Biology subjects

Misaka, T.

Publications and source records attributed to Misaka, T..

3 recordsLinked to original sources

bioRxiv2026

TGM2-mediated histone serotonylation is an epigenetic cardioprotective mechanism in HFpEF

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with incompletely understood molecular mechanisms. Histone serotonylation is a recently identified epigenetic modification in which serotonin is covalently conjugated to glutamine 5 of histone H3 in H3K4me3-marked nucleosomes. Here, we investigated the role of transglutaminase 2 (TGM2)-mediated histone serotonylation in HFpEF. In a mouse model of HFpEF induced by salty drinking water, unilateral nephrectomy and aldosterone infusion (SAUNA), cardiac H3K4me3Q5ser and nuclear TGM2 levels were increased. Cardiomyocyte-specific TGM2-deficient mice developed aggravated HFpEF phenotypes after SAUNA exposure, including worsened diastolic dysfunction, reduced exercise capacity, pulmonary congestion and delayed cardiomyocyte relaxation. CUT&RUN sequencing identified H3K4me3Q5ser-enriched regions predominantly around transcription start sites after SAUNA exposure, with notable enrichment at genes associated with G2/M checkpoint-related stress-response signaling. RNA sequencing further showed that activation of this pathway was impaired in SAUNA-exposed TGM2-deficient hearts. In cardiac myocytes, calcium-binding sites and nuclear localization of TGM2 support checkpoint-related stress-response gene activation in cardiac myocytes. Pharmacological WEE1 inhibition, which activates downstream CDK1-associated checkpoint signaling, partially rescued the aggravated HFpEF phenotype in TGM2-deficient mice. Finally, in patients with HFpEF, lower circulating serotonin levels were associated with adverse cardiac outcomes, and cardiomyocyte H3K4me3Q5ser levels correlated with serum serotonin concentrations. These findings suggest that cardiomyocyte TGM2-mediated histone serotonylation represents a stress-adaptive, cardioprotective epigenetic mechanism in HFpEF.

pathology↗

bioRxiv2026

Macrophage extracellular traps promote maladaptive cardiac remodelling and heart failure via PAD4-dependent mechanisms

AimsThe activation of inflammatory cells, particularly macrophages, plays a pivotal role in the pathogenesis of cardiac remodelling and heart failure. Emerging evidence indicates that extracellular traps released from inflammatory immune cells contribute to the progression of various pathologies. However, the clinical relevance and mechanistic role of macrophage extracellular traps (METs) in heart failure remain to be elucidated. Methods and ResultsEndomyocardial biopsy specimens from 69 patients with heart failure were analysed by fluorescent immunostaining to identify and quantify METs. The numbers of METs per myocardial tissue area in patients with heart failure showed a negative correlation with left ventricular (LV) ejection fraction and a positive correlation with LV end-diastolic diameter. Patients with higher MET counts had significantly lower event-free survival from the composite cardiac events. In a murine model of pressure overload by transverse aortic constriction (TAC), METs were most abundantly observed at 3 days post-TAC and remained detectable throughout the 4-week observation period. In vitro, time-dependent MET formation was induced by an intrinsic trigger of mitochondrial DNA in bone marrow-derived macrophages from wild-type (WT) mice, but not in peptidyl arginine deiminase 4 (PAD4)-deficient macrophages, indicating that PAD4 activity is indispensable for MET formation. The recipient mice transplanted with bone marrow cells from PAD4 knockout mice showed more preserved cardiac function, reduced myocardial fibrosis, and improved survival in response to TAC, compared to those transplanted with WT mice. Ex vivo analyses demonstrated that conditioned medium containing METs from WT macrophages induced fibroblast-to-myofibroblast transition via Toll-like receptor 4 signalling. ConclusionsPAD4-dependent MET formation from bone marrow-derived macrophages represents a novel driver of cardiac remodelling. Targeting MET formation may offer a potential therapeutic strategy for heart failure. Translational PerspectiveMacrophage extracellular traps (METs) are abundant in myocardial tissue from patients with heart failure with reduced ejection fraction and are associated with adverse left ventricular remodelling and worse clinical outcomes. These findings support myocardial MET burden as a potential tissue biomarker to improve risk stratification in heart failure patients. In mice, pressure overload induces MET formation, and hematopoietic PAD4 deficiency suppresses myocardial METs, attenuates fibrosis, preserves cardiac function, and improves survival. Mechanistically, mitochondrial DNA-enriched cardiomyocyte-derived exophers trigger PAD4-dependent METs, which activate cardiac fibroblasts through TLR4 signalling. Suppressing METs represents a potential therapeutic strategy to attenuate the progression of heart failure. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/711858v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@11b9b57org.highwire.dtl.DTLVardef@17386f7org.highwire.dtl.DTLVardef@1a1f002org.highwire.dtl.DTLVardef@942bbc_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2025

The Renowned Flavor Compound Cinnamaldehyde Induces Sweet Taste by Targeting the Transmembrane Domain of T1R3 in the Sweet Taste Receptor

Numerous flavor compounds are known to evoke sweet taste sensations, yet their direct interaction with the sweet taste receptor remains poorly understood. Traditionally, flavor-induced sweetness was attributed to aromatic properties rather than the taste qualities of these compounds. This study aims to elucidate whether the sweet taste receptor mediates flavor-induced sweet sensations by investigating the agonistic activities of 94 flavor compounds on cultured cells expressing the sweet taste receptor (T1R2/T1R3). The results demonstrated that cinnamaldehyde (CA) and p-methoxycinnamaldehyde (PMCA) activate the sweet taste receptor. These compounds not only induce the receptor response but also enhance receptor activity when combined with various sweeteners or sweet proteins. Due to PMCAs structural similarity to lactisole, a well-known negative allosteric modulator (NAM) of the sweet taste receptor interacting with the transmembrane domain (TMD) of T1R3, CA and PMCA are hypothesized to interact with the T1R3 TMD as ago-PAMs (agonists and positive allosteric modulators). Mutational analyses confirmed that CA and PMCA interact with the T1R3 TMD, with distinct binding sites compared to lactisole. Additionally, because of structural parallels between PMCA and lactisole, we investigated the structure-activity relationships among 79 compounds to determine whether they function as ago-PAMs or NAMs. Most compounds acted as inhibitors, while those with specific planar structures acted as ago-PAMs. In conclusion, this study identified CA and PMCA as novel ago-PAMs that interact with the T1R3 TMD of the sweet taste receptor. These findings significantly advance our understanding of how flavor compounds influence sweet taste perception at the molecular level. Significance StatementNumerous flavor compounds evoke sweet taste sensations, yet their interaction with the sweet taste receptor is not well understood. This study identifies cinnamaldehyde (CA) and p-methoxycinnamaldehyde (PMCA) as activators of the sweet taste receptor, interacting with the transmembrane domain (TMD) of T1R3. CA and PMCA also act as positive allosteric modulators of other sweeteners (ago-PAMs). We discovered two binding sites in the T1R3 TMD, with CA and PMCA binding to different sites than lactisole, a known negative allosteric modulator. These findings identify CA and PMCA as novel ago-PAMs and significantly advance our understanding of how flavor compounds influence sweet taste perception at the molecular level.

molecular biology↗