Biology subjects

Bonnet, s.

Publications and source records attributed to Bonnet, s..

4 recordsLinked to original sources

bioRxiv2026

Multi-Omic Profiling Defines the Renal Mechanisms of Cardiovascular-Kidney-Metabolic Syndrome in Pulmonary Arterial Hypertension

Background: Cardiovascular-kidney-metabolic (CKM) syndrome integrates cardiac, renal, and metabolic abnormalities that drive multi-organ injury. In pulmonary arterial hypertension (PAH), CKM manifests as systemic metabolic derangements, right ventricular dysfunction, and renal compromise. Renal dysfunction strongly predicts mortality in PAH, yet current therapies provide little renal benefit. Moreover, the mechanisms driving PAH nephropathy remain poorly understood, limiting our ability to effectively treat PAH-CKM. Methods: Single-nucleus RNA sequencing identified cell-type-specific transcriptional alterations in autopsy-derived kidneys from control (n=5) and PAH (n=4) patients. Mitochondrial, cytoplasmic, and phosphoproteomic analyses profiled proteomic alterations. AlphaFold 3/ChimeraX modeling defined the predicted structural consequences of altered protein phosphorylation. Histological analysis assessed renal fibrosis, glomerular structure, immune cell infiltration, and nephron segment density. Results: 3 of 4 PAH patients exhibited renal impairment, with a cohort mean estimated glomerular filtration rate of 61 plus or minus 36 mL/min/1.73m squared. snRNA-seq identified a distinct cellular architecture in PAH kidneys, marked by an increase in thick ascending limb, proximal tubule, and immune cell nuclei and depletion of collecting duct nuclei. Transcriptional profiling demonstrated proximal tubule and thick ascending limb cells both upregulated fatty acid oxidation, ferroptosis, and cuproptosis pathways. PAH lymphocytes displayed heightened T87 cell receptor signaling, natural killer cell-mediated cytotoxicity, and Th17 differentiation. Histological analyses demonstrated increased perivascular fibrosis, glomerular T-cell infiltration, and a reduction in glomerular basement membrane density in PAH kidneys. Mitochondrial and cytoplasmic proteomics revealed broad metabolic dysfunction characterized by impaired {beta}-oxidation, TCA cycle activity, amino acid metabolism, transsulfuration, and urea cycle pathways. Phosphoproteomics predicted increased GSK3{beta}, STK, and casein kinase activity in PAH kidneys. Finally, using the totality of our data, we nominated multiple druggable targets that could be evaluated to counteract PAH nephropathy. Conclusions: Integrated multi-omic profiling demonstrates PAH nephropathy is defined by glomerular structural remodeling, proximal nephron ferroptotic and cuproptotic signaling, amino acid metabolic dysregulation, and innate and adaptive leukocyte activation. Future studies intervening on these pathways could lead to the development of novel therapeutics to augment renal function in PAH.

molecular biology↗

bioRxiv2026

Cardiomyocyte NLRP3 signaling in right heart failure is sexually dimorphic via estrogen receptor α

RationaleRV adaptation in pulmonary hypertension is sexually dimorphic and more preserved in women. NLRP3 inflammasome activation contributes to RV failure (RVF) development. However, regulators and downstream effects of NLRP3 activation in the RV remain unknown. ObjectivesWe investigated whether NLRP3 inflammasome activation in RVF is sexually dimorphic, whether NLRP3 is active in RV cardiomyocytes (RVCMs) and causes RVCM contractile dysfunction, and whether 17{beta}-estradiol (E2) and its receptor ER attenuate this process. MethodsWe studied RV tissues from PAH patients with RVF, RV tissues and RVCMs isolated from wild-type and ER loss-of-function mutant rats with RVF, isolated perfused rat hearts, and human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. NLRP3 activation was assessed via RNA-sequencing, proteomics, immunostaining, and downstream target quantification. RV contractility was assessed via pressure-volume loops, perfused heart studies, and contractility and calcium assessments in isolated RVCMs. Measurements and Main ResultsNLRP3 was upregulated in RVCMs during RVF and resulted in altered RVCM calcium handling and RVCM contractile dysfunction. In human RVs, hiPSC-cardiomyocytes and rat RVs, NLRP3 activation and NLRP3-induced RVCM contractile dysfunction were sexually dimorphic and male-biased. Ovariectomy and loss of ER in females eliminated this sex bias. E2, via ER, prevented RVCM NLRP3 activation and NLRP3-induced RVCM contractile dysfunction in males and ovariectomized females during both acute and chronic RV pressure overload. ER directly interacted with NLRP3. ConclusionsNLRP3-driven RVCM contractile dysfunction is male-biased. E2 inhibits NLRP3 through ER to preserve RVCM contractility. Targeting E2-ER-NLRP3 signaling may offer novel therapeutic strategies for RVF in low estrogen states. ImpactThis is the first study to define a novel estradiol-estrogen receptor -NLRP3 axis that modulates RV cardiomyocyte function and RV adaptation in pulmonary hypertension. We demonstrate for the first time that NLRP3 activation is therapeutically targetable in low estrogen states via NLRP3 inhibitors or 17{beta}-estradiol. These findings have direct implications for therapeutic strategies aimed at preserving or restoring RV contractile function in pulmonary hypertension, a current area of unmet clinical need.

molecular biology↗

bioRxiv2025

Levosimendan Ameliorates Adverse Pulmonary Vascular Remodeling in Group-2 Pulmonary Hypertension.

