Targeting GGTase-I activates RHOA, increases macrophage reverse cholesterol transport, and reduces atherosclerosis in mice.

Abstract

BACKGROUND:

Statins have antiinflammatory and antiatherogenic effects that have been attributed to inhibition of RHO protein geranylgeranylation in inflammatory cells. The activity of protein geranylgeranyltransferase type I (GGTase-I) is widely believed to promote membrane association and activation of RHO family proteins. However, we recently showed that knockout of GGTase-I in macrophages activates RHO proteins and proinflammatory signaling pathways, leading to increased cytokine production and rheumatoid arthritis. In this study, we asked whether the increased inflammatory signaling of GGTase-I-deficient macrophages would influence the development of atherosclerosis in low-density lipoprotein receptor-deficient mice.

METHODS AND RESULTS:

Aortic lesions in mice lacking GGTase-I in macrophages (Pggt1b▵/▵) contained significantly more T lymphocytes than the lesions in controls. Surprisingly, however, mean atherosclerotic lesion area in Pggt1b▵/▵ mice was reduced by ≈60%. GGTase-I deficiency reduced the accumulation of cholesterol esters and phospholipids in macrophages incubated with minimally modified and acetylated low-density lipoprotein. Analyses of GGTase-I-deficient macrophages revealed upregulation of the cyclooxygenase 2-peroxisome proliferator-activated-γ pathway and increased scavenger receptor class B type I- and CD36-mediated basal and high-density lipoprotein-stimulated cholesterol efflux. Lentivirus-mediated knockdown of RHOA, but not RAC1 or CDC42, normalized cholesterol efflux. The increased cholesterol efflux in cultured cells was accompanied by high levels of macrophage reverse cholesterol transport and slightly reduced plasma lipid levels in vivo.

CONCLUSIONS:

Targeting GGTase-I activates RHOA and leads to increased macrophage reverse cholesterol transport and reduced atherosclerosis development despite a significant increase in inflammation.

• Authors: Omar M Khan, Murali K Akula, Kristina Skålen, Christin Karlsson, Marcus Ståhlman, Stephen G Young, Jan Borén, Martin O Bergo
• Journal: Circulation (Circulation) Vol. 127 Issue 7 Pg. 782-90 (Feb 19 2013) ISSN: 1524-4539 [Electronic] United States
• PMID: 23334894 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CD36 Antigens
• PPAR gamma
• Scarb1 protein, mouse
• Scavenger Receptors, Class B
• Cholesterol
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Alkyl and Aryl Transferases
• geranylgeranyltransferase type-I
• RhoA protein, mouse
• rho GTP-Binding Proteins
• rhoA GTP-Binding Protein

Topics

• Alkyl and Aryl Transferases (genetics, metabolism)
• Animals
• Aorta (metabolism, pathology)
• Atherosclerosis (metabolism, pathology)
• Biological Transport (physiology)
• Bone Marrow Cells (cytology)
• CD36 Antigens (metabolism)
• Cell Line, Tumor
• Cholesterol (metabolism)
• Cyclooxygenase 2 (metabolism)
• Female
• Foam Cells (cytology, enzymology)
• Humans
• Leukemia, Monocytic, Acute
• Macrophages, Peritoneal (cytology, enzymology)
• Male
• Mice
• Mice, Knockout
• PPAR gamma (metabolism)
• Scavenger Receptors, Class B (metabolism)
• Signal Transduction (physiology)
• Vasculitis (metabolism, pathology)
• rho GTP-Binding Proteins (genetics, metabolism)
• rhoA GTP-Binding Protein