Journal of Clinical Medicine Review Autoimmune Rheumatic Diseases: An Update on the Role of Atherogenic Electronegative LDL and Potential Therapeutic Strategies Der-Yuan Chen 1,2,3 , Tatsuya Sawamura 4,5 , Richard A. F. Dixon 6 , José Luis Sánchez-Quesada 7,8 and Chu-Huang Chen 5,9,10, * 1 Translational Medicine Center, China Medical University Hospital, Taichung 404, Taiwan; dychen1957@gmail.com 2 Rheumatology and Immunology Center, China Medical University Hospital, Taichung 404, Taiwan 3 College of Medicine, China Medical University, Taichung 404, Taiwan 4 Department of Molecular Pathophysiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; sawamura@shinshu-u.ac.jp 5 Department of Life Innovation, Institute for Biomedical Sciences, Shinshu University, Matsumoto 390-8621, Japan 6 Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, TX 77030, USA; RDixon@texasheart.org 7 Cardiovascular Biochemistry Group, Biomedical Research Institute IIB Sant Pau, 08041 Barcelona, Spain; jsanchezq@santpau.cat 8 CIBER of Diabetes and Metabolic Diseases (CIBERDEM), 08041 Barcelona, Spain 9 Vascular and Medicinal Research, Texas Heart Institute, Houston, TX 77030, USA 10 New York Heart Research Foundation, Mineola, NY 11501, USA   * Correspondence: cchen@texasheart.org; Tel.: +832-355-9026 Citation: Chen, D.-Y.; Sawamura, T.; Abstract: Atherosclerosis has been linked with an increased risk of atherosclerotic cardiovascu- Dixon, R.A.F.; Sánchez-Quesada, J.L.; lar disease (ASCVD). Autoimmune rheumatic diseases (AIRDs) are associated with accelerated Chen, C.-H. Autoimmune Rheumatic Diseases: An Update on the Role of atherosclerosis and ASCVD. However, the mechanisms underlying the high ASCVD burden in Atherogenic Electronegative LDL and patients with AIRDs cannot be explained only by conventional risk factors despite disease-specific Potential Therapeutic Strategies. J. factors and chronic inflammation. Nevertheless, the normal levels of plasma low-density lipoprotein Clin. Med. 2021, 10, 1992. https:// (LDL) cholesterol observed in most patients with AIRDs do not exclude the possibility of increased doi.org/10.3390/jcm10091992 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 Academic Editor: Mitsuhiro Takeno counterparts, LDL (+) and LDL (−). Electronegative L5 and LDL (−) have similar chemical composi- tions and can induce adverse inflammatory reactions in vascular cells. Notably, the percentage of Received: 22 February 2021 L5 or LDL (−) in total LDL is increased in normolipidemic patients with AIRDs. Electronegative Accepted: 2 May 2021 L5 and LDL (−) are not recognized by the normal LDL receptor but instead signal through the Published: 6 May 2021 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 Publisher’s Note: MDPI stays neutral (−) and discuss the potential targeting of LOX-1 or IL-1β signaling as new therapeutic modalities for with regard to jurisdictional claims in published maps and institutional affil- these diseases. iations. Keywords: electronegative LDL; L5; atherosclerotic cardiovascular disease (ASCVD); autoimmune rheumatic diseases (AIRDs); lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1); inter- leukin 1β (IL-1β) Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and 1. Introduction conditions of the Creative Commons Atherosclerosis is a chronic inflammatory process that leads to vascular atheromatous Attribution (CC BY) license (https:// plaque buildup, usually not developing into full-blown atherosclerotic cardiovascular creativecommons.org/licenses/by/ disease (ASCVD) until later in life [1]. However, an exception is patients with autoimmune 4.0/). J. Clin. Med. 2021, 10, 1992. https://doi.org/10.3390/jcm10091992 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 1992 2 of 15 rheumatic diseases (AIRDs), who often present with accelerated ASCVD manifestations in- cluding death at a young age [2]. Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis (PM)/dermatomyositis (DMtis), and primary Sjögren’s syndrome (pSS) [3–7] are some of the AIRDs associated with accelerated ASCVD caused by inflammatory processes that result from multiorgan immune dysregulation [8]. The high ASCVD burden in these patients can be attributed to a combination of traditional risk factors, disease-specific factors, chronic inflammation, genetic components, and the use of medications [9–18]. Genetic aberrations associated with SLE-related ASCVD include variants of the genes encoding interferon regulatory factor 8 (IRF8) [19], mannose-binding lectin [20], and signal recognition particle 54-antisense 1 (SRP54-AS1) [21]. Variants of the gene encoding apolipoprotein (apo)E have been shown to be related to ASCVD risk in patients with RA [22]. Dyslipidemia usually refers to elevated levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) and decreased levels of high-density lipoprotein cholesterol (HDL-C) [23]. Although dyslipidemia may occur in some patients with AIRDs [24–27], plasma LDL-C levels are almost universally normal in these patients at the time of admission for ASCVD complications [28,29]. LDL is a lipoprotein class that varies in density, size, electric charge, and composition among its particles. In most experi- mental studies of atherogenic LDL, the LDL must first undergo ex vivo oxidation to exhibit atherogenicity, whereas native LDL, such as L1, is harmless in vitro or in vivo, even at a supranormal high concentration [30]. Notably, electronegative LDL is a naturally occurring LDL that exerts potent atherogenic effects in cells and animals without undergoing ex vivo oxidation [31]. Human plasma LDL can be divided into a dichotomy of electropositive and electroneg- ative counterparts, namely, LDL (+) and LDL (−), by using anion-exchange chromatog- raphy [32]. Alternatively, LDL can also be divided into five subfractions with increasing electronegativity, called L1 to L5 [33]. L5 and LDL (−) differ from native LDL in their physicochemical and biological characteristics, including size, density, lipid and protein composition, phospholipase activity, and apo B100 conformation [34,35]. Elevations in L5 or LDL (−) percentages in total LDL have been observed in patients with familial hypercholesterolemia [36], type 1 or type 2 diabetes mellitus (DM) [37–40], coronary artery disease [41,42], uremia [43], ischemic peripheral arterial disease [44], ST-elevation myocar- dial infarction (STEMI) [45,46], or acute ischemic stroke [47]. Furthermore, increases in the L5 percentage (i.e., L5%) and L5 levels are associated with the intensity of metabolic syndrome [48] and are speculated to be involved in the pathogenesis of ASCVD in patients with severe mental illness [49]. L5 and LDL (−) are not recognized by the normal LDL receptor (LDLR) because of their electronegativity; rather, they signal through lectin-like oxidized LDL receptor 1 (LOX-1) to induce a broad spectrum of inflammatory reactions in adipose tissue [50] and vascular cells [51], as well as endothelial cell (EC) dysfunction and inflammation [52]. Accordingly, both L5 and LDL (−) stimulate inflammasome formation, which involves the participation and release of several cytokines, including interleukin 1β (IL-1β), IL-6, and IL-18 [51,53,54]. In monocytes, toll-like receptor 4 (TLR4) and cluster of differentiation 14 (CD14) mediate cytokine release promoted by LDL (−) [54,55]. Of importance, patients with AIRDs have been documented to have elevated levels of L5 or LDL (−) in circula- tion [56,57]. Because AIRD-related ASCVD presents a significant threat to many young patients [2,11,16,58,59], it is imperative to update the mechanistic roles of L5 and LDL (−) in the pathogenesis of AIRD-related ASCVD and the preclinical modalities that have a potential therapeutic value. In this review, we highlight the existing evidence regarding the atherogenic roles of L5 and LDL (−) in AIRDs. Because these electronegative LDLs signal through LOX-1, the potential therapeutic implications of targeting LOX-1 are also discussed. We searched the MEDLINE database using the PubMed interface and reviewed the literature published in the English language from 1988 up to 30 November 2020. The keywords searched J. Clin. Med. 2021, 10, 1992 3 of 15 for this review included atherosclerosis, atherogenesis, vascular inflammation, ASCVD, LDL-C, oxidized LDL, electronegative LDL, LDL (−), L5 LDL, LOX-1, inflammasomes, proinflammatory cytokines, IL-1β, AIRDs, SLE, SSc, PM/DMtis, pSS, therapeutic strategies, cytokine-targeting agents, LOX-1-targeting therapy, proprotein convertase subtilisin/kexin type 9 (PCSK9), and microRNAs. The relevant drugs included statins, corticosteroids, nons- teroidal anti-inflammatory drugs (NSAIDs), and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). 