Angiotensin II Increases Macrophage-mediated Modification of Low Density Lipoprotein via a Lipoxygenase-dependent Pathway

Kathrin J. Scheidegger, Susan Butler, Joseph L. Witztum
1997 Journal of Biological Chemistry  
The molecular and cellular mechanisms by which hypertension enhances atherosclerosis are poorly understood. Angiotensin II (Ang II) has been implicated in the regulation of cellular lipoxygenases (LO), which are thought to play a role in atherogenesis by inducing oxidative modification of low density lipoprotein (LDL). We sought to test the hypothesis that Ang II would stimulate murine macrophage LO activity (which has both 12-and 15-LO activity). Competitive binding studies revealed the
more » ... revealed the presence of Ang II AT 1 receptors on mouse peritoneal macrophages (MPM) and J-774 cells, but not on the RAW cell line. Valsartan, a specific AT 1 receptor antagonist inhibited Ang II binding, whereas PD 123319, an AT 2 receptor antagonist did not. Incubation of MPM or J-774 cells with Ang II (10 pM to 1 M) for 24 h led to a 2.5-3. 5-fold increase in LO activity, measured as generated 13-HODE or 12(S)-HETE. This stimulation was inhibited by valsartan, but not by PD 123319. In contrast, Ang II did not stimulate LO activity in RAW macrophages. Semiquantitative reverse transcriptase-polymerase chain reaction showed a 2-3-fold increase in LO mRNA in MPM, but not in RAW cells after treatment with Ang II. Ang II also induced an increase in 12-LO protein. In addition, pretreatment of J-774 cells with Ang II increased in a dose-dependent manner the ability of the cells to modify LDL, resulting in greater chemotactic activity for monocytes, typical of minimally modified LDL. This stimulation was inhibited by AT 1 receptor blockade. In summary, these data suggest that Ang II increases macrophage LO activity via AT 1 receptor-mediated mechanisms and this further increases the ability of the cells to generate minimally oxidized LDL. These studies provide a link between hypertension and the associated increased atherosclerosis observed in hypertensive patients.
doi:10.1074/jbc.272.34.21609 pmid:9261183 fatcat:zainf3uznvdnpol77emyjzll5a