A Role of Isolevuglandins in Essential Hypertension and Systemic Lupus Erythematosus

项目总结

PROJECT SUMMARY Essential hypertension and systemic lupus erythematosus (SLE) are devastating conditions for United States Veterans. An estimated one-third of the world’s population suffers from hypertension despite a large number of treatment options. SLE is a heterogeneous disease the treatment of which is limited to the use of non-specific global immunosuppression. There is a lack of understanding of the mechanisms underlying these conditions. Isolevuglandins (IsoLGs) are oxidation products of fatty acids that form as a result of reactive oxygen species. These molecules adduct covalently to lysine residues of proteins. Adducted proteins are then presented as autoantigens to T-cells resulting in immune cell activation and resultant hypertension and systemic autoimmunity. Based upon previously published studies and preliminary data, it is clear that both essential hypertension and SLE are initiated by this process of isoLG-adduct formation, processing, and immune cell activation. I have discovered an important role of the immunoproteasome subunit LMP7 in the presentation of isoLG-adducted autoantigens, the development of hypertension, and aortic inflammation in a mouse model of essential hypertension. Additionally, in a mouse model of SLE, I have also discovered that treatment with an isoLG scavenger, 2-hydroxybenzylamine, attenuates hypertension and systemic autoimmunity. Finally, I found that a subset of patients with SLE exhibit isoLG accumulation within antigen presenting cells, suggesting a unique clinical profile and potential therapeutic opportunities for these patients. I hypothesize that within antigen presenting cells in both hypertension and SLE, isoLG adducts are processed and displayed by an immunoproteasome dependent mechanism with a primary role of the immunoproteasome subunit LMP7. Additionally, patients with SLE that exhibit isoLG-adduct accumulation exhibit unique disease characteristics. My specific aims are: (1) To determine a role of isoLG-adducts in SLE-associated hypertension and disease heterogeneity. (2) To determine the role of immunoproteasome function in isoLG-adducted antigen presentation and hypertension. (3) To determine the role of LMP7 function in immune activation, isoLG-adducted antigen presentation, and hypertension in SLE. To accomplish these aims we will recruit SLE patients and obtain peripheral blood mononuclear cells. Cells will be studied by flow cytometry for the presence of isoLG-adduct accumulation within unique populations of antigen presenting cells. IsoLG-adduct levels will be compared with clinical parameters to determine the parameters that correlate with adduct accumulation. To study the function of the immunoproteasome, I will utilize mice globally deficient for the three subunits of the immunoproteasome (TKO mice). I have also generated a conditional knockout of the chymotrypsin subunit of the immunoproteasome (LMP7fl/fl) which will be crossed to CD11c-Cre transgenic animals to generate an antigen presenting cell specific LMP7 deficient animal. These animals will be studied for the development of hypertension and inflammation in the setting of two well established acquired models of essential hypertension in mice. To study the role of LMP7 in SLE, I propose to examine the effect of the LMP7 inhibitor PR-957 in the B6.SLE123 murine model of SLE. Additionally, I will study the effect of dendritic cell specific LMP7 deletion in a model of chemically-induced SLE by treating LMP7fl/fl/CD11c-Cre with pristane. Animals will be studied for the development of hypertension, immune cell expansion, autoantibody production, and renal injury. Together, these studies hold the promise of elucidating novel mechanistic insights into essential hypertension and SLE. Moreover, they will provide novel therapeutic opportunities for the treatment of these conditions.