Elevated Levels of Autoantibodies against ATP2B4 and BMP-1 in Sera of Patients with Atherosclerosis-related Diseases

Abstract

Background: Atherosclerosis-related life-style diseases such as cerebral infarction (CI), cardiovascular disease (CVD), diabetes mellitus (DM), and chronic kidney disease (CKD) are a serious problem in the recently aging society. The development of novel and sensitive diagnostic markers is necessary and expected for the early treatment. Methods and Results: Through the first screening by phage expression cloning, we identified ATPase, Ca ++ transporting, plasma membrane 4 (ATP2B4) and bone morphogenetic protein 1 (BMP-1) as antigens recognized by IgG antibodies in the sera of patients with atherosclerosis. The presence of autoantibodies against these antigens in serum specimens was confirmed by Western blotting. We then compared serum antibody levels against recombinant ATP2B4 and BMP-1 proteins between healthy donors (HD) and patients with atherosclerotic diseases, such as CI, transient ischemic attack (TIA), CVD, DM, or CKD, by the Alpha (amplified luminescent proximity homogeneous assay)-LISA method. The results revealed that both antibody levels were significantly higher in patients with these diseases than in HD and exhibited most prominent differences in CKD vs. HD. Correlation analysis showed that both antibody levels were well correlated with the degree of artery stenosis, such as maximum intima-media thickness with some different patterns, i.e., anti-ATP2B4 antibody levels were related to hypertension, whereas anti-BMP-1 antibodies were related to smoking habits. Conclusions:The serum antibody levels against ATP2B4 and BMP-1 can be useful diagnostic markers for atherosclerosis and its related diseases caused by hypertension and smoking habits, respectively.

Association of serum levels of antibodies against MMP1, CBX1, and CBX5 with transient ischemic attack and cerebral infarction

“…Blood biochemistry was also assessed as previously described [17, 40-43], including white blood cells, red blood cells, platelets, total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c), triglycerides (TG), total protein, albumin, total bilirubin, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltranspeptidase, alkaline phosphatase, lactate dehydrogenase, uric acid, C-reactive protein, and glycated hemoglobin. A total of 357 specimens were examined, including 123 specimens obtained from HDs, 77 from TIA patients, and 157 from aCI patients.…”

“…For example, autoantibodies, such as those against RPA2, ATP2B4, and TUBB2C have been identified as atherosclerosis and/or CI markers [16, 17, 41]. The onset of CI may induce the spread of various antigens; however, antibodies against these antigens are not detectable until at least 2 weeks after disease onset.…”

“…Similar expression cloning was also applied to autoimmune diseases, such as systemic lupus erythematosus, Kawasaki disease, Behçet’s disease, and multiple sclerosis [36-39]. We used SEREX for atherosclerosis-related diseases and identified antibodies against RPA2 [16] and SOSTDC1 [40] in ischemic stroke, TUBB2C [41] and adiponectin in DM [22], and ATP2B4, BMP-1 [17], DHPS [42], SH3BP5 [43], GADD34 [44], and PRCP [45] in arteriosclerosis-related diseases. In the present study, we performed SEREX screening using sera from TIA patients to identify specific and novel biomarkers of TIA with the aim of early detection of TIA as well as prediction of CI onset.…”

Association of Serum Anti-Prolylcarboxypeptidase Antibody Marker with Atherosclerotic Diseases Accompanied by Hypertension

“…The following previously described blood test data were also included; total cholesterol (T-CHO), low-density lipoprotein cholesterol (LDL-C), potassium, high-density lipoprotein cholesterol, total protein, blood sugar, albumin, cholinesterase, sodium, uric acid, blood urea nitrogen, alkaline phosphatase, alanine aminotransferase, α-glutamyl transpeptidase, hemoglobin A1c, total bilirubin, chlorine, estimated glomerular filtration ratio, albumin/globulin ratio, creatinine, aspartate aminotransferase, triglyceride, and lactate dehydrogenase [25,26,[29][30][31]. The average values and SDs of these parameters are shown in Supplementary Table S1.…”

“…We also identified the following autoantibody-recognized antigens by recombinant cDNA expression cloning (SEREX) method or protein array method: TACSTD2 [12], TRIM21 [13], SLC2A1 [14], MKRN1 [15], ECSA [16], and CCNL2 [17] in esophageal squamous cell carcinoma; FIR/PUF60 in colon carcinoma [18]; SH3GL1 [19] and filamin C [20] in low-grade glioma; TLN1 in multiple sclerosis [21]; RPA2 [22] and SOSTDC1 [23] in ischemic stroke; NRD1 in acute coronary syndrome [24]; TUBB2C [25], GADD34 [26], and adiponectin [27] in DM; COPE in obstructive sleep apnea [28]; and ATP2B4 [29], BMP-1 [22,29], DHPS [30], and SH3BP5 [31] in arteriosclerosis-related diseases.…”