendrikx
Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands.
Yvonne
Y
Oligschlaeger
Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands.
Patrick J
PJ
van Gorp
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria; Center for Molecular Medicine (CeMM), Austrian Academy of Sciences, Vienna, Austria.
Christoph J
CJ
Binder
Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands.
Marjo M P C
MMPC
Donners
Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands. Electronic address: r.sverdlov@maastrichtuniversity.nl.
Ronit
R
Shiri-Sverdlov
D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D001692:Biological Transport; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077296:Niemann-Pick C1 Protein; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D022242:Pneumococcal Vaccines / Q000008:administration & dosage / Q000276:immunology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013296:Streptococcus pneumoniae / Q000276:immunology; D014916:Whole-Body Irradiation
D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D022242:Pneumococcal Vaccines; D011506:Proteins; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D002784:Cholesterol
Antibodies; Cholesterol/metabolism; Macrophages/monocytes; Oxidized lipids; Vascular biology