2. Epidemiology of ASCVD in Patients with AIRDs Cumulative evidence has indicated that the rate of subclinical atherosclerosis is higher in patients with AIRDs than in age- and sex-matched healthy control individuals [8,60–62]. AIRD-related ASCVD [4] has been documented in patients with RA [63,64], SLE [28,65,66], SSc [67], PM/DMtis [68], and pSS [69,70]. If ASCVD is present, the mortality rate is significantly higher in patients with AIRDs than in those without AIRDs [71,72]. ASCVD is the leading cause of mortality in patients with RA [73]. SLE-associated mortality was originally believed to appear in a bimodal pattern, with an early peak attributable to active lupus and a later peak attributable to ASCVD [5,74]. The bimodal pattern was later flattened after Cervera et al. [75] reported that ASCVD could occur at any time during the disease course. These findings strongly indicate the importance of early screening and intervention for ASCVD in patients with AIRDs. 3. Electronegative LDL and Its Atherogenicity Freshly isolated human plasma L5 and LDL (−) are highly atherogenic. They are treated to prevent oxidation during isolation, affirming that they are the naturally occurring LDL culprits responsible for atherosclerosis development and ASCVD progression. 3.1. The Atherogenic Mechanisms of Electronegative LDL L5 was isolated for the first time from human plasma in 2003 [33,76] and was shown to inhibit the transcription of the pro-survival gene fibroblast growth factor-2 (FGF-2) in ar- terial ECs through an Akt-mediated autoregulatory loop, thereby disrupting mitochondrial stability and inducing apoptosis [76]. Furthermore, neutralizing the PAF receptor (PAFR) significantly attenuated the L5-induced downregulation of FGF2 and the concomitant apop- tosis of ECs, suggesting that L5 signals in part through PAFR [76,77]. Although L5 is not an oxidized LDL (oxLDL) entity, it shares many functional properties with experimentally prepared oxLDL. Similarly, to oxLDL, L5 stimulates the p53-dependent activation of the proapoptotic protein Bax, leading to the apoptosis of differentiated endothelial progenitor cells (EPCs) [78]. L5, which is increased in the plasma of chronic smokers, impairs EPC differentiation by inhibiting Akt phosphorylation via LOX-1 [31]. The atherogenicity of L5 can be attributed to the multiple stress pathways it induces in vascular ECs [79]. By downregulating the expression of the endoplasmic reticulum (ER) chaperone proteins ORP150, Grp94, and Grp58, L5 induces ER stress by suppressing mitochondrial proteins Prdx3 and ATP synthase and decreases the mitochondrial mem- brane potential to result in mitochondrial dysfunction [79]. Additionally, L5 upregulates heterogeneous nuclear ribonucleoproteins (hnRNP) C1/C2 to promote macrophage recruit- ment and monocyte chemoattractant protein 1 (MCP-1) to accelerate inflammation [79]. Of importance, L5 upregulates vascular endothelial growth factor (VEGF) to facilitate in- flammatory angiogenesis and downregulates FGF-2 transcription to inhibit compensatory angiogenesis [76,79–81]. Increased plasma C-reactive protein (CRP) levels are associated with the occurrence and severity of acute coronary syndrome [82]. By augmenting CRP expression in vascular ECs, L5 further intensifies its proinflammatory property [83]. In ECs, L5 selectively downregulates mitochondria-stabilizing Bcl-2 and upregulates mitochondria-destabilizing Bax and Bad proteins [84]. Exposure of differentiated EPCs to L5 also results in an increased transfer of mitochondria-derived superoxide anion to J. Clin. Med. 2021, 10, 1992 4 of 15 p53, which stimulates a conformational change in Bax that promotes its translocation to the mitochondria, resulting in the apoptosis of these cells [78]. Daily intravenous injection of human L5 into C57B6/J mice during a course of four weeks can induce aortic endothelial senescence accompanied by γH2AX deposition and DNA damage [85]. In cultured human aortic ECs, L5 can augment mitochondrial oxygen consumption and free radical production, leading to ATM activation, nuclear γH2AX deposition, Chk2 phosphorylation, and TP53 stabilization. L5 also decreases human telomerase reverse transcriptase (hTERT) protein levels and activity. In conclusion, L5 may promote mitochondrial free radical production and activate the DNA damage response to induce premature vascular endothelial senescence that leads to atherosclerosis. An alternative signaling pathway of LDL (−) in monocytes and macrophages is through its binding to the TLR4/CD14 complex [55]. The binding of LDL (−) to CD14 signals the TLR4 and PI3K/Akt pathway, leading to the activation of nuclear factor-kB (NF-kB), activator protein-1 (AP-1), and cAMP response element-binding protein (CREB) nuclear transcription factors and the subsequent release of numerous cytokines [54]. In this context, LDL (−) activates the inflammasome, acting as a priming signal for IL-1β secretion and inducing the expression of pro-IL-1β and NLRP3 receptor [53]. 