Essential hypertension and systemic lupus erythematosus (SLE) are devastating conditions. 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, 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 in the presentation of isoLG-adducted autoantigens, the development of hypertension, and aortic inflammation in a mouse model of essential hypertension. Moreover, in a mouse model of SLE, I have also discovered that treatment of mice 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, isoLG adducts are processed and displayed by an immunoproteasome dependent mechanism. 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 antigen presentation and hypertension. 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 specific populations of antigen presenting cells. IsoLG-adduct levels will be compared with clinical parameters to determine the characteristics 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. 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.
Hypertension and lupus are autoimmune conditions that are devastating and for which there are no curative therapies. This project is designed to study the function of isolevuglandins, a product of reactive oxygen species, in both conditions. These discoveries are directly applicable to the design of novel diagnostic and therapeutic approaches for cardiovascular disease and systemic autoimmunity.
