Biology subjects

Thireau, J.

Publications and source records attributed to Thireau, J..

5 recordsLinked to original sources

bioRxiv2026

RyR2-Dependent Calcium Leak Drives the Acute Cardiovascular Manifestations of Ciguatera Poisoning: implications for an emerging climate-sensitive cardiotoxic disease

Background: Ciguatera is the most prevalent non-bacterial seafood poisoning worldwide. It results from the consumption of fish contaminated with ciguatoxins (CTXs). Cardiovascular manifestations are frequently reported in affected patients; however, the molecular mechanisms underlying CTX-induced cardiac dysfunction remain poorly understood. Methods: We investigated the effects of purified CTX-1B and CTX-3C on human induced pluripotent stem-cell-derived ventricular cardiomyocytes. Electrophysiology, intracellular calcium cycling and contractility, and cellular structure were assessed. The RyR2 channel activity was studied in planar lipid bilayers, and molecular docking was used to identify a potential CTX-1B interaction site. Consequences on cardiac function were assessed in rats using echocardiography and EKG. Findings: We found that ciguatoxin exposure rapidly increased diastolic intracellular calcium, with severe impacts on the cardiac excitation-contraction coupling, and caused sarcomeric disorganization in human cardiomyocytes. Single-channel recordings indicated that CTX-1B prolonged RyR2 openings at resting cytosolic calcium and altered ATP-dependent gating. These findings are consistent with a state-dependent remodeling of RyR2 gating rather than uniform potentiation. Docking placed CTX-1B within the RyR2 transmembrane region, near ATP-associated regulatory elements. In rats, CTX-1B caused premature atrial contractions, ventricular ectopy, and acute cardiac dysfunction, with impaired relaxation. Interpretation: These findings identify RyR2-dependent calcium leak as a plausible contributor to ciguatoxin cardiotoxicity and extend the established model based on sodium-channel activation and altered sarcolemmal ion handling. Combined disruption of membrane excitability and intracellular calcium release could explain the rapid electrical and mechanical abnormalities associated with ciguatera. As intensive international shipping traffic and the global dispersal of harmful microalgae via ballast water expand exposure risk alongside the international seafood trade, ciguatera should be considered an emerging global cardiovascular hazard.

physiology↗

bioRxiv2026

A novel mouse model of hypertensive emergency with multiorgan microvascular disease implicating the VEGFA/sFlt-1 balance

BackgroundHypertensive emergency (HTEM) is defined by abrupt blood pressure elevation with acute multi-organ damage, yet the mechanisms predisposing only a subset of hypertensive individuals to HTEM remain unclear. Progress has been limited by the lack of a mouse model that faithfully replicates human disease. We aimed to identify determinants of susceptibility to hypertensive microvascular injury and characterize a murine model of HTEM. MethodsMale C57BL/6J (B6J) and 129S2/SvPasCrl (129Sv) mice were exposed to severe hypertension via angiotensin II infusion combined with a high-salt diet. We assessed survival, renal and retinal injury, cardiac function and electrophysiology, vascular permeability, circulating angiogenic factors, and glomerular transcriptional profiles using single-cell RNA sequencing. Bone marrow transplantation and recombinant human PlGF-2 treatment were used to investigate mechanisms driving endothelial injury. ResultsDespite comparable blood pressure, 129Sv mice, but not B6J, developed malignant hypertension with albuminuria, acute kidney injury, retinal hemorrhages, microvascular leakage, cardiac dysfunction, and arrhythmias. Hypertensive 129Sv mice exhibited markedly elevated circulating sFlt-1. PlGF-2 supplementation partially reversed albuminuria, preserved glomerular ultrastructure, and reduced retinal hemorrhages. Bone marrow transfers revealed contributions from both hematopoietic and non-hematopoietic 129Sv compartments to sFlt-1 overproduction and organ injury. Single-cell transcriptomics revealed profound repression of angiogenic, metabolic, and stress-response pathways in glomerular endothelial cells, a repression partially restored by PlGF-2. ConclusionsWe identify 129Sv mice as a robust model of HTEM, exhibiting multi-organ microvascular injury that closely mirrors the human condition. Our results reveal blood-pressure-independent susceptibility to organ damage and implicate dysregulated VEGFA/sFlt-1 signaling as a central driver of endothelial dysfunction, highlighting angiogenic imbalance as a potential therapeutic target.