3.2. The Assocation of Electronegative LDL with ASCVD in Patients with AIRDs In three comprehensive studies, researchers have recently shown that circulating L5 levels are significantly increased in patients with RA or SLE whose plasma LDL-C levels are equal to or lower than those of healthy control individuals [56,57,86]. In a cohort of patients with RA, the plasma L5% and L5 concentration were significantly higher in those with subclinical atherosclerosis than in those without it, despite similar LDL-C levels among all the study participants [56]. The plasma L5% and L5 concentration were also positively correlated with the extent of carotid artery atherosclerosis reflected by the intima– media thickness (IMT), disease activity score, and 10-year ASCVD risk score [56]. Further investigation revealed that L5 contributes to atherogenesis by augmenting macrophage foam cell formation, upregulating integrin CD11c expression, and enhancing inflammatory mediators including IL-6, IL-8, and tumor necrosis factor (TNF)-α [86]. These findings provide a mechanistic link between L5 and ASCVD development and clinical manifesta- tions [56,57,79,86]. Most importantly, both L5% and L5 concentration declined significantly after six months of DMARD therapy in RA patients [56], suggesting the dynamic and reversible nature of L5 formation. SLE is a systemic vascular disease that mostly affects young females [87]. The rapid progression of ASCVD in patients with SLE often leads to accelerated vascular aging and death that cannot be explained by conventional risk stratification in this age-and-sex group [2,28,65]. Similar to the scenario of patients with RA, patients with SLE also have a significantly higher L5% and L5 concentration in circulation than do healthy control individuals despite patients with SLE having a plasma LDL-C level lower than that of control individuals [57]. In patients with SLE, increased L5% correlates positively with mean blood pressure, IMT, pulse wave velocity, and blood levels of CD16+ monocytes and CX3CL1 cytokines [57]. Both L5 and the total LDL of patients with SLE have a high content of lysophosphatidylcholine (LPC) and platelet-activating factor (PAF). When administered to young ApoE−/− mice, L5 and total LDL of patients with SLE can induce increases in plasma CX3CL1, aortic fatty-streak areas, aortic vascular aging, and macrophage infiltration into the aortic wall [57]. As expected, LPC exerts similar effects in vivo, whereas LDL from control individuals has negligible effects. In vitro, synthetic PAF and LPC can also induce CD16 expression in human monocytes and monocyte–EC adhesion, as does the lipid moiety of L5 in patients with SLE [57]. Thus, plasma L5 levels are increased in both patients with RA and those with SLE, thereby contributing to their accelerated atherosclerosis. Increased plasma L5 levels are also associated with an increased risk of ASCVD in patients with various other clinical diagnoses, including patients with uremia [43], ischemic peripheral arterial disease [44], or asymptomatic type 2 DM [39,40]. J. Clin. Med. 2021, 10, 1992 5 of 15 The risk of ASCVD in patients with asymptomatic type 2 DM is equivalent to that in patients with RA [88]. 3.3. Combined Atherogenicity of Electronegative VLDL and LDL Triglyceride-rich lipoproteins, very low-density lipoprotein (VLDL) in particular, may exert atherogenic effects both directly and as a precursor of LDL. VLDL can also be chro- matographically divided into subfractions with increasing electronegativity (V1–V5); the most electronegative subfraction, V5, is more toxic in ECs than L5 is at an equal concen- tration [89]. Notably, the combined electronegativity of L5 and V5 is significantly greater in individuals with a high risk of ASCVD than in those with a low risk of CHD [42]. In ApoE−/− mice, the combined increased electronegativity of LDL and VLDL is accompanied by increased lipid accumulation and cellular senescence in the aorta, further substantiating their contribution to ASCVD [42]. 