👤 Taeko K Naruse

The global distribution of lipoprotein(a) [Lp(a)] levels varies due to racial and ethnic differences. However, the clinical relevance of Lp(a) levels in Japanese patients has not been fully explored. We investigated the association of Lp(a) levels, the Suita score, and the presence of high-risk plaque (HRP) as well as that of ≥ 50% stenosis, quantitative plaque volume, and the value of coronary artery calcium score in coronary computed tomographic angiography (CCTA), among 272 Japanese patients (mean age: 65 years) in whom serum Lp(a) levels were measured due to suspected coronary artery disease. HRP was defined as positive remodeling and/or low attenuation. Plaque volume was quantified as the percent plaque volume. HRP was identified in 33 (12.1%) patients. The prevalence of HRP, ≥ 50% stenosis, and percent plaque volume progressively increased with higher Lp (a) levels and Suita scores. In multivariate analyses, Lp(a) and the Suita score independently predicted HRP when assessed as continuous (p = 0.02, p＜0.001, respectively) or categorical variables (p = 0.005, p = 0.007, respectively). Patients in the highest tertile of Lp(a) and classified as high- or intermediate-risk by the Suita score had the highest HRP risk, whereas those in the lower 2 tertiles and low-risk group had the lowest. Incorporating Lp(a) into the Suita score improved the prediction of HRP beyond the Suita score alone (p = 0.005). The combinatorial value of assessing Lp(a) levels and Suita score may provide useful insight regarding Japanese patients undergoing CCTA for the prediction of HRP. Show less

Angiopoietin-like protein 4 (ANGPTL4) is produced in chronic or acute inflammation. Although ANGPTL4 increases in the periodontal ligament fibroblasts during hypoxia, the involvement and role of ANGPTL4 in periodontitis have not been elucidated. In this study, we investigated whether ligature-induced experimental periodontitis and/or Porphyromonas gingivalis lipopolysaccharides (Pg-LPS) would upregulate ANGPTL4 expression and whether ANGPTL4 would somehow involve in the expression of matrix metalloproteinases (MMPs) which are key molecules in the process of periodontal tissue destruction. Experimental periodontitis was induced in 6-week-old male Sprague-Dawley rats by placing a nylon suture around the neck of the maxillary second molar. Two weeks after the induction of periodontitis, the periodontal tissue was excised and analyzed by histological/immunohistochemical staining and gene expression analyses. Human gingival fibroblasts (hGFs) were stimulated with Pg-LPS. The gene expression of ANGPTLs and receptors involved in ANGPTL4 recognition were observed. We also confirmed the changes in gene expression of MMPs upon stimulation with human ANGPTL4. Furthermore, we downregulated ANGPTL4 expression by short interfering RNA in hGFs and investigated the effect of Pg-LPS on MMP production. Induction of periodontitis significantly increased the expression of ANGPTL4 in the gingiva. Pg-LPS significantly increased the gene and protein expression of ANGPTL4 in hGFs but not the gene expression of other ANGPTLs or ANGPTL receptors. Recombinant human ANGPTL4 significantly increased MMP13 gene expression in hGFs. We also confirmed that MMP13 expression was increased in the gingiva during experimental periodontitis. Pg-LPS induced MMP13 gene expression in hGFs. These results suggest the pivotal role of ANGPTL4 in periodontitis. Periodontitis increases ANGPTL4 expression in the gingiva, further suggesting that increased ANGPTL4 may be a factor involved in enhancing MMP13 expression. Show less

Glucose-dependent insulinotropic polypeptide (GIP) exerts extra-pancreatic effects via the GIP receptor (GIPR). Herein, we investigated the effects of GIP on force-induced bone remodeling by orthodontic tooth movement using a closed-coil spring in GIPR-lacking mice (GIPRKO) and wild-type mice (WT). Orthodontic tooth movements were performed by attaching a 10-gf nickel titanium closed-coil spring between the maxillary incisors and the left first molar. Two weeks after orthodontic tooth movement, the distance of tooth movement by coil load was significantly increased in GIPRKO by 2.0-fold compared with that in the WT. The alveolar bone in the inter-root septum from the root bifurcation to the apex of M1 decreased in both the GIPRKO and WT following orthodontic tooth movement, which was significantly lower in the GIPRKO than in the WT. The GIPRKO exhibited a significantly decreased number of trabeculae and increased trabecular separation by orthodontic tooth movement compared with the corresponding changes in the WT. Histological analyses revealed a decreased number of steady-state osteoblasts in the GIPRKO. The orthodontic tooth movement induced bone remodeling, which was demonstrated by an increase in osteoblasts and osteoclasts around the forced tooth in the WT. The GIPRKO exhibited no increase in the number of osteoblasts; however, the number of osteoclasts on the coil-loaded side was significantly increased in the GIPRKO compared with in the WT. In conclusion, our results demonstrate the impacts of GIP on the dynamics of bone remodeling. We revealed that GIP exhibits the formation of osteoblasts and the suppression of osteoclasts in force-induced bone remodeling. Show less

