Biology subjects

Nattel, S.

Publications and source records attributed to Nattel, S..

7 recordsLinked to original sources

bioRxiv2025

Network-Based Analysis of Human Astrocytes Links Aging to Neurodegenerative and Cardiovascular Diseases

Astrocytes are central to brain homeostasis, supporting neuronal metabolism, synaptic activity, and the blood-brain barrier. With aging, these glial cells undergo molecular and functional changes that weaken support functions and promote neuroinflammation, contributing to neurodegeneration. Yet the systems-level mechanisms of astrocytic aging remain poorly defined in human models. Because aging also heightens risk for cardiovascular disease, cognitive impairment, type 2 diabetes, and systemic inflammation, clarifying shared astrocytic pathways is critical for understanding brain-body crosstalk. Using an in vitro human astrocyte model exposed to sublethal oxidative stress (10 {micro}M H2O2), we profiled transcriptomic changes and identified differentially expressed genes across antioxidant defences, proteostasis, transcriptional regulation, vesicular trafficking, and inflammatory signalling. We then performed seven network-prioritization analyses on a curated human protein-protein interactome: one seeded with the astrocyte H2O2-responsive genes and six with phenotype-associated gene sets (Alzheimers disease, cardiovascular disease, cognitive impairment, type 2 diabetes, oxidative stress, and inflammation). Intersecting the top 5% scoring genes from each run yielded a 127-gene core shared across all seven, enriched for proteostasis, DNA repair, mitochondrial regulation, and telomere and nuclear envelope maintenance. Structure-guided analyses highlighted vulnerable interfaces, including lamin A/C-lamin B1, -actinin-filamins, 14-3-3 dimers, and aminoacyl-tRNA synthetase assemblies, where pathogenic variants are predicted to destabilize or aberrantly stabilize protein interactions. Structure-based interface predictions also highlight potential interactions between APP-VCP/p97 and p53-14-3-3{zeta} that link proteostasis and stress signalling. Together, these findings define a conserved astrocytic vulnerability network that may couple neurodegeneration with cardiovascular disease and nominate structurally testable targets for biomarkers and interventions.

bioinformatics↗

bioRxiv2025

Resistance to Atrial Fibrillation Domestication and Mitochondrial Dysfunction in Sheep: a potential key role of the TCA Cycle and mitochondrial redox state

BackgroundAtrial fibrillation (AF) often progresses from paroxysmal to more stable forms. It is well-recognized that patients vary in their AF progression, but underlying mechanisms remain unclear. This work, performed in a sheep AF-model, aimed to identify atrial redox and energetic status differences between animals developing stable AF (AF-S) versus those resistant to AF-stabilization (AF-R). MethodsAF was monitored with telemetry and maintained with bursts of atrial tachystimulation whenever sinus rhythm resumed. Electrophysiological remodeling was assessed via contact mapping. Structural remodeling was described by histology. Proteomic, metabolomic, enzymatic and bioenergetic remodeling were evaluated using frozen left atrial appendage (LAA) tissues and isolated LAA mitochondria. Healthy young rats were used to investigate if an induced metabolic challenge could stabilize AF episodes upon transesophageal atrial tachypacing challenge. ResultsAF-S sheep developed stable AF (>24-hours self-sustained) after 13 days on average, whereas AF-R sheep failed to develop self-sustained AF despite 120 days of electrically-maintained AF. Contact mapping and histological analysis revealed similar electro-structural remodeling in both groups. Metabolic analysis showed significant differences in tricarboxylic acid (TCA) cycle enzymes activities and a 45% increase in AF-S LAA succinate content versus AF-R. AF-S mitochondria showed abnormal mitochondrial succinate oxidation, associated with a significant 20% decrease in ATP synthesis rate, 22% increase in ROS emission and mitochondrial inner membrane hyperpolarization. The ratios of ATP to ADP, NAD+ to NADH, and Complex I/II were disturbed in AF-S compared to AF-R. Calculated mitochondrial NAD+ to NADH ratios suggest a reduced state of in-vivo AF-R mitochondria compared to the oxidized state of AF-S. Exogenous succinate was metabolized when incubated with rat atrial cardiomyocytes and altered redox balance, while intravenous succinate stabilized atrial arrhythmias induced by tachypacing in vivo. ConclusionsSheep resistant to AF-progression showed specific TCA cycle, energetic and redox adaptations compared to animals that developed self-sustained AF. In this animal model, mitochondrial TCA cycle remodeling and associated redox and energetic responses determined the resistance to AF domestication, with potential relevance to identify new mechanistic determinants of AF progression in humans.

pathology↗

bioRxiv2025

Time-dependent Mitochondrial Remodeling in Experimental Atrial Fibrillation and Potential Therapeutic Relevance