4. Role of LOX-1 in Electronegative LDL Signaling Liquid chromatography/mass spectrometry (LC/MSE ) analysis revealed that L10 s protein framework is composed of 99% apoB100 with trace amounts of other proteins, whereas L5 contains 60% apoB100 with higher amounts of apo(a), apoE, apoAI, and apoCIII than does L1. In contrast to L1, which has an isoelectric point (pI) of 6.620, L5 has a pI of 5.5 or less, which contributes to its electronegativity, rendering it unrecognizable by LDLR [90]. LOX-1, originally discovered by Sawamura et al. [91] in 1997, is a 50-kDa type II membrane protein of the C-type lectin family. An important scavenger receptor, LOX-1 exhibits binding activity for multiple ligands, including oxidized LDL (ox-LDL), polyan- ionic chemicals, anionic phospholipids, cellular ligands (apoptotic/aged cells, activated platelets, and bacteria), and bile salt-dependent lipase [92,93]. After being internalized via LOX-1, L5 exerts its signaling in vascular ECs and monocytes [50–54,84,90]. In ApoE−/− mice, the specific overexpression of LOX-1 in the endothelium promotes atherosclerosis and inflammation [94]. High-cholesterol diet-induced plaque formation and proinflammatory signals can be reduced by deleting the LOX-1 gene [95]. LOX-1 is also a sensor of danger signals [96] involved in reactive oxygen species generation, which leads to NLRP3 inflammasome activation [97]. In addition, the binding of L5 or LDL (−) to LOX-1 leads to intracellular signaling and activates multiple downstream events that are critical steps in atherosclerosis. Recent studies have revealed that LDL (−) from patients with STEMI could induce the production of IL-1β, granulocyte colony-stimulating factor (G-CSF), and granulocyte/monocyte (GM)-CSF through a LOX-1-dependent path- way [98,99] and that the atherogenic and proinflammatory responses elicited by LDL (−) could be offset by blocking LOX-1 with a neutralizing antibody or shRNA knockdown [98]. Moreover, increased LOX-1 expression has been observed in human atherosclerotic le- sions and in experimental animal models [100,101], supporting a crucial role of LOX-1 in atherosclerosis. 4.1. The Potential Atherogenic Role of LOX-1 in Patients with AIRDs The evidence that LOX-1 plays a role in AIRD-associated ASCVD is substantiated by the finding that plasma from patients with RA can upregulate LOX-1 expression in human macrophages [102]. In addition, CRP can enhance endothelial LOX-1 expression [103]. CRP and LOX-1 may form a positive feedback loop with L5 in atherogenesis, whereby increased levels of atherogenic LDL in patients with cardiovascular risks induce ECs to express CRP, which may in turn increase the expression of LOX-1 to promote the uptake of electronegative LDL into ECs [104]. A recent study confirmed that plasma L5 but not L1 from patients with both RA and subclinical atherosclerosis can enhance LOX-1 expression in macrophages [56]. In addition, LOX-1 expression levels in patients with RA positively correlate with plasma L5% or L5 concentrations and are significantly associated with 10-year ASCVD risk scores [56]. Another study showed that perturbations in plasma lipid content can activate LOX-1 L5 concentrations and are significantly associated with 10-year ASCVD risk scores [56]. Another study showed that perturbations in plasma lipid content can activate LOX-1 ex- J. Clin. Med. 2021, 10, 1992 pression and promote inflammatory responses, suggesting that LOX-1 is a potential driver 6 of 15 of ASCVD risk in patients with SLE [105]. LOX-1 expression can be upregulated by other inflammatory mediators [84], and the binding of L5 to LOX-1 leads to the feedforward elevation of LOX-1 expression expression and promote [56], further inflammatory promoting responses, subsequent suggesting atherogenic that LOX-1 and in- is a potential flammatory responses. driver of ASCVD risk in patients with SLE [105]. LOX-1 expression can be upregulated by other inflammatory mediators [84], and the binding of L5 to LOX-1 leads to the feedfor- ward elevation 4.2. Atherogenic of LOX-1ofexpression Signaling [56], further Electronegative LDL andpromoting subsequent LOX-1 in atherogenic Patients with AIRDs and inflammatory responses. A schematic summary of the pathogenic role of electronegative LDL and LOX-1 sig- naling 4.2. in AIRD-related Atherogenic ASCVD Signaling is shown inLDL of Electronegative Figure 1. Thein and LOX-1 emergence of AIRDs Patients with ASCVD in patients with AIRDs is believed A schematic to result summary of thefrom complex pathogenic interactions role amongLDL of electronegative