Biology subjects

Hidaka, Y.

Publications and source records attributed to Hidaka, Y..

3 recordsLinked to original sources

bioRxiv2025

The coiled-coil domain of myosin-11 as a potential biomarker to detect patients with atherosclerotic cardiovascular disease risk

BackgroundAtherosclerosis leads to severe clinical complications, and biomarkers that could predict its progression are highly desired. Phenotypic changes and dysregulation of smooth muscle cells contribute substantially to both subclinical and clinical atherosclerosis. Plasma levels of myosin-11, a smooth muscle cell-specific myosin, have been reported to increase in patients with clinical manifestations of atherosclerosis, including coronary artery disease and/or peripheral artery disease. This study aimed to investigate the association between circulating myosin-11 levels and atherosclerotic cardiovascular disease (ASCVD) risk in patients without symptomatic atherosclerosis. Methods and resultsThis prospective study recruited 161 participants: 80 patients with either hypertension, dyslipidemia, or diabetes mellitus but without symptomatic atherosclerosis (ASCVD risk group); 50 patients with ischemic heart disease (IHD group); and 31 control participants (Controls). We developed rat monoclonal antibodies specific for the coiled-coil domain of myosin-11 and quantified circulating myosin-11 levels using an enzyme-linked immunosorbent assay with these antibodies. Myosin-11 levels were highest in the IHD group, followed by the ASCVD risk group. Both groups had significantly higher myosin-11 levels than Controls. The area under the receiver-operating characteristic curve of myosin-11 was 0.980 for IHD versus Controls and 0.874 for ASCVD risk versus Controls. Univariate analysis detected significant associations between myosin-11 levels and hypertension and age. The association between myosin-11 levels and hypertension remained significant after multivariate logistic regression analysis. ConclusionsCirculating myosin-11 levels are elevated in patients with ASCVD risk. Myosin-11 levels may be a useful biomarker for stratification of asymptomatic individuals with higher risk of ASCVD. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIWe developed a sandwich enzyme-linked immunosorbent assay (ELISA) consisting of rat monoclonal antibodies specific for the coiled-coil domain of myosin-11 to detect trace concentrations of myosin-11 in blood circulation. C_LIO_LIPlasma myosin-11 concentrations were elevated in both asymptomatic individuals with traditional risk factors for atherosclerotic cardiovascular disease and in patients with symptomatic coronary atherosclerosis. C_LIO_LIThis elevation may be a potential marker independent of other circulating biomarkers, traditional risk score, and non-invasive imaging analyses. C_LI What Are the Clinical Implications?O_LICirculating myosin-11 may serve as a potential biomarker for identifying dysregulation of arterial smooth muscle cells during the progression of atherosclerosis. C_LIO_LIFurther studies are warranted to evaluate whether myosin-11 levels, in combination with other reported biomarkers and risk scores, could aid in stratification of asymptomatic individuals with higher risk of ASCVD. C_LI

biochemistry↗

bioRxiv2023

Spatiotemporal EP4-fibulin-1 expression is associated with vascular intimal hyperplasia