pathology↗

bioRxiv2022

The autism-associated Meis2 gene is necessary for cardiac baroreflex regulation in mice

Recent understanding of Autism Spectrum Disorder (ASD) showed that peripheral primary mechanosensitive neurons involved in touch sensation and central neurons affected in ASD share transcriptional regulators. Mutant mice for ASD-associated transcription factors exhibit impaired primary tactile perception, and restoring those genes specifically in primary sensory neurons rescue some of the anxiety-like behavior and social interaction defects. Interestingly, peripheral mechanosensitive sensory neurons also project to internal organs including the cardio-vascular system, and an imbalance of the cardio-vascular sympatho-vagal regulation is evidenced in ASD and intellectual disability. ASD patients have decreased vagal tone, suggesting dysfunction of sensory neurons involved in cardio-vascular sensing. In light of our previous finding that the ASD-associated Meis2 gene is necessary for normal touch neurons development and function, we investigated here if its inactivation in mouse peripheral sensory neurons also affects cardio-vascular sympatho-vagal regulation and baroreflex. Combining echocardiography, pharmacological challenge, blood pressure monitoring and heart rate variability analysis, we found that Meis2 mutant mice exhibited a blunted vagal response independently of any apparent cardiac malformation. These results suggest that defects in primary sensory neurons with mechanosensitive identity could participate in the imbalanced cardio-vascular sympatho-vagal tone found in ASD patients, reinforcing current hypotheses on the role of primary sensory neurons in the etiology of ASD.

physiology↗

bioRxiv2022

High-Resolution Ultrasound and Speckle Tracking: a non-invasive approach to assess in vivo gastrointestinal motility during development

Gastrointestinal motor activity has been extensively studied in adults, conversely only few studies have investigated fetal motor skills. When the gastrointestinal tract starts to contract during the embryonic period and how this function evolves during development are not known. Here, we adapted a non-invasive high-resolution echography technique combined with speckle tracking analysis to examine the gastrointestinal tract motor activity dynamics during chick embryo development. We provided the first recordings of fetal gastrointestinal motility in living embryos. We found that although gastrointestinal contractions appear very early during development, they become synchronized only at the end of the fetal period. To validate this approach, we used various pharmacological inhibitors and BAPX1 gene overexpression in vivo. We found that the enteric nervous system determinates the onset of the synchronized contractions in the stomach. Moreover, alteration of smooth muscle fiber organization led to an impairment of this functional activity. Altogether, our findings show that non-invasive high-resolution echography and speckle tracking analysis allow visualizing and quantifying gastrointestinal motility during development and highlight the progressive acquisition of functional and coordinated gastrointestinal motility before birth.

developmental biology↗

bioRxiv2022

Characterization of the adult zebrafish electrocardiogram

BackgroundThe use of zebrafish to explore cardiac physiology has been widely adopted within the scientific community. Whether this animal model can be used to determine drug cardiac toxicity via electrocardiogram (ECG) analysis, is still an ongoing question. Several reports indicate that the recording configuration severely affects the ECG waveforms and its derived-parameters, emphasizing the need for improved characterization. MethodsECGs were recorded from adult zebrafish hearts in 3 different configurations (unexposed heart, exposed heart and extracted heart) to identify the most reliable method to explore ECG recordings at baseline and in response to commonly used clinical therapies. ResultsWe found that the exposed heart configuration provided the most reliable and reproducible ECG recordings of waveforms and intervals. We were unable to determine T-wave morphology in unexposed hearts. In extracted hearts, ECG intervals were lengthened and P-waves were unstable. However, in the exposed heart configuration, we were able to reliably record ECGs and subsequently establish the QT-RR relationship (Holzgrefe correction) in response to changes in heart rate. ConclusionsThe exposed heart configuration appears to be the most reliable technique to record ECGs in adult zebrafish. In this configuration, the QT-RR relationship, an important parameter in cardiac toxicity evaluation, can be determined using the Holzgrefe correction.

physiology↗