traditional and LOX-1 cardiovas- sig- cular naling in AIRD-related ASCVD is shown in Figure 1. The emergence of ASCVD in patients and risk factors, disease-specific factors, disease-related inflammatory mediators, the with medications used. Increased AIRDs is believed levels to result from of electronegative complex LDL traditional interactions among in patients with diabetes cardiovascu- [37–39] may lar risk be produced factors, by lipolysis, disease-specific factors,generating an increased disease-related levelmediators, inflammatory of non-esterified and the fatty medications used. Increased levels of electronegative LDL in patients acid (NEFA) [33]. Cigarette smoking promotes a significant increase in the production with diabetes [37–39] of L5, may be produced contributing by lipolysis, generating to smoking-associated an increased ASCVD level[31,106]. via LOX-1 of non-esterified Moreover, fatty acid fed rabbits (NEFA) [33]. Cigarette smoking promotes a significant increase in the production of L5, an atherogenic diet were shown to produce highly proinflammatory LDL (−) [107]. The contributing to smoking-associated ASCVD via LOX-1 [31,106]. Moreover, rabbits fed an high affinity of LDL (−) for LOX-1 but low affinity for LDLR may be explained by its high atherogenic diet were shown to produce highly proinflammatory LDL (−) [107]. The high NEFA content affinity of LDL[108], its high (−) for LOX-1degree but lowofaffinity aggregation for LDLR [109], mayand the presence be explained by its of anNEFA high abnormal conformation content [108], of its apoB100 [110].of high degree The L5 and LDL aggregation (−)and [109], signaling pathways the presence of anmediated abnormal con-by LOX- 1 provide formationfurther insight[110]. of apoB100 into the Thepathogenesis L5 and LDL (−of ASCVD pathways ) signaling and may represent mediated by a therapeutic LOX-1 target for patients provide with AIRDs. further insight into the pathogenesis of ASCVD and may represent a therapeutic target for patients with AIRDs. Figure 1. The probable atherogenic role of electronegative LDL (LDL(−)/L5) in patients with AIRDs. The increased Figurelevels 1. Theof probable atherogenic LDL (−) may be producedroleby of lipolysis electronegative LDL (LDL(−)/L5) with non-esterified in(NEFA) fatty acid patients with AIRDs. loading Thewith in patients increased levels diabetes. of LDLCigarette (−) maysmoking be produced by lipolysis with non-esterified fatty acid (NEFA) loading in patients with diabetes. is associated with L5 formation and LOX-1-induced atherosclerosis. C-reactive protein induces LOX-1 Cigarette smoking is associated expression. with L5/LDL (−L5 formation ) and the LOX-1 and LOX-1-induced signaling pathway leadatherosclerosis. C-reactive to atherogenesis, vascularprotein inducesand inflammation, LOX-1 expres- platelet sion. L5/LDL (−) and the LOX-1 activation/aggregation. LDL:signaling low-density pathway leadLOX-1: lipoprotein; to atherogenesis, vascular lectin-like oxidized inflammation, low-density and platelet lipoprotein receptor activa- 1; tion/aggregation. LDL: low-density HTN: hypertension; DM: diabeteslipoprotein; LOX-1:nonsteroidal mellitus; NSAIDs: lectin-like anti-inflammatory oxidized low-densitydrugs;lipoprotein receptor 1;oxLDL: Abs.: autoantibodies; HTN: hy- pertension; DM: oxidized diabetes LDL; IL-1β: mellitus; interleukinNSAIDs: 1β; CVD:nonsteroidal anti-inflammatory cardiovascular disease. drugs; Abs.: autoantibodies; oxLDL: oxidized LDL; IL-1β: interleukin 1β; CVD: cardiovascular disease. J. Clin. Med. 2021, 10, 1992 7 of 15 5. Proposed Therapeutic Strategies for Targeting ASCVD in Patients with AIRDs Epidemiologic studies have shown increased morbidity and mortality rates due to ASCVD in patients with AIRDs [4,39–47,51], suggesting the importance of screening and preventive strategies for ASCVD, as well as its management. Although there is a paucity of consensus or randomized studies regarding therapeutic strategies for ASCVD in AIRDs, both the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) recommendations emphasize that patients with AIRDs should undergo risk factor monitoring, CVD risk modification, and dyslipidemia therapy, if needed [111,112]. 