Facilitated Replacement of Kupffer Cells Expressing a Paraoxonase-1 Transgene Is Essential for Ameliorating Atherosclerosis in Mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-08, Vol.102 (31), p.11029-11034
• Main Authors: Bradshaw, Gary, Gutierrez, Alejandra, Miyake, Jon H., Davis, Kimberly R., Li, Andrew C., Glass, Christopher K., Curtiss, Linda K., Davis, Roger A., Breslow, Jan L.
• Format: Article
• Language: English
• Subjects: Animals; Arteriosclerosis - enzymology; Arteriosclerosis - genetics; Arteriosclerosis - pathology; Arteriosclerosis - therapy; Aryldialkylphosphatase - genetics; Atherosclerosis; Base Sequence; Biological Sciences; Blood plasma; Bone marrow; Bone Marrow Transplantation; Cholesterols; DNA, Complementary - genetics; Gadolinium - pharmacology; Gene Expression; Gene therapy; Genetic Therapy; Kupffer cells; Kupffer Cells - drug effects; Kupffer Cells - enzymology; Kupffer Cells - pathology; Lesions; Liver; Low density lipoprotein receptors; Macrophages; Male; Medical research; Messenger RNA; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Receptors, LDL - deficiency; Receptors, LDL - genetics; Rodents; Stem cells; Transgenes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0502677102

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 ( GdCl3), an agent that rapidly causes Kupffer cell apoptosis. One month later, GdCl3-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 GdCl3exhibited 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 GdCl3showed no protection from atherosclerosis. In addition, mice engrafted with HSCs not expressing the PON1-Tg but injected with GdCl3also showed no protection from atherosclerosis. These findings, showing that GdCl3-enhanced hepatic expression of the PON1-Tg is essential for reducing atherosclerosis, indicate that Kupffer cells play an important role in atherogenesis. GdCl3-facilated replacement of Kupffer cells may enhance the efficacy of other HSC-based gene therapies.