BACKGROUNDChanges in mitochondria have been implicated in atrial fibrillation (AF), but their manifestations and significance are poorly understood. Here, we studied changes in mitochondrial morphology and function during AF and assessed the effect of a mitochondrial-targeted intervention in a large animal model. METHODS AND RESULTSAtrial cardiomyocytes (ACMs) were isolated from dogs in electrically-driven AF for periods of 24 hours to 3 weeks and from humans with/without longstanding persistent AF. Mitochondrial Ca2+-concentration ([Ca2+]Mito), reactive oxygen species (mtROS) production, membrane potential ({Delta}{Psi}m), permeability transition-pore (mPTP) opening and flavin adenine dinucleotide (FAD) were measured via confocal microscopy; nicotine adenine dinucleotide (NADH) under ultraviolet light. mtROS-production increased within 24 hours and superoxide-dismutase type-2 was significantly reduced from 3-day AF. [Ca2+]Mito and mPTP-opening frequency/duration increased progressively during AF. Mitochondrial depolarization was detectable 24 hours after AF-onset. NADH increased by 15% at 24-hour AF, concomitant with increased pyruvate-dehydrogenase expression, then gradually decreased. Mitochondria enlarged and elongated at 24-hour and 3-day AF, followed by progressive fragmentation, rupture and shrinkage. Mitochondrial fusion protein-1 (MFN1) was reduced from 3-day to 3-week AF and phosphorylated dynamin-related protein-1 (p-DRP1ser-616) increased after 1 week of canine AF and in human AF. Addition of the mitochondrial antioxidant MitoTempo attenuated action-potential shortening and L-type Ca2+-current (ICaL)-downregulation in canine and human AF ACMs in vitro. Administration of the orally-active mitochondrial-targeted ubiquinone mitoquinone to dogs during 3-week AF prevented mitochondrial Ca2+-overload, mtROS-overproduction, structural damage and abnormalities in {Delta}{Psi}m and respiration. Functionally, mitoquinone reduced AF-induced Ca2+-current downregulation, action-potential abbreviation, contractile dysfunction and fibrosis, preventing AF-substrate development and AF-sustainability. CONCLUSIONSMitochondria show a series of changes during AF, with early hyperfunction and enhanced ROS-generation, followed by progressive damage and dysfunction. Mitochondrial-targeted therapy prevents mitochondrial dysfunction and attenuates adverse AF-related remodeling, positioning mitochondrial protection as a potential novel therapeutic target in AF.

pathology↗

bioRxiv2023

Revealing Shared Proteins and Pathways in Cardiovascular and Cognitive Diseases Using Protein Interaction Network Analysis

One of the primary goals of systems medicine is detecting putative proteins and pathways involved in disease progression and pathological phenotypes. Vascular Cognitive Impairment (VCI) is a heterogeneous condition manifesting as cognitive impairment resulting from vascular factors. The precise mechanisms underlying this relationship remain unclear, which poses challenges for experimental research. Here, we applied computational approaches like systems biology to unveil and select relevant proteins and pathways related to VCI by studying the crosstalk between cardiovascular and cognitive diseases. In addition, we specifically included signals related to oxidative stress, a common etiologic factor tightly linked to aging, a major determinant of VCI. Our results show that pathways associated with oxidative stress are quite relevant, as most of the prioritized vascular-cognitive genes/proteins were enriched in these pathways. Our analysis provided a short list of proteins that could be contributing to VCI: DOLK, TSC1, ATP1A1, MAPK14, YWHAZ, CREB3, HSPB1, PRDX6, and LMNA. Moreover, our experimental results suggest a high implication of glycative stress, generating oxidative processes and post-translational protein modifications through advanced glycation end-products (AGEs). We propose that these products interact with their specific receptors (RAGE) and Notch signaling to contribute to the etiology of VCI.

systems biology↗

bioRxiv2023

Spatial autocorrelation dimension as a potential determinant for the temporal persistence of human atrial and ventricular fibrillation.