5.1. Modifications of Traditional CVD Risk Factors Given that cigarette smoking is implicated in L5–LOX-1 signaling pathway-related atherosclerosis [31,106] and that smoking cessation could reduce an independent ASCVD risk marker (i.e., the LOX index) [113], smoking cessation should be a priority. Avoidance of intense aerobic exercise is recommended because it may increase the NEFA content of LDL (−) [114]. Considering that an atherogenic diet induces LDL (−)-related inflamma- tion [107], replacing it with the Mediterranean diet may reduce ASCVD risk in patients with AIRDs [115]. 5.2. Tight Control of Disease Activity and the Adjustment of Medications Given that AIRD-related immune dysregulation has an important role in premature atherosclerosis, the control of disease activity is essential. In patients with AIRDs, ASCVD risk is significantly associated with acute-phase reactants, inflammatory cytokines, autoan- tibody positivity, and specific T cell subsets [116,117]. The acute-phase reactant CRP in patients with AIRDs can enhance endothelial LOX-1 expression [103]. Chang et al. [56] also revealed a relationship between the plasma L5 proportion and the RA disease activity. The inflammatory mechanisms in AIRDs may intensify oxidative stress, triggering a broad range of proatherogenic lipid changes [118]. According to the EULAR guidelines [111,112], adequate control of disease activity reduces the risk of ASCVD in patients with AIRDs. Given the pathogenic role of proinflammatory cytokines in AIRD-related atherosclerosis, tight control of disease activity with biologic DMARDs, including TNF-α inhibitors, IL-6 inhibitors, and IL-17 inhibitors, may reduce the risk of ASCVD [119–121]. Increasing evidence has indicated that corticosteroids are associated with hypertension and dyslipidemia [122] and that nonsteroidal NSAIDs may adversely affect cardiovascular outcomes [123]. The EULAR guidelines recommend using the lowest dose of corticosteroids and prescribing NSAIDs with caution [111,112]. In contrast, recent studies revealed a beneficial effect of hydroxychloroquine (HCQ) on cardiovascular outcomes in patients with RA [124,125]. Other csDMARDs, such as methotrexate, could also reduce ASCVD risk [126]. 5.3. Lipid-Lowering Therapy Although cardiovascular interventional trials have not been performed specifically in patients with AIRDs, statins are the preferred therapeutic agent for dyslipidemia. Statin therapy could reduce the proportion of LDL (−) and attenuate inflammation in patients with hyperlipidemia [127,128]. Simvastatin therapy improves the affinity of LDL (−) for the LDLR in parallel with a decrease in the proportion of LDL (−) [127]. Given a bidirectional link between LOX-1 and PCSK9, especially in an inflammatory status [129], a PCSK9 inhibitor could reduce LOX-1 expression. L5 is a promising marker for predicting ASCVD [56,57,86]. The therapeutic goal of controlling L5 should be to lower its plasma concentration below 1.7 mg/dL. If the L5 concentration is higher than 1.7 mg/dL, a lipid- lowering treatment, such as statins or PCSK9 inhibitors, may be required regardless of the absolute LDL level [130]. in. Med. 2021, 10, x FOR PEER REVIEW 8o J. Clin. Med. 2021, 10, 1992 5.4. Potential Therapeutic Strategy Targeting Electronegative LDL and LOX-1 Pathway 8 of 15 Given that LOX-1 is a multiligand and multifunctional receptor underlying card vascular dysfunction and ASCVD [92–96,105], a therapy targeting LOX-1 is promising a treatment for Therapeutic 5.4. Potential atherosclerosis and vasculopathy Strategy Targeting Electronegative [131]. LDL andMicroRNAs, LOX-1 Pathway which are sh noncoding RNAs, Given that have LOX-1been recently identified is a multiligand as immune and multifunctional regulators receptor underlyingthat post-transcr cardiovas- cular tionally dysfunction repress mRNA and expression. ASCVD [92–96,105], Recenta therapy studiestargeting LOX-1 is promising have revealed that microRNAas a let- treatment for atherosclerosis and vasculopathy [131]. MicroRNAs, which and microRNA-98 may target LOX-1 as a therapy for atherosclerosis [132,133]. In ad are short noncod- ing RNAs, have been recently identified as immune regulators that post-transcriptionally tion, repress the transcription factor NF-κB mRNA expression. is involved Recent studies in the development have revealed that microRNAand let-7gprogression and both vascular microRNA-98 inflammation and ASCVD may target LOX-1 [134]. as a therapy for Interestingly, NF-κB and atherosclerosis [132,133]. sirletin-1 featu In addition, the characteristics the transcriptionoffactor antagonistic crosstalk NF-κB is involved [135]. in the Sirletin-1and development drives anti-inflammatory progression of both