Biology subjects

Romero, G.

Publications and source records attributed to Romero, G..

5 recordsLinked to original sources

bioRxiv2026

Therapeutic potential of Relaxin-2 in Heart Failure with preserved Ejection Fraction (HFpEF)

AimsHeart failure with preserved ejection fraction (HFpEF) afflicts millions annually and current treatments provide symptomatic relief. Here, we investigate the therapeutic potential of synthetic human Relaxin-2 (RLX) at reversing diastolic dysfunction (DD) and reducing arrhythmia vulnerability. Methods and ResultsMale ZSF1 rats were placed on a normal diet (ND, N=10 controls) or a high-fat diet (HFD, N=11), resulting in the development of DD in 11-weeks, based on serial echocardiograms (enlarged left atrium (LA), wall thickness, doppler flow: E/e). Once HFpEF was confirmed, control and HFpEF rats were randomly treated with Relaxin (400{micro}g/kg/day RLX, N=6) or the vehicle (N=5) for 2-weeks using implanted minipumps. Echocardiograms were repeated at weeks 1 and 2, then hearts were isolated, optically mapped, subjected to programmed electrical stimulation (PES) and tissues dissected for immuno-fluorescence (IF), and qPCR analysis. Circulating levels of glucose, RLX and NT-pro-ANP were measured, pre- and post-treatment. Echocardiograms indicated that RLX reversed DD by reducing LA dimensions and E/e. Optical mapping revealed that 1/3 of HFpEF hearts exhibited sustained atrial and ventricular arrhythmia which were blocked by RLX as it tended to increase conduction velocity (CV). Based on IF, RLX increased Nav1.5, Connexin-43, {beta}-catenin and Wnt1 expression. There were no significant changes in fibrosis in this HFpEF model. NT-pro-ANP was elevated in HFpEF and reduced towards control values by RLX. qPCR analysis showed that RLX decreased DKK1 and MMP1A and increased SCN5A expression compared to Vehicle treatment (N=6 and 5, respectively). ConclusionsThe ZSF1 model showed clear signs of HFpEF, including DD, enlargement of the LA, enhanced hemodynamic stress, increased vulnerability to sustained AF and VF, and elevated glucose and blood pressure. RLX treatment largely reversed DD, hemodynamic stress, and suppressed sustained arrhythmias. RLX elicited cardiac genomic changes, most likely through Wnt/canonical signaling, demonstrating RLXs potential as a therapy for HFpEF.

physiology↗

bioRxiv2024

Quantitative and Kinetic Proteomics Reveal ApoE Isoform-dependent Proteostasis Adaptations in Mouse Brain

Apolipoprotein E (ApoE) polymorphisms modify the risk of neurodegenerative disease with the ApoE4 isoform increasing and ApoE2 isoform decreasing risk relative to the wild-type control ApoE3 isoform. To elucidate how ApoE isoforms alter the proteome, we measured relative protein abundance and turnover in transgenic mice expressing a human ApoE gene (isoform 2, 3, or 4). This data provides insight into how ApoE isoforms affect the in vivo synthesis and degradation of a wide variety of proteins. We identified 4849 proteins and tested for ApoE isoform-dependent changes in the homeostatic regulation of [~]2700 ontologies. In the brain, we found that ApoE4 and ApoE2 both lead to modified regulation of mitochondrial membrane proteins relative to the wild-type control ApoE3. In ApoE4 mice, this regulation is not cohesive suggesting that aerobic respiration is impacted by proteasomal and autophagic dysregulation. ApoE2 mice exhibited a matching change in mitochondrial matrix proteins and the membrane which suggests coordinated maintenance of the entire organelle. In the liver, we did not observe these changes suggesting that the ApoE-effect on proteostasis is amplified in the brain relative to other tissues. Our findings underscore the utility of combining protein abundance and turnover rates to decipher proteome regulatory mechanisms and their potential role in biology.

