Hypertension and endothelial dysfunction in the pristane model of systemic lupus erythematosus

Abstract

Autoimmune diseases such as psoriasis, rheumatoid arthritis, and systemic lupus erythematosus (SLE) have high rates of hypertension and cardiovascular disease. Systemic lupus erythematosus is a prototypic autoimmune disorder that primarily affects women of childbearing age and is associated with a loss of self‐tolerance, autoreactive B and T lymphocytes, and the production of autoantibodies, especially to nuclear components. In this study, we hypothesized that the pristane‐inducible model of SLE would develop hypertension and vascular dysfunction as the disease progressed. To test this hypothesis, female C57BL/6 mice were administered PBS or pristane. Seven months after pristane administration, mice developed various autoantibodies, including anti‐dsDNA IgG, anti‐ssDNA IgG, and anti‐nRNP IgG, as well as hypergammaglobulinemia. Several other immunological changes, including increased circulating neutrophils and increased CD4−CD8− (double negative) thymocytes were also detected. Mean arterial pressure (MAP) was elevated in pristane‐treated mice when compared to PBS‐treated mice. In addition, second‐order mesenteric arteries from pristine‐treated mice had impaired relaxation to the endothelium‐dependent vasodilator acetylcholine compared to PBS‐treated mice. These data suggest that the immune system dysfunction present in the pristane model of lupus contributes to the development of hypertension and vascular dysfunction.

Connexin 43 Expression in Cutaneous Biopsies of Lupus Erythematosus

“…40 However, although blood vessels are so important in LE, the role of endothelial alteration in LE is far from being completely understood. Somehow, the immune system dysfunction contributes to vascular dysfunction in systemic LE, 41 which triggers most clinical manifestations of the disease. 42 For instance, vascular responsiveness (measured in terms of flow-mediated diameter percent change) is impaired in adults with systemic LE when compared with age-matched controls.…”

Vascular Inflammation in Mouse Models of Systemic Lupus Erythematosus

“…Some strains including MRL/Fas lpr , BXSB, and (NZW/BXSB) F1, may also develop myocardial infarctions ( 55 ). NZB/NZW F1 mice and some induced models develop hypertension, which may be used as another measure of CVD progression ( 23 , 25 , 27 , 32 – 36 , 44 ).…”

“…Since many SLE mouse models do not display overt atherosclerosis and hypertension in the same manner as humans, histological, and blood pressure studies are often insufficient for assessing CVD progression. In these cases, vascular disease can be measured by functional studies in which isolated arteries are forced to contract, and then are exposed to various vasodilators to observe the extent of vasorelaxation ( 23 – 25 , 27 – 30 , 34 , 35 , 37 – 40 ). This type of study can be done on any mouse model.…”

“…The main mouse models generally used to study SLE hypertension are pristane-induced models and the NZB/NZW F1 strain. C57BL/6 and BALB/c mice develop increased arterial pressure when treated with pristane, suggesting that that an increase in type I IFN contributes to hypertension ( 23 , 25 ).…”

“…Vasorelaxation in response to Ach is impaired in many models of SLE that have type I IFN as a major driver of disease, including ApoE −/− mice exposed to IFNα-expressing adenovirus ( 39 ), pristane or imiquimod-treated mice ( 23 – 25 , 27 , 28 ), NZB/NZW F1 mice ( 35 , 37 , 38 ), and NZM2328 mice ( 39 ). Generally, these mice do not display impaired vasorelaxation in response to sodium nitroprusside, which induces vasorelaxation by acting directly on the vascular smooth muscle.…”