sponses and enhances the resolution of vascular inflammation. Based on thethe vascular inflammation and ASCVD [134]. Interestingly, NF-κB and sirletin-1 feature findings characteristics of antagonistic crosstalk [135]. Sirletin-1 drives anti-inflammatory responses previous studies, meta-analyses, reviews, recommendations, and our results, we propo and enhances the resolution of vascular inflammation. Based on the findings of previous a potential studies,therapeutic meta-analyses, strategy reviews, with an emphasis recommendations, andonourtargeting results, wethe L5/LDL propose (−) and LOX a potential pathway in patients therapeutic with strategy withAIRDs (Figure an emphasis 2). on targeting the L5/LDL (−) and LOX-1 pathway in patients with AIRDs (Figure 2). Figure 2. A potential therapeutic strategy for the targeting L5/LDL(−) and LOX-1 pathway in patients with AIRDs. Major therapeutic strategies include modifications of the traditional CVD risk factors; control of AIRD activity; and the Figure 2. Ause potential therapeutic of lipid-lowering agents,strategy for the targeting cytokine-targeting L5/LDL(−) agents, and and LOX-1 LOX-1-targeting therapy.pathway in patients CVD: cardiovascular with LDL: disease; AIRDs. Major therapeuticlow-density strategies include HCQ: lipoprotein; modifications of the traditional hydroxychloroquine; CVD risk factors; DMARDs: disease-modifying control ofdrugs; anti-rheumatic AIRD activity; PCSK9: and the use of proprotein lipid-lowering agents, convertase cytokine-targeting subtilisin/kexin agents, type 9; miRNA: and LOX-1-targeting microRNA; therapy. NF-kB: nuclear factor-kB; CVD: IL-1β: cardiovascular interleukin 1β. disease; LDL: low- density lipoprotein; HCQ: hydroxychloroquine; DMARDs: disease-modifying anti-rheumatic drugs; PCSK9: proprotein convertase subtilisin/kexin type 9; miRNA: microRNA; NF-kB: nuclear factor-kB; IL-1β: interleukin 1β. 6. Conclusions Accelerated atherosclerosis with an increased risk of ASCVD is well-documented patients with AIRDs. Furthermore, cumulative evidence has indicated that the L5/LDL and LOX-1 signaling pathway contributes to atherogenicity. We propose probable mec anisms behind this signaling in the pathogenesis of AIRD-related ASCVD and a potent therapeutic strategy targeting L5/LDL (−) and LOX-1 signaling. Regularly updating the pathologic mechanisms and therapeutic strategies will be critical as new eviden J. Clin. Med. 2021, 10, 1992 9 of 15 6. Conclusions Accelerated atherosclerosis with an increased risk of ASCVD is well-documented in patients with AIRDs. Furthermore, cumulative evidence has indicated that the L5/LDL (−) and LOX-1 signaling pathway contributes to atherogenicity. We propose probable mechanisms behind this signaling in the pathogenesis of AIRD-related ASCVD and a potential therapeutic strategy targeting L5/LDL (−) and LOX-1 signaling. Regularly updating these pathologic mechanisms and therapeutic strategies will be critical as new evidence emerges. Author Contributions: Conceptualization, C.-H.C. and D.-Y.C.; methodology, D.-Y.C. and C.-H.C.; software, D.-Y.C. and C.-H.C.; validation, D.-Y.C., T.S., R.A.F.D., J.L.S.-Q. and C.-H.C.; formal analysis, C.-H.C.; investigation, C.-H.C.; resources, C.-H.C.; data curation, D.-Y.C. and C.-H.C.; writing— original draft preparation, D.-Y.C.; writing—review and editing, C.-H.C.; visualization, D.-Y.C., T.S., R.A.F.D., J.L.S.-Q. and C.-H.C.; supervision, C.-H.C.; project administration, C.-H.C.; funding acquisition, C.-H.C. and D.-Y.C. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by the Vascular and Medicinal Research Fund, Texas Heart Institute, #765-64050, Houston, TX, USA, a grant (MOST 107-2314-B-039-053-MY3) from the Ministry of Science and Technology, Taiwan, and PI16/00471 from Instituto de Salud Carlos III, Spanish Ministry of Health (co-financed by the European Regional Development Fund). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Acknowledgments: The authors thank Nicole Stancel, ELS(D) of the Department of Scientific Publi- cations at Texas Heart Institute in Houston, Texas, for manuscript editing. Conflicts of Interest: The authors declare no conflict of interest. References 1. Libby, P. Inflammation in Atherosclerosis. Arter. Thromb. Vasc. Biol. 2012, 32, 2045–2051. [CrossRef] 2. Manzi, S.; Meilahn, E.N.; Rairie, J.E.; Conte, C.G.; Medsger, T.A.; Jansen-McWilliams, L.; D’Agostino, R.B.; Kuller, L.H. 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