Ablation of short single cones (SSCs) expressing short-wavelength-sensitive opsin (SWS1) is well analyzed in the field of regenerative retinal cells. In contrast with ablation studies, the phenomena caused by the complete deletion of SWS1 are less well-understood. To assess the effects of SWS1 deficiency on retinal structure, we established and analyzed sws1-mutant medaka. To visualize SWS1, a monoclonal anti-SWS1 antibody and transgenic reporter fish (Tg(sws1:mem-egfp)) were generated. We also developed a CRISPR/Cas-driven sws1-mutant line. Retinal structure of sws1 mutant was visualized using anti-SWS1, 1D4, and ZPR1 antibodies and coumarin derivatives and compared with wild type, Tg(sws1:mem-egfp), and another opsin (lws) mutant. Our rat monoclonal antibody specifically recognized medaka SWS1. Sws1 mutant retained regularly arranged cone mosaic as lws mutant and its SSCs had neither SWS1 nor long wavelength sensitive opsin. Depletion of sws1 did not affect the expression of long wavelength sensitive opsin, and vice versa. ZPR1 antibody recognized arrestin spread throughout double cones and long single cones in wild-type, transgenic, and sws1-mutant lines. Comparative observation of sws1-mutant and wild-type retinas revealed that ZPR1 negativity is not a marker for SSCs with SWS1, but SSCs themselves. Loss of functional sws1 did not cause retinal degeneration, indicating that sws1 is not essential for cone mosaic development in medaka. Our two fish lines, one with visualized SWS1 and the other lacking functional SWS1, offer an opportunity to study neural network synapsing with SSCs and to clarify the role of SWS1 in vision. Show less

There is an overlap between the physiological cardiac remodeling associated with training in athletes, the so-called athlete's heart, and mild forms of hypertrophic cardiomyopathy (HCM), the most common hereditary cardiac disease. HCM is often accompanied by unfavorable outcomes including a sudden cardiac death in the adolescents. Because one of the initial signs of HCM is abnormality in electrocardiogram (ECG), athletes may need to monitor for ECG findings to prevent any unfavorable outcomes. HCM is caused by mutations in genes for sarcomere proteins, but there is no report on the systematic screening of gene mutations in athletes. One hundred and two genetically unrelated young Japanese athletes with abnormal ECG findings were the subjects for the analysis of four sarcomere genes, MYH7, MYBPC3, TNNT2 and TNNI3. We found that 5 out of 102 (4.9%) athletes carried mutations: a heterozygous MYH7 Glu935Lys mutation, a heterozygous MYBPC3 Arg160Trp mutation and another heterozygous MYBPC3 Thr1046Met mutation, all of which had been reported as HCM-associated mutations, in 1, 2 and 2 subjects, respectively. This is the first study of systematic screening of sarcomere gene mutations in a cohort of athletes with abnormal ECG, demonstrating the presence of sarcomere gene mutations in the athlete's heart. Show less

Signals from extraembryonic tissues in mice determine which proximal epiblast cells become primordial germ cells (PGCs). After their specification, approximately 40 PGCs appear at the base of the allantoic bud and migrate to the genital ridges, where they expand to about 25 000 cells by Embryonic Day (E)13.5. The heterochromatin protein 1 (HP1) family members HP1alpha, HP1beta, and HP1gamma (CBX5, CBX1, and CBX3, respectively) are thought to induce heterochromatin structure and to regulate gene expression by binding methylated histone H3 lysine 9. We found a dramatic loss of germ cells before meiosis in HP1gamma mutant (HP1gamma(-/-)) mice that we generated previously. The reduction in PGCs in HP1gamma(-/-) embryos was detectable from the early bud stage (E7.25), and the number of HP1gamma(-/-) PGCs was gradually reduced thereafter. Bromodeoxyuridine incorporation into PGCs was significantly reduced in E7.25 and E12.5 HP1gamma(-/-) embryos. Furthermore, a lower proportion of HP1gamma(-/-) PGCs than wild-type PGCs was in S phase, and a higher proportion, respectively, was in G1 phase at E12.5. Moreover, the proportion of p21 (Cip, official symbol CDKN1A)-positive HP1gamma(-/-) PGCs was increased, suggesting that the G1/S phase transition was inhibited. However, no differences were detected between fate determination, migration, apoptosis, or histone modification of PGCs of control embryos and those of HP1gamma(-/-) embryos. Therefore, the reduction in PGCs in HP1gamma(-/-) embryos could be caused by impaired cell cycle in PGCs. These results suggest that HP1gamma plays an important role in keeping enough germ cells by regulating the PGC cell cycle. Show less