AimsPulmonary hypertension (PH) due to left heart disease (Group-2PH) is the most common form of PH and comprises two distinct subtypes: isolated post-capillary-PH (IpcPH) and combined post-and pre-capillary-PH (CpcPH). Despite its high prevalence and poor prognosis, no targeted therapies are currently approved, largely due to the absence of reliable preclinical models that recapitulate these human hemodynamic phenotypes. Levosimendan, a calcium sensitizer with inotropic and vasodilatory properties, has shown promise in early clinical trials for Group-2PH, but its mechanisms of action remain unclear. This study aimed to develop and validate experimental models of IpcPH and CpcPH and to assess the therapeutic effects of levosimendan on pulmonary vascular remodeling, inflammation, and cardiac function to support ongoing clinical translation. Methods and ResultsIn a multicentre preclinical study, we established two rodent models that faithfully replicate the human IpcPH and CpcPH hemodynamic profiles. CpcPH animals exhibited severe pulmonary vascular remodeling, inflammatory cell infiltration, and a distinct pro-proliferative transcriptomic signature, whereas IpcPH animals showed minimal pulmonary vascular involvement. Levosimendan (3 mg/kg/day, 3 weeks) improved biventricular function and pulmonary hemodynamics in both models. In CpcPH, levosimendan additionally reduced pulmonary vascular remodeling, attenuated inflammation, and partially reversed disease-associated transcriptomic reprogramming. Transcription factor enrichment analysis identified NF-{kappa}B as a key upstream regulator inhibited by treatment. In a translational extension, nine circulating inflammation-related-proteins differentiated CpcPH from IpcPH patients; among them, TNF, IL-12B, 4E-BP1, NT-3, NGF, FGF21, and FGF23 predicted poor survival. IL-18 and 4E-BP1 were elevated in CpcPH lungs and decreased following levosimendan treatment. ConclusionsInflammation is a major contributor to adverse pulmonary vascular remodeling in CpcPH. Levosimendan improves cardiac performance and mitigates pulmonary vascular inflammation and remodeling, supporting its potential as a dual-action therapeutic agent in Group-2PH. These findings validate novel preclinical models and provide mechanistic evidence reinforcing ongoing clinical evaluation of levosimendan in this condition. Translational perspectiveGroup-2 PH lacks targeted therapies, partly due to the absence of validated preclinical models. We validated models recapitulating human IpcPH and CpcPH and identified inflammation as a key driver of pulmonary vascular remodeling in CpcPH. Levosimendan improved biventricular function and reduced vascular remodeling and inflammation through NF-{kappa}B inhibition. Circulating IL-18 and 4E-BP1 reflected disease severity and treatment response. These findings establish robust translational models, reveal inflammatory mechanisms underlying CpcPH, and provide mechanistic evidence supporting ongoing clinical trials of levosimendan as a dual-action therapeutic strategy in Group-2 PH.

molecular biology↗

bioRxiv2024

ATP Citrate Lyase Drives Vascular Remodeling Diseases Development Through Metabolic-Epigenetic Reprograming.

Our study explores the previously uncharted role of ATP-citrate lyase (ACLY) in vascular remodeling within the pulmonary and coronary arteries, providing novel insights into the pathogenesis of pulmonary hypertension and coronary artery diseases. ACLY, involved in de novo lipid synthesis and histone acetylation, has emerged as a key regulator in sustaining vascular smooth muscle cell (VSMC) proliferation and survival. Utilizing human coronary and pulmonary artery tissues, our findings reveal an upregulation of ACLY expression during vascular remodeling processes. Inhibition of ACLY, achieved through pharmacological and molecular interventions in humans primary cultured VSMCs, leads to decreased proliferation, migration, and resistance to apoptosis. Mechanistically, these effects are associated with diminished glycolysis, lipid synthesis, GCN5-dependent histone acetylation, and FOXM1 activation. In vivo experiments, combining pharmacological and VSMC-specific ACLY knockout mice, ACLY inhibition demonstrates its efficacy in mitigating coronary artery remodeling and reducing pulmonary hypertension. Notably, initiating ACLY inhibition post-disease onset reverses pathological conditions, positioning ACLY as a promising therapeutic target. Human ex vivo tissue culture further supports our findings, showing reduced vascular remodeling in cultured human coronary artery rings and a reversal of pulmonary artery remodeling in precision-cut lung slices upon ACLY inhibition. This study introduces a groundbreaking concept, linking disparate abnormalities in vascular diseases to a common pathogenetic denominator, ACLY. The identified "multiple hit" therapeutic approach presents potential targets for addressing complex vascular diseases, offering avenues for future clinical interventions. ONE SENTENCE SUMMARYOur study delineates the pivotal role of ATP-citrate lyase in orchestrating vascular remodeling, establishing it as a compelling translational target for therapeutic interventions in pulmonary hypertension and coronary artery disease.

physiology↗