Lack of a significant role of P-Rex1, a major regulator of macrophage Rac1 activation and chemotaxis, in atherogenesis.
BACKGROUND
Rho GTPases are known to play important roles in regulating multiple cellular processes that include cell polarization and migration. Among these Rho GTPases, Rac has been shown to be essential for F actin formation and cell migration. P-Rex1 is a guanine nucleotide exchange factor (GEF) that was previously found to mediate the activation of Rac2, but not Rac1, in mouse neutrophils.


OBJECTIVE
Here we examined the role of P-Rex1 in mouse macrophages and atherogenesis.


RESULTS
PBD (p21 binding domain) pull down assay was performed to compare the Rac1 activation in WT and P-Rex1-deficient macrophage. In addition, transwell assay was conducted to compare chemotaxis of WT and P-Rex1-deficient macrophage. We found that P-Rex1 is a major Rac1 regulator in mouse macrophages as its deficiency significantly compromises macrophage chemotaxis, superoxide production (SOD), and Rac1 activation in response to chemoattractants. The potential role of P-Rex1 in atherogenesis is also investigated by transferring P-Rex1-deficient bone marrow cells to LDLR deficient mice. Contrary to our prediction, P-Rex1 deficiency did not alter atherogenesis, suggesting chemoattractant-induced macrophage migration may not have a significant role in atherogenesis.


CONCLUSIONS
P-Rex1 is one of the major GEFs in macrophage regulating Rac1 activation and chemotaxis.
Wang
Zhenglong
Z
Program for Vascular Biology and Therapeutics and Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Dong
Xuemei
X
Li
Zhong
Z
Smith
Jonathan D
JD
Wu
Dianqing
D
D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002633:Chemotaxis; D004789:Enzyme Activation; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D010587:Phagocytosis; D013481:Superoxides / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; C511197:PREX1 protein, mouse; D013481:Superoxides; D020830:rac1 GTP-Binding Protein