Biology subjects

Gromova, T.

Publications and source records attributed to Gromova, T..

5 recordsLinked to original sources

bioRxiv2025

Low Dose GLP-1 Therapy Attenuates Pathological Cardiac and Hepatic Remodelling in HFpEF Independent of Weight Loss

BACKGROUND AND AIMSHeart failure with preserved ejection fraction (HFpEF) remains a therapeutic challenge. GLP-1 receptor agonists (GLP-1RAs) show clinical promise, and the prevailing hypothesis is that their benefits are primarily driven by weight loss and the downstream benefits of improved functional status. We investigated the weight loss-independent effects of low-dose GLP-1RA therapy in a clinically relevant rodent model of severe cardiometabolic HFpEF. METHODSTen-week-old male ZSF1 obese rats with spontaneous HFpEF were treated with low-dose semaglutide (30 nmol/kg twice weekly, n=6) or vehicle for 16 weeks. Comprehensive assessments included body weight, 2-D echocardiography, invasive hemodynamics, exercise capacity as well as cardiac and hepatic fibrosis and lipid deposition. The study utilized advanced multi-omics approaches, including single-cell RNA sequencing of the heart and liver, as well as cardiac, hepatic and plasma proteomics, to explore underlying mechanisms. RESULTSIn ZSF1 obese rats, low-dose semaglutide in the absence of weight loss, significantly improved cardiac function, exercise tolerance, and attenuated fibrosis in the heart and liver. Interestingly, semaglutide therapy reduced cardiac and hepatic lipid content as well as lipid droplets in cardiac myocytes and hepatocytes. Mechanistically, multi-omics analyses of cardiac and hepatic tissues revealed that semaglutide exerted these benefits by improving cardiac metabolism, interfering with pro-fibrotic and pro-hypertrophic signals, and by reducing systemic inflammation. CONCLUSIONSLow-dose semaglutide provides significant cardioprotective, hepatoprotective, and metabolic benefits in HFpEF independent of weight loss. Our findings support the investigation of lower GLP-1RA dosing in HFpEF and other cardiovascular conditions, including in non-obese patients, to expand the clinical utility of these potent drugs. Translational PerspectiveWe demonstrate that low-dose semaglutide attenuates HFpEF-mediated pathological cardiac and hepatic remodelling in HFpEF independently of the weight loss effects of GLP-1 receptor activation. Primary mechanisms are attenuated cardiac and hepatic fibrosis and reverse lipid transport. These findings provide a mechanistic basis for the direct cardiovascular actions of GLP-1RAs, revealing their potential to modulate key disease drivers like fibrosis and lipotoxicity. These data support the use of lower, better-tolerated doses of GLP-1RAs to treat HFpEF, potentially benefiting a wider range of patients, including those who are not obese or who suffer from side effects with current GLP-1 regimens.

pharmacology and toxicology↗

bioRxiv2024

Dysregulation of Nitrosylation Dynamics Promotes Nitrosative Stress and Contributes to Cardiometabolic Heart Failure with Preserved Ejection Fraction

BackgroundRecent reports suggest increased myocardial iNOS expression leads to excessive protein s-nitrosylation, contributing to the pathophysiology of HFpEF. However, the relationship between NO bioavailability, dynamic regulation of protein s-nitrosylation by trans- and de-nitrosylases, and HFpEF pathophysiology has not been elucidated. Here, we provide novel insights into the delicate interplay between NO bioavailability and protein s-nitrosylation in HFpEF. MethodsPlasma nitrite, nitrosothiols (RsNO), and 3-nitrotyrosine (3-NT) were measured in HFpEF patients and in controls. Studies in WKY or ZSF1 obese rats were performed to evaluate HFpEF severity, NO signaling, and total nitroso-species (Rx(s)NO) levels. snRNA sequencing was performed to identify key genes involved in NO signaling and s-nitrosylation regulation. ResultsIn HFpEF patients, circulating RsNO and 3-NT were significantly elevated while nitrite, a biomarker for NO bioavailability, remained unchanged. In ZSF1 obese rats, NO bioavailability was significantly reduced while Rx(s)NO levels exhibited an age-dependent increase as HFpEF progressed. snRNA seq highlighted significant upregulation of a trans-nitrosylase, hemoglobin-beta subunit (HBb), which was corroborated in human HFpEF hearts1. Subsequent experiments confirmed HBb upregulation and revealed significant reductions in enzyme activity of two major de-nitrosylases, Trx2 and GSNOR in ZSF1 obese hearts. Further, elevated RxNO levels, increased HBb expression, and reduced activity of Trx2 and GSNOR were identified in the kidney and liver of the ZSF1 obese rats. ConclusionsOur data reveal circulating markers of nitrosative stress (RsNO and 3-NT) are significantly elevated in HFpEF patients. Data from the ZSF1 obese rat model mirror the results from HFpEF patients and reveal that pathological accumulation of RxNO/nitrosative stress in HFpEF may be in part, due to the upregulation of the trans-nitrosylase, HBb, and impaired activity of the de-nitrosylases, Trx2 and GSNOR. Our data suggest that dysregulated protein nitrosylation dynamics in the heart, liver, and kidney contribute to the pathogenesis of cardiometabolic HFpEF. Translational PerspectiveOur findings describe for the first time that circulating RsNO and 3-NT are significantly upregulated in HFpEF patients suggesting systemic nitrosative stress in HFpEF, and demonstrate a profound disconnect between insufficient physiological NO signaling and pathological nitrosative stress in HFpEF, which is in stark contrast to HFrEF in which both NO bioavailability and protein s-nitrosylation are attenuated. Further, this study provides novel mechanistic insights into a critical molecular feature of HFpEF in humans and animal models: nitrosative stress arises predominantly from imbalance of trans-nitrosylases and de-nitrosylases, thereby leading to impaired NO bioavailability concomitant with increased protein s-nitrosylation. Importantly, these perturbations extend beyond the heart to the kidney and liver, suggesting HFpEF is characterized by a systemic derangement in trans- and de-nitrosylase activity and providing a unifying molecular lesion for the systemic presentation of HFpEF pathophysiology. These findings have direct clinical implications for the modulation of NO levels in the HFpEF patient, and indicate that restoring the balance between trans- and denitrosylases may be novel therapeutic targets to ameliorate disease symptoms in HFpEF patients.

