Biology subjects

Alzamrooni, A.

Publications and source records attributed to Alzamrooni, A..

4 recordsLinked to original sources

bioRxiv2026

Soluble Urokinase Plasminogen Activator Receptor Primes Macrophages and Worsens Heart Failure with Preserved Ejection Fraction

BackgroundHeart failure with preserved ejection fraction (HFpEF) is a systemic inflammatory syndrome with few effective therapies. Soluble urokinase plasminogen activator receptor (suPAR), a circulating immune-derived glycoprotein, independently predicts adverse outcomes in HFpEF beyond natriuretic peptides, but whether it is a causal driver or a passive marker of inflammatory burden has remained unresolved. MethodsWe tested the hypothesis that elevated circulating suPAR is sufficient to amplify HFpEF by acting on the innate immune system. suPAR-transgenic (suPAR-Tg) and wild-type mice were subjected to a cardiometabolic two-hit model (high-fat diet plus L-NAME) for 15 weeks. Cardiac structure and diastolic function were assessed by serial echocardiography alongside blood pressure, glucose tolerance, and gravimetric endpoints, and left ventricular tissue was profiled by bulk RNA sequencing with in silico cellular deconvolution. Myeloid populations in the heart, spleen, and peripheral blood were quantified by spectral flow cytometry and corroborated by galectin-3 immunofluorescence, and the direct effect of suPAR on macrophages was tested by priming bone marrow-derived macrophages with recombinant suPAR before LPS and IFN-{gamma} stimulation. ResultsSustained suPAR elevation worsened the established HFpEF phenotype, producing greater diastolic dysfunction (higher E/e' and E/A ratios) and pulmonary congestion without altering blood pressure or ejection fraction, indicating a mechanism downstream of the canonical hemodynamic stimulus. Bulk RNA sequencing of left ventricular tissue revealed a coordinated transcriptional shift, with suppression of mitochondrial oxidative phosphorylation and amplification of innate and adaptive immune programs, including interleukin-1{beta} production, leukocyte chemotaxis, and antigen presentation. Spectral flow cytometry demonstrated stepwise expansion of CCR2 inflammatory monocytes and macrophages across cardiac, splenic, and peripheral compartments, corroborated in situ by increased galectin-3 macrophage density. In vitro, recombinant suPAR was not a stand-alone inflammatory ligand but instead primed bone marrow-derived macrophages to markedly amplify TNF-, IL-1{beta}, IL-6, and NLRP3 responses to LPS and IFN-{gamma}. ConclusionsTogether, these findings establish that elevated suPAR is sufficient to act as an upstream amplifier of HFpEF, identify the CCR2 inflammatory monocyte-macrophage axis as its proximate effector, and convert two decades of epidemiologic association into a mechanistically grounded, therapeutically tractable hypothesis with immediate relevance to clinical-stage anti-suPAR antibodies.

immunology↗

bioRxiv2025

Targeting Metabolic Dysfunction and Inflammation with Sotagliflozin Reverses Diastolic Dysfunction in Experimental HFpEF

BackgroundHeart failure with preserved ejection fraction (HFpEF) is increasingly prevalent and strongly associated with cardiometabolic comorbidities including obesity, hypertension, and metabolic dysfunction. While SGLT2 inhibitors have demonstrated clinical benefits in HFpEF, the mechanisms underlying dual SGLT1/2 inhibition remain incompletely understood. MethodsWe utilized a murine model of cardiometabolic HFpEF induced by high-fat diet combined with L-NAME administration. Following disease establishment, mice received sotagliflozin (30 mg/kg) or vehicle for 10 weeks. Comprehensive assessments included echocardiography, indirect calorimetry, cardiac metabolomics, bulk RNA sequencing with cell-type deconvolution, and high-dimensional immune profiling by flow cytometry and CyTOF. ResultsSotagliflozin significantly attenuated weight gain and improved glucose tolerance without normalizing blood pressure. Metabolic cage analyses revealed a sustained reduction in respiratory exchange ratio, indicating enhanced fatty acid oxidation, corroborated by elevated cardiac acylcarnitine intermediates including palmitoylcarnitine and dodecanoylcarnitine. Echocardiography demonstrated that sotagliflozin protected against diastolic dysfunction, normalizing isovolumic relaxation time and E/e ratio while reducing left ventricular mass and myocardial fibrosis. Transcriptomic profiling revealed upregulation of mitochondrial fatty acid {beta}-oxidation pathways and suppression of inflammatory signaling cascades including IL-1 processing and TLR pathways. Flow cytometric analysis demonstrated reduced cardiac infiltration of neutrophils, CCR2+ inflammatory monocytes/macrophages, and IL-1{beta}-expressing immune cells. Splenic immune cell expansion characteristic of systemic inflammation was similarly attenuated. ConclusionsDual SGLT1/2 inhibition with sotagliflozin exerts coordinated cardiometabolic benefits in experimental HFpEF through metabolic reprogramming toward enhanced lipid utilization and suppression of cardiac and systemic inflammation. These findings establish that sotagliflozin targets the intertwined metabolic-inflammatory axis central to HFpEF pathogenesis, providing mechanistic insight into the therapeutic efficacy of dual SGLT inhibition in cardiometabolic heart failure. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/691021v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@146dfbforg.highwire.dtl.DTLVardef@ba784org.highwire.dtl.DTLVardef@122ecfcorg.highwire.dtl.DTLVardef@1f49a1a_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Comparative Analysis of Housing Temperature Impact on Heart Failure with Preserved Ejection Fraction in J vs N Strain C57BL/6 Mice