biochemistry↗

bioRxiv2024

Sex-dependent adipose glucose partitioning by the mitochondrial pyruvate carrier

ObjectiveThe mitochondrial pyruvate carrier (MPC) occupies a critical node in intermediary metabolism, prompting interest in its utility as a therapeutic target for the treatment of obesity and cardiometabolic disease. Dysregulated nutrient metabolism in adipose tissue is a prominent feature of obesity pathophysiology, yet the functional role of adipose MPC has not been explored. We investigated whether the MPC shapes the adaptation of adipose tissue to dietary stress in female and male mice. MethodsThe impact of pharmacological and genetic disruption of the MPC on mitochondrial pathways of triglyceride assembly (lipogenesis and glyceroneogenesis) was assessed in 3T3L1 adipocytes and murine adipose explants, combined with analyses of adipose MPC expression in metabolically compromised humans. Whole-body and adipose-specific glucose metabolism were subsequently investigated in male and female mice lacking adipocyte MPC1 (Mpc1AD-/-) and fed either standard chow, high-fat western style, or high-sucrose lipid restricted diets for 24 weeks, using a combination of radiolabeled tracers and GC/MS metabolomics. ResultsTreatment with UK5099 or siMPC1 impaired the synthesis of lipids and glycerol-3-phosphate from pyruvate and blunted triglyceride accumulation in 3T3L1 adipocytes, whilst MPC expression in human adipose tissue was negatively correlated with indices of whole-body and adipose tissue metabolic dysfunction. Mature adipose explants from Mpc1AD-/- mice were intrinsically incapable of incorporating pyruvate into triglycerides. In vivo, MPC deletion restricted the incorporation of circulating glucose into adipose triglycerides, but only in female mice fed a zero fat diet, and this associated with sex-specific reductions in tricarboxylic acid cycle pool sizes and compensatory transcriptional changes in lipogenic and glycerol metabolism pathways. However, whole-body adiposity and metabolic health were preserved in Mpc1AD-/- mice regardless of sex, even under conditions of zero dietary fat. ConclusionThese findings highlight the greater capacity for mitochondrially driven triglyceride assembly in adipose from female versus male mice and expose a reliance upon MPC-gated metabolism for glucose partitioning in female adipose under conditions of dietary lipid restriction.

physiology↗

bioRxiv2024

Lateral olivocochlear neurons modulate cochlear responses to noise exposure

The sense of hearing originates in the cochlea, which detects sounds across dynamic sensory environments. Like other peripheral organs, the cochlea is subjected to environmental insults, including loud, damage-inducing sounds. In response to internal and external stimuli, the central nervous system directly modulates cochlear function through olivocochlear neurons (OCNs), which are located in the brainstem and innervate the cochlear sensory epithelium. One population of OCNs, the lateral olivocochlear (LOC) neurons, target spiral ganglion neurons (SGNs), the primary sensory neurons of the ear. LOCs alter their transmitter expression for days to weeks in response to noise exposure (NE), suggesting that they are well-positioned to tune SGN excitability over long time periods in response to auditory experience. To examine how LOCs affect auditory function after NE, we characterized the transcriptional profiles of OCNs and found that LOCs exhibit transient changes in gene expression after NE, including upregulation of multiple neuropeptide-encoding genes. Next, by generating intersectional mouse lines that selectively target LOCs, we chemogenetically ablated LOC neurons and assayed auditory responses at baseline and after NE. Compared to controls, mice lacking LOCs showed stronger NE-induced functional deficits one day later and had worse auditory function after a two-week recovery period. The number of remaining presynaptic puncta at the SGN synapse with inner hair cells did not differ between control and LOC-ablated animals, suggesting that the primary role of LOCs after NE is likely not one of protection, but one of compensation, ensuring that SGN function is enhanced during periods of need.

neuroscience↗

bioRxiv2022

Deciphering the tissue-specific regulatory role of intronless genes across cancers

Intronless genes (IGs) or single-exon genes lacking an intron are found across most Eukaryotes. Notably, IGs display a higher transcriptional fidelity as they are not regulated through alternative splicing, suggesting better predictability biomarkers and easier regulation as targets for therapy. Cancer is a complex disease that relies on progressive uncontrolled cell division linked with multiple dysfunctional biological processes. Tumor heterogeneity remains the most challenging feature in cancer diagnosis and treatment. Given the clinical relevance of IGs, we aim to identify their unique expression profiles and interactome, that may act as functional signatures across eight different cancers. We identified 940 protein-coding IGs in the human genome, of which about 35% were differentially expressed across the analyzed cancer datasets. Specifically, [~]78% of differentially expressed IGs were undergoing transcriptional reprogramming with elevated expression in tumor cells. Remarkably, in all the studied tumors, a highly conserved induction of a group of deacetylase-histones located in a region of chromosome 6 enriched in nucleosome and chromatin condensation processes. This study highlights that differentially expressed human intronless genes across cancer types are prevalent in epigenetic regulatory roles participating in specific PPI networks for ESCA, GBM, and LUAD tumors. We determine that IGs play a key role in the tumor phenotype at transcriptional and post-transcriptional levels, with important mechanisms such as interactomics rewiring.

genomics↗