physiology↗

bioRxiv2024

Rapid onset fibrotic remodeling and ventricular dysfunction induced by phenylephrine involve targeted reprogramming of myocyte and fibroblast transcriptomes

Catecholamine dysregulation is a common feature of multiple acute and chronic cardiac conditions, including heart failure. To investigate the role of altered -adrenergic stimulation on cardiac function, we developed a short-term exposure model, administering phenylephrine subcutaneously to mice for one week. Compared to vehicle-injected controls, phenylephrine-treated animals exhibited increased ejection fraction, decreased chamber size, diastolic dysfunction and ventricular hypertrophy in the absence of hypertension. Remarkably, these animals developed extensive fibrotic remodeling of the tissue that plateaued at 24 hours and myocyte hypertrophy localized to regions of fibrotic deposition after 3 days of treatment. Transcriptome analyses of purified myocyte and fibroblast populations from these hearts revealed an unexpected role for myocytes in the production of extracellular matrix. Comparison with other models of cardiac stress, including pressure overload hypertrophy and cytokine activation of fibroblasts, identified stimulus-specific transcriptional circuits associated with cardiac pathology. Given the rapid, robust fibrotic response that preceded myocyte hypertrophy, intercellular communication analyses were conducted to investigate fibroblast to myocyte signaling, identifying potential crosstalk between these cells. These studies thoroughly describe and phenotypically characterize a new model of short-term catecholamine stress and provide an atlas of transcriptional remodeling in myocytes and fibroblasts. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/617933v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@1e504faorg.highwire.dtl.DTLVardef@a9d5c1org.highwire.dtl.DTLVardef@10809aorg.highwire.dtl.DTLVardef@16b288d_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2022

Histone H1.0 Couples Cellular Mechanical Behaviors to Chromatin Structure

Tuning of genome structure and function is accomplished by chromatin binding proteins, which determine the transcriptome and phenotype of the cell. We sought to investigate how communication between extracellular stress and chromatin structure may regulate cellular mechanical behaviors. We demonstrate that the linker histone H1.0, which compacts nucleosomes into higher order chromatin fibers, controls genome organization and cellular stress response. Histone H1.0 has privileged expression in fibroblasts across tissue types in mice and humans, and modulation of its expression is necessary and sufficient to mount a myofibroblast phenotype in these cells. Depletion of histone H1.0 prevents transforming growth factor beta (TGF-{beta})-induced fibroblast contraction, proliferation and migration in a histone H1 isoform-specific manner via inhibition of a transcriptome comprised of extracellular matrix, cytoskeletal and contractile genes. Histone H1.0 is associated with local regulation of gene expression via mechanisms involving chromatin fiber compaction and reprogramming of histone acetylation, rendering the cell stiffer in response to cytokine stimulation. Knockdown of histone H1.0 prevented locus-specific histone H3 lysine 27 acetylation by TGF-{beta} and decreased levels of both HDAC1 and the chromatin reader BRD4, thereby preventing transcription of a fibrotic gene program. Transient depletion of histone H1.0 in vivo decompacts chromatin and prevents fibrosis in cardiac muscle, thereby linking chromatin structure with fibroblast phenotype in response to extracellular stress. Our work identifies an unexpected role of linker histones to orchestrate cellular mechanical behaviors, directly coupling cellular force generation, nuclear organization and gene transcription. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/518399v1_ufig1.gif" ALT="Figure 1"> View larger version (103K): org.highwire.dtl.DTLVardef@11a38e1org.highwire.dtl.DTLVardef@8c4ab4org.highwire.dtl.DTLVardef@7c822aorg.highwire.dtl.DTLVardef@45d02b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2019

A New Role for Telomerase in Promoting Meiotic Homolog Pairing Fidelity

We report a role for telomerase, beyond its known function of telomeric DNA end extension, in maintaining normal chromosome dynamics during meiosis in Saccharomyces cerevisiae. When telomerase at telomeres was reduced by various genetic means, increased frequencies of crossover and noncrossover recombination events occurred. To investigate the mechanism of this increased meiotic recombination, we examined the kinetics of meiosis events, and tracked the movement of chromosomes in live cells during meiotic prophase. Cytoskeletal forces acting on telomeres during meiosis have been shown to promote active chromosome motion needed to pair homologous chromosomes. Here we show that changes in telomerase interaction with telomeres using a tlc1-11 mutant result in altered meiotic motion. Specifically, reduction in telomerase at telomeres leads to a decreased frequency of high velocity chromosome pulls. In the tlc1-11 mutant, we see earlier synapsis and increased genome-wide recombination for the majority of the cells and lower gamete viability. Notably, homologous pairing is not delayed unlike other telomere binding mutants. Although synapsis initiates earlier, the overall timing of synapsis remains the same, except for a subset of cells that do not exit meiosis I. Together, these results suggest that the strong pulling component of the active chromosome motion promotes homolog pairing fidelity, likely by pulling apart improperly associated regions. Our combined observations are consistent with a model in which telomerase-mediated telomeric anchoring to the nuclear envelope helps engage and properly transmit cytoskeletal forces to chromosomes. Thus, telomerase contributes to efficient chromosome movements leading to normal gamete viability.

cell biology↗