AimsCyclooxygenase-2- and microsomal prostaglandin E synthase-1-derived prostaglandin E2 (PGE2) are involved in vascular intimal hyperplasia (IH). Although extensive studies have revealed the roles of PGE2 receptors (EPs) in IH, spatiotemporal EP expressions and downstream targets have not been fully elucidated. In this study, we focused on EP4 and investigated its role in vascular IH. Methods and ResultsWe generated EP4 reporter mice (Ptger4-IRES-nlsLacZ) and found prominent EP4 expression in the proliferative neointima 2 weeks after femoral artery wire injury. Expression of EP4 were returned to the baseline level 4 weeks after vascular injury (VI). Injury-induced IH was diminished in vascular smooth muscle cell (VSMC)-specific EP4 heterozygous deficient mice (Ptger4fl/+;SM22-Cre) 2 and 4 weeks after VI compared to SM22-Cre, whereas injury-induced IH was exacerbated in VSMC-specific EP4-overexpressing mice (Ptger4-Tg) compared to controls (non-Tg). Systemic EP4 antagonist administration reduced VI-induced IH in wild-type mice. We investigated the role of extracellular matrix proteins, as downstream regulated targets of EP4. Stimulation of EP4 increased mRNA and protein levels of fibulin-1 (a multifunctional glycoprotein) in Ptger4-Tg VSMCs. Fibulin-1C or -1D recombinant proteins increased VSMC proliferation, whereas proliferation was decreased in fibulin-1-deficient VSMCs. We generated multiple deletion mutants of fibulin-1C and found that EGF-like modules 6-8 appear to be involved in fibulin-1-mediated proliferation. Among binding partners of fibulin-1, extracellular matrix protein 1 (ECM1) was upregulated by EP4 stimulation, and fibulin-1 and ECM1 proteins additively enhanced VSMC proliferation. Similar to EP4 expression, both fibulin-1 and ECM1 were abundantly expressed in the neointima 2 weeks after VI. Furthermore, injury-induced IH was attenuated in VSMC-specific fibulin-1 deletion mice (Fbln1fl/fl;SM22-Cre) compared to Fbln1fl/fl. ConclusionsEP4 was upregulated in proliferative IH, and EP4-induced fibulin-1 cooperated with ECM1 to promote IH through VSMC proliferation. The calcium binding EGF-like modules 6-8 of fibulin-1 are indicated to regulate cell proliferation. A Translational PerspectiveRecent advances in drug-eluting stents have significantly contributed to the reduction of vascular IH. However, the detailed mechanism underlying IH after stenting remains to be elucidated. We found that prostaglandin E2-EP4-induced fibulin-1 plays a role in IH through VSMC proliferation. It is well recognized that prostaglandin E2 plays a role in IH, but inhibition of cyclooxygenase-2 has side effects such as thrombogenesis. Because EP4 and fibulin-1 were upregulated specifically in the neointima after vascular injury, oral or local administration of an EP4 antagonist or the downregulation of fibulin-1 would be potential therapeutic strategies to restrain IH.

physiology↗

bioRxiv2022

Delayed antigen-specific CD4+ T cell induction correlates with impaired immune responses to SARS-COV-2 mRNA vaccination in the elderly

Despite the clinical efficacy of coronavirus disease 2019 mRNA vaccines, the elderly demonstrate lower IgG levels and neutralizing titers and a higher risk of severe diseases. CD4+ T cells play a central role in regulating antigen-specific antibody and CD8+ T-cell responses; however, because their composition and functionality change significantly with age, relationships between age-associated defects in T cells and the immunogenicity of or reactogenicity to mRNA vaccines are unclear. Using a vaccine cohort (n = 216), we found that the elderly (aged [≥]65 years) showed delayed induction and early contraction of vaccine-specific CD4+ T cells, and that the compromised C-X-C motif chemokine receptor 3+ circulating T follicular helper cell response after the first dose was associated with the lower IgG levels. Additionally, the elderly experienced significantly fewer systemic adverse effects (AEs) after the second dose, with those exhibiting few AEs showing lower cytokine+ CD4+ T cells after the first dose and lower antibody levels after the second dose. Furthermore, T helper 1 cells in the elderly expressed higher levels of programmed cell death protein-1, a negative regulator of the T-cell response, which was associated with less production of vaccine-specific CD4+ T cells and impaired CD8+ T-cell expansion. Thus, efficient induction of vaccine-specific effector/memory CD4+ T cells after the first dose may trigger robust cytokine production after the second dose, leading to effective vaccine responses and higher systemic reactogenicity. These results suggested that an enhanced CD4+ T-cell response after the first dose is key to improved vaccination efficacy in the elderly. One Sentence SummaryWe compared immunogenicity and reactogenicity to COVID-19 mRNA vaccine in 107 adults (aged <65 years) and 109 elderly (aged [≥]65) individuals.

immunology↗