title: Facilitated replacement of Kupffer cells expressing a paraoxonase-1 transgene is essential for ameliorating atherosclerosis in mice.
abstract: Resident macrophages (i.e., Kupffer cells) are derived from hematopoietic stem cells (HSCs) and are primarily responsible for the removal from plasma of oxidized forms of low-density lipoprotein (LDL). The therapeutic potential of Kupffer cell expression of a transgene encoding paraoxonase-1 (PON1), whose plasma activity correlates with the protection from atherosclerosis, was examined in mice rendered atherosclerosis-susceptible through genetic deletion of the LDL receptor. Mice having their bone marrow engrafted with HSCs expressing the PON1 transgene (PON1-Tg) driven by a macrophage-specific promoter were injected i.v. with saline (vehicle only) or with gadolinium chloride (GdCl(3)), an agent that rapidly causes Kupffer cell apoptosis. One month later, GdCl(3)-facilitated Kupffer cell apoptosis increased the hepatic expression of transgenic PON1 mRNA by 9-fold. After 12 weeks of being fed a cholesterol-enriched atherogenic diet, mice injected with GdCl(3) exhibited 50% reductions in both aortic sinus atherosclerotic lesions (P < 0.0097) and surface lesions of the abdominal aorta (P < 0.006). In contrast, mice receiving HSCs expressing the PON1-Tg but not treated with GdCl(3) showed no protection from atherosclerosis. In addition, mice engrafted with HSCs not expressing the PON1-Tg but injected with GdCl(3) also showed no protection from atherosclerosis. These findings, showing that GdCl(3)-enhanced hepatic expression of the PON1-Tg is essential for reducing atherosclerosis, indicate that Kupffer cells play an important role in atherogenesis. GdCl(3)-facilated replacement of Kupffer cells may enhance the efficacy of other HSC-based gene therapies.
authors.affiliation: Department of Biology and Heart Institute, San Diego State University, San Diego, CA 92182, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Bradshaw
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gutierrez
authors.forename: Jon H
authors.initials: JH
authors.lastname: Miyake
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Davis
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Li
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.forename: Linda K
authors.initials: LK
authors.lastname: Curtiss
authors.forename: Roger A
authors.initials: RA
authors.lastname: Davis
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D043303:Aryldialkylphosphatase / Q000235:genetics*; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D018076:DNA, Complementary / Q000235:genetics; D005682:Gadolinium / Q000494:pharmacology*; D015870:Gene Expression; D015316:Genetic Therapy; D007728:Kupffer Cells / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics
chemical_list: D018076:DNA, Complementary; D011973:Receptors, LDL; D005682:Gadolinium; D043303:Aryldialkylphosphatase; C038958:gadolinium chloride