Autoimmune Rheumatic Diseases: An Update on the Role of Atherogenic Electronegative LDL and Potential Therapeutic Strategies

Abstract

Atherosclerosis has been linked with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Autoimmune rheumatic diseases (AIRDs) are associated with accelerated atherosclerosis and ASCVD. However, the mechanisms underlying the high ASCVD burden in patients with AIRDs cannot be explained only by conventional risk factors despite disease-specific factors and chronic inflammation. Nevertheless, the normal levels of plasma low-density lipoprotein (LDL) cholesterol observed in most patients with AIRDs do not exclude the possibility of increased LDL atherogenicity. By using anion-exchange chromatography, human LDL can be divided into five increasingly electronegative subfractions, L1 to L5, or into electropositive and electronegative counterparts, LDL (+) and LDL (−). Electronegative L5 and LDL (−) have similar chemical compositions and can induce adverse inflammatory reactions in vascular cells. Notably, the percentage of L5 or LDL (−) in total LDL is increased in normolipidemic patients with AIRDs. Electronegative L5 and LDL (−) are not recognized by the normal LDL receptor but instead signal through the lectin-like oxidized LDL receptor 1 (LOX-1) to activate inflammasomes involving interleukin 1β (IL-1β). Here, we describe the detailed mechanisms of AIRD-related ASCVD mediated by L5 or LDL (−) and discuss the potential targeting of LOX-1 or IL-1β signaling as new therapeutic modalities for these diseases.

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“…Cardiovascular disease (CVD) is the leading non-communicable chronic disease cause of death worldwide (Mendis, 2017; Zhao et al, 2019). Rheumatic disease (RD), a life-threating disease that affects 11.6%–46.4% of the adult population (American College of Rheumatology [ACR], 2023; Zeng et al, 2008) increases the risk of premature atherosclerosis CVD in sufferers and imposes high burdens on individuals, families, and healthcare resources (Chen et al, 2021; Mahtta et al, 2020; Rahman et al, 2013). RD encompasses over 200 distinct rheumatologic conditions characterized by pain and reduced mobility and physical function in one or more areas of the musculoskeletal system.…”