Biology subjects

Reverte-Salisa, L.

Publications and source records attributed to Reverte-Salisa, L..

3 recordsLinked to original sources

bioRxiv2026

Activation of perivascular thermogenic fat improves aortic stenosis

Aim: Aortic stenosis (AS) is a common condition with exponential increases in incidence in aging populations. Perivascular adipose tissue (PVAT) forms the outer layer of the aortic wall and has - especially in the thoracic area - characteristics of thermogenic adipose tissue, which dissipates energy and releases endocrine factors. Here, we set out to investigate the role of thermogenic PVAT in AS. Methods and results: We studied the role of (PVAT) in the development of AS in a murine model of AS. To specifically delineate the role of PVAT activity in AS, we used a pharmacological {beta}3-adrenergic agonist as well as cold exposure in combination with a genetic mouse model with deficient PVAT development. To investigate the role of thermogenic adipose tissue in human AS, we used 18F-FDG PET-CT imaging. We found that pharmacological activation of thermogenic adipose tissue resulted in an improvement of AS, but not in mice genetically deficient in PVAT. Similarly, PVAT was found to be protective against AS during physiological stimulation of PVAT using cold exposure. Mechanistically, PVAT activation resulted in enhanced aortic distensibility and cellular remodeling of the aortic wall, possibly via release of polyunsaturated fatty acids and oxylipins from perivascular adipocytes. Finally, analysis of thermogenic fat activity in humans revealed that mediastinal thermogenic fat activity correlated negatively with diagnostic criteria of AS severity, suggesting an important role for PVAT activity in human AS. Conclusion: Our data indicate that PVAT activation reduces aortic stenosis and supports aortic remodeling to improve ascending aorta hemodynamics. PVAT activation might be a novel therapeutic target to ameliorate AS progression. Translational perspective: Currently, there are no effective strategies for treating AS other than valve replacement. Since the molecular mechanisms underlying the disease progression remain unclear, there are no pharmacological agents approved for either treatment or prevention of this disease. Furthermore, AS development cannot currently be predicted and is often only diagnosed when patients develop symptoms, which may be 10-20 years after disease onset. Therefore, identifying novel mechanisms that improve aortic valve function and prevent AS is of high medical need. This study identifies activation of PVAT-dependent aortic remodeling as a potential new therapeutic approach to improve or prevent AS.

physiology↗

bioRxiv2026

Mathematical Modeling of the Canonical Aryl Hydrocarbon Receptor Pathway

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in xenobiotic sensing, as well as development, immunity, and tissue homeostasis. AhR signaling can proceed through a canonical and non-canonical pathway; the present study focuses on the canonical pathway. While ligand-dependent differences in binding affinities and direct ligand degradation kinetics are well known, and subtle differences in ligand binding can shape downstream signaling, it is still unclear which biochemical reaction steps within the canonical pathway are responsible for distinct ligand-specific transcriptional responses. Here, we developed a mechanistic ordinary differential equation model of the canonical AhR pathway. We calibrated the model to time-resolved qPCR measurements of Cyp1a1 and Ahrr mRNA in mouse bone-marrow-derived macrophages exposed to structurally diverse, environmentally relevant ligands with known immunomodulatory activity (3-methylcholanthrene, indolo[3,2-b]carbazole, and bisphenol A) using global optimization under a heteroskedastic likelihood. To dissect ligand specificity, we evaluated 528 candidate models that allow one or two ligand-involving reaction rate constants to vary. Akaike-based model selection reveals a dominant dynamical regime governed by promoter occupancy and target-gene mRNA synthesis, indicating that ligand-specific transcriptional responses are primarily encoded at the level of transcriptional regulation rather than upstream signaling events. The resulting model is made available in SBML and PEtab formats for reproducibility, and to enable further research into whether ligand-specific effects are conserved or rewired across cell types.

systems biology↗

bioRxiv2024

Differential cell type-specific function of the aryl hydrocarbon receptor and its repressor in diet-induced obesity and fibrosis

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor regulating xenobiotic responses as well as physiological metabolism. Dietary AhR ligands activate the AhR signaling axis in the intestine and throughout the organism, whereas AhR activation is negatively regulated by the AhR repressor (AhRR). While AhR-deficient mice are known to be resistant to diet-induced obesity (DIO), we here demonstrate that AhRR deficiency also leads to a robust, but not as profound protection from DIO and hepatosteatosis. Under conditions of DIO, AhRR-/- mice did not accumulate TCA cycle intermediates in the circulation in contrast to wild-type (WT) mice, indicating protection from metabolic dysfunction. This effect could be mimicked by dietary supplementation of AhR ligands in WT mice. Because of the predominant expression of the AhRR in myeloid cells, AhRR-deficient macrophages were analyzed for changes in metabolism and showed major metabolic alterations regarding oxidative phosphorylation and mitochondrial activity as well as increased expression of genes involved in de novo lipogenesis and mitochondrial biogenesis. Mice with a genetic deficiency of the AhRR in myeloid cells did not show alterations in weight gain after high fat diet (HFD) but demonstrated ameliorated liver damage compared to control mice. Further, deficiency of the AhR in myeloid cells also did not affect weight gain but led to enhanced liver damage and adipose tissue fibrosis compared to controls. Although conditional ablation of either the AhR or AhRR in myeloid cells did not recapitulate the phenotype of the global knockout, our findings suggest that enhanced AhR signaling in myeloid cells deficient for AhRR protects from diet-induced liver damage and fibrosis, whereas myeloid cell-specific AhR deficiency is detrimental.

immunology↗