IntroductionHeart failure studies are conducted in preclinical animal models with different genotypic strains, 7-times higher metabolic rate, 5 to 6 times higher heart rate, and are housed in a cold-stressed environment of 23{degrees}C, unlike humans. These differences severely affect how animals respond to interventions, particularly those that lead to the development of metabolic syndrome, such as the two-hit model of diet-induced obesity (DIO) and N-nitro-L-arginine methyl ester (L-NAME) administration. A two-hit model of diet-induced obesity (DIO) and L-NAME administration has been proposed to induce heart failure with preserved ejection fraction (HFpEF) and mimic the hallmarks of metabolic syndrome and inflammation-induced heart failure in humans [1]. However, studies have reported conflicting results using this model. In this study, we examined the influence of mouse strain and environmental temperature on the development of metabolic syndrome and HFpEF using a two-hit model. MethodsEight-week-old, C57BL/6 mice (n=30) from the J and N strains were randomized to receive a high-fat diet (HFD) plus L-NAME versus a regular chow diet; and were randomized to be housed at a regular temperature of 23 {degrees}C versus a thermoneutral temperature of 30 {degrees}C. Glucose tolerance test (GTT, 2g/kg body weight), blood pressure via tail cuff, and echocardiography were conducted at baseline and, then at 5 and 15 weeks. Metabolic phenotyping was conducted at week 15 by using the Promethion Sable System. ResultsOur study revealed the significant effects of housing temperature and strain on the development of metabolic syndrome and HFpEF following the initiation of HFD +L-NAME over 5 and 15 weeks. At 5 weeks, both strains showed thermoneutral housing-induced attenuation of the effects of HFD + L-NAME on blood pressure and glucose tolerance, with the J strain exhibiting reduced diastolic dysfunction. By week 15, thermoneutral housing decreased energy expenditure (EE) and fat oxidation in both strains, while specifically reducing the respiratory exchange ratio (RER)_and glucose oxidation in J strain. Ejection fraction increased in both strains compared with the Chow group, except for J strain at 23 {degrees}C. Notably, physical activity levels remained constant across the groups, suggesting that the observed metabolic changes were not activity related. These findings highlight the complex physiological adaptations of these strains to different housing temperatures. ConclusionsThermoneutral housing conditions elicited strain-specific metabolic and cardiac effects in mice, with the J strain showing more pronounced responses. These findings highlight the critical influence of ambient temperature on experimental outcomes in rodent models, emphasizing the need to consider housing conditions when interpreting the results of metabolic and cardiovascular research.

immunology↗

bioRxiv2024

Metabolic Adaptations in Adult Spiny Mouse (Acomys) Cardiomyocytes Facilitate Enhanced Cardiac Recovery Following Myocardial Infarction

The adult mammalian heart has limited regenerative capacity following injury, leading to progressive heart failure and mortality. Recent studies have identified the spiny mouse (Acomys) as a unique model for mammalian cardiac regeneration, exhibiting enhanced recovery after myocardial infarction compared to commonly used laboratory mouse strains. However, the cellular and molecular mechanisms underlying this regenerative response remain poorly understood. In this study, we performed a comprehensive characterization of the metabolic adaptations to ischemic injury in cardiomyocytes of Acomys in comparison to the non-regenerative Mus Musculus. To investigate the transcriptomic and metabolomic profiles of cardiomyocytes in response to myocardial infarction, we utilized single-nucleus RNA sequencing (snRNA-seq) in sham-operated animals and 1, 3, and 7 days post-myocardial infarction. Complementary targeted metabolomics, stable isotope-resolved metabolomics, and functional mitochondrial assays were performed on heart tissues from both species to validate the transcriptomic findings and elucidate the metabolic adaptations in cardiomyocytes following ischemic injury. Transcriptomic analysis revealed that Acomys cardiomyocytes upregulate genes associated with glycolysis, the pentose phosphate pathway, and glutathione metabolism while downregulating genes involved in oxidative phosphorylation following injury. These metabolic changes were linked to decreased production of reactive oxygen species and increased antioxidant capacity, evidenced by the upregulation of genes such as Prdx1, Sod1, Sod2, and G6pd. Our targeted metabolomic studies supported these findings, showing a shift from fatty acid oxidation to glycolysis and ancillary biosynthetic pathways in Acomys cardiomyocytes post-injury. Functional mitochondrial studies indicated a higher reliance on glycolysis in Acomys compared to Mus, underscoring the unique metabolic adaptations of Acomys cardiomyocytes. Stable isotope tracing experiments confirmed a shift in glucose utilization from oxidative phosphorylation in Acomys. In conclusion, our study identifies unique metabolic adaptations in Acomys cardiomyocytes that contribute to their enhanced regenerative capacity following myocardial infarction. These findings provide novel insights into the role of metabolism in regulating cardiomyocyte proliferation and cardiac repair in adult mammals. By targeting the specific metabolic pathways and regulators identified in Acomys, such as glycolytic enzymes and PCK2, we may be able to develop innovative therapies to promote cardiac regeneration in patients with ischemic heart disease. Our work highlights the importance of metabolic flexibility in determining cardiomyocyte regenerative responses and establishes Acomys as a valuable model for studying cardiac regeneration in adult mammals. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/595229v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@dba53aorg.highwire.dtl.DTLVardef@3c8a74org.highwire.dtl.DTLVardef@a60251org.highwire.dtl.DTLVardef@e2142c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