Biology subjects

Vogel, N.

Publications and source records attributed to Vogel, N..

3 recordsLinked to original sources

bioRxiv2024

Lactobacillus Restructures the Micro/Mycobiome to Combat Glycoprotein-130 Associated Microtubule Remodeling and Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

Emerging data demonstrate systemic and local inflammation regulate right ventricular (RV) adaption in preclinical and human pulmonary arterial hypertension (PAH). Pathological RV inflammation is targetable as antagonism of glycoprotein-130 (GP130) signaling counteracts pathological microtubule remodeling and improves RV function in rodents. Microtubules control several aspects of cardiomyocyte biology including cellular and nuclear size/structure, t-tubule homeostasis, and the proper localization of connexin-43. The intestinal microbiome regulates systemic inflammation, but the impact of the gut microbiome on the GP130-microtubule axis in RV failure is unknown. Here, we examined how the anti-inflammatory bacteria, Lactobacillus, modulated cellular and physiological RV phenotypes in preclinical and clinical PAH. Lactobacillus supplementation restructured the gut micro/mycobiome, suppressed systemic inflammation, combatted pathological GP130-mediated RV cardiomyocyte microtubule remodeling, and augmented RV function in rodent PAH. Moreover, Lactobacillus was associated with superior RV adaption in human PAH. These data further support the hypothesis that inflammation negatively impacts RV adaption in PAH, and identify the gut microbiome as a potentially targetable regulator of RV function in PAH.

physiology↗

bioRxiv2024

Ferroptosis Inhibition Combats Metabolic Derangements and Improves Cardiac Function in Pulmonary Artery Banded Pigs

Right heart failure (RHF) is a leading cause of mortality in multiple cardiovascular diseases and preclinical and human data suggest impaired metabolism is a significant contributor to right-sided cardiac dysfunction. Ferroptosis is a nonapopotic form of cell death driven by impaired metabolism. Rodent data suggests ferroptosis inhibition can restore mitochondrial electron transport chain function and enhance cardiac contractility in left heart failure models, but the effects of ferroptosis inhibition in translational large animal models of RHF are unknown. Here, we showed ferrostatin-1 mediated ferroptosis antagonism improve right heart structure and function in pulmonary artery banded pigs. Molecularly, ferrostatin-1 restored mitochondrial cristae structure and combatted downregulation of electron transport chain proteins. Metabolomics and lipidomics analyses revealed ferrostatin-1 improved fatty acid metabolism. Thus, these translational data suggest ferroptosis may be a therapeutic target for RHF. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/590907v2_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@9c36fforg.highwire.dtl.DTLVardef@1deda21org.highwire.dtl.DTLVardef@1c2e4e1org.highwire.dtl.DTLVardef@409181_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2023

Experiments in micro-patterned model membranes support the narrow escape theory

The narrow escape theory (NET) predicts the escape time distribution of Brownian particles confined to a domain with reflecting borders except for one small window. Applications include molecular activation events in cell biology and biophysics. Specifically, the mean first passage time [Formula] can be analytically calculated from the size of the domain, the escape window, and the diffusion coefficient of the particles. In this study, we systematically tested the NET in a disc by variation of the escape opening. Our model system consisted of micro-patterned lipid bilayers. For the measurement of [Formula], we imaged diffusing fluorescently-labeled lipids using single-molecule fluorescence microscopy. We overcame the lifetime limitation of fluorescent probes by re-scaling the measured time with the fraction of escaped particles. Experiments were complemented by matching stochastic numerical simulations. To conclude, we confirmed the NET prediction in vitro and in silico for the disc geometry in the limit of small escape openings. Significance StatementIn the biological context of a cell, a multitude of reactions are facilitated by diffusion. It is astonishing how Brownian motion as a cost-efficient but random process is mediating especially fast reactions. The formalism of the narrow escape theory is a tool to determine the average timescale of such processes to be completed (mean first passage time, MFPT) from the reaction space and diffusion coefficient. We present the systematic proof of this formalism experimentally in a bio-mimetic model system and by random walk simulations. Further, we demonstrate a straightforward solution to determine the MFPT from incomplete experimental traces. This will be beneficial for measurements of the MFPT, reliant on fluorescent probes, that have prior been inaccessible.

biophysics↗