Background: Despite being central to atrial fibrillation (AF) and ventricular fibrillation (VF) mechanisms and therapy, the factors governing AF and VF termination are poorly understood. It has been noted that ratio of system size (L) and the two-point spatial correlation length ({xi}2) are associated with time until termination in transient spatiotemporally chaotic systems, but the relationship between these characteristics and termination has not been systematically studied in human AF and VF. Objective: We aimed assess whether the time to cardiac fibrillation termination can be predicted using a novel estimator, the spatial autocorrelation dimension (Di), defined as the ratio of L and {xi}2, in human AF and VF. Methods: Di was computed and compared in a multi-centre, multi-system study with data for sustained versus spontaneously terminating human AF/VF. VF data was collected during coronary-bypass surgery; and AF data during clinically indicated AF ablation. We analyzed: i) VF mapped using a 256-electrode epicardial sock (n=12pts); ii) AF mapped using a 64-electrode constellation basket-catheter (n=15pts); iii) AF mapped using a 16-electrode HD-grid catheter (n=42pts). To investigate temporal fibrillation persistence, the response of AF-episodes to flecainide (n=7pts) was also studied. Results: Spontaneously terminating fibrillation demonstrated a lower Di (P<0.001 all systems). Lower Di was also seen in paroxysmal compared to persistent AF (P=0.002). Post-flecainide, Di decreased over time (P<0.001). Lower Di was also associated with longer-lasting episodes of AF/VF (R2>0.90, P<0.05 in all cases). Using k-means clustering, two distinct clusters and their centroids were identified i) a cluster of spontaneously terminating episodes, and ii) a cluster of sustained epochs. Conclusion: Di predicts the temporal persistence of cardiac fibrillation. This finding provides potentially important insights into a possible common pathway to termination and therapeutic approaches.

physiology↗

bioRxiv2021

Transcriptomic profiling of atrial fibrillation canine models at disease onset

BackgroundAtrial fibrillation (AF), the most common sustained arrhythmia, is associated with increased morbidity, mortality, and health-care costs. AF develops over many years and is often related to substantial atrial structural and electrophysiological remodeling. AF may lack symptoms at onset and atrial biopsy samples are generally obtained in subjects with advanced disease, so it is difficult to study earlier-stage pathophysiology in humans. MethodsHere, we characterized comprehensively the transcriptomic (miRNAseq and mRNAseq) changes in the left atria of two robust canine AF-models after one week of electrically-maintained AF, without or with ventricular rate-control via atrioventricular node-ablation/ventricular pacing. ResultsOur RNA-sequencing experiments identified thousands of genes that are differentially expressed, including a majority that have never before been implicated in AF. Gene-set enrichment analyses highlighted known (e.g. extracellular matrix structure organization) but also many novel pathways (e.g. muscle structure development, striated muscle cell differentiation) that may play a role in tissue remodeling and/or cellular transdifferentiation. Of interest, we found dysregulation of a cluster of non-coding RNAs, including many microRNAs but also the MEG3 long non-coding RNA orthologue, located in the syntenic region of the imprinted human DLK1-DIO3 locus. Interestingly (in the light of other recent observations), our analysis identified gene-targets of differentially expressed microRNAs at the DLK1-DIO3 locus implicating glutamate signaling in AF pathophysiology. ConclusionsOur results capture molecular events that occur at an early stage of disease development using well-characterized animal models, and may therefore inform future studies that aim to further dissect the causes of AF in humans.

genomics↗

bioRxiv2019

Renewal theory provides a universal quantitative framework to characterise the continuous regeneration of rotational events in cardiac fibrillation

BackgroundCardiac fibrillation is thought to be maintained by rotational activity, with pivoting regions called phase singularities (PSs). Despite a century of research, no clear quantitative framework exists to model the fundamental processes responsible for the continuous formation and destruction of rotors in fibrillation.\n\nObjectiveWe conducted a multi-modality, multi-species study of AF/VF under the hypothesis that PS formation/destruction in fibrillation can be modelled as self-regenerating renewal processes, producing exponential distributions of inter-event times governed by constant rate-parameters defined by the prevailing properties of the system.\n\nMethodsPS formation/destruction was studied and cross-validated in 5 models, using basket recordings and optical mapping from: i) human persistent AF (n = 20), ii) tachypaced sheep AF (n = 5), iii) rat AF (n = 4), iv) rat VF (n = 11) and v) computer simulated AF (SIM). Hilbert phase maps were constructed. PS lifetime data were fitted by exponential probability distribution functions (PDFs) computed using maximum entropy theory, and the rate parameter ({lambda}) determined. A systematic review was conducted to cross-validate with source data from literature.\n\nResultsPS destruction/formation distributions showed good fits to an exponential in all systems (R2 [≥] 0.90). In humans,{lambda} = 4.6%/ms (95%CI,4.3,4.9)), sheep 4.4%/ms (95%CI,4.1,4.7)), rat AF 38%/ms (95%CI,22,55), rat VF 46%/ms (95%CI,31.2,60.2) and SIM 5.4%/ms (95%CI,4.1,6.7). All PS distributions identified through systematic review were exponential with {lambda} comparable to experimental data.\n\nConclusionThese results provide a universal quantitative framework to explain rotor formation and destruction in AF/VF, and a platform for therapeutic advances in cardiac fibrillation.

physiology↗