Biology subjects

Ruschitzka, F.

Publications and source records attributed to Ruschitzka, F..

4 recordsLinked to original sources

bioRxiv2026

Chemogenetic Hydrogen Sulfide Rescues Vascular Senescence in Ageing

Vascular senescence is a central driver of whole-body ageing, yet rescue strategies remain limited. Here we show that hydrogen sulfide (H2S) bioavailability declines in ageing and atherosclerosis and is associated with endothelial senescence. Developing a novel remote-control, endothelial-specific, mitochondria-targeted chemogenetic system, we spatiotemporally controlled H2S generation and thereby mitigated endothelial senescence-driven programs and reversed vascular remodeling in aged mice.

cell biology↗

bioRxiv2026

Gut Microbiota Production of Phenylacetate Programs Vascular Niche Senescence and Drives Atherosclerosis

Vascular senescence is a key contributor to ageing-related diseases, including atherosclerosis. Initial intervention is based on aggressive management of traditional risk factors, yet microbial metabolites remain underestimated as modifiable factors. We recently identified phenylacetate (PAA), a gut microbiota-linked metabolite, as a potent accelerator of endothelial senescence, raising the question of its causal role in atherosclerosis. Here, we show that PAA promotes vascular niche senescence and perivascular adipose tissue (PVAT) dysfunction, associated with atherosclerosis in humans and mice. Furthermore, PAA administration to atherosclerosis-prone mice was sufficient to drive atherosclerosis without altering lipid profile. Mechanistically, we found that PAA induces senescence-messaging secretome, containing IL-6, from endothelial cells, which stimulates Notch1 and disrupts insulin signaling in adipocytes. Blocking the PAA-IL-6-Notch1 axis as well as senolytics rescued adipocyte senescence and dysfunction. Identification of the strong link between PAA and atherosclerosis opens new avenues for microbiome-targeted preventive and therapeutic strategies in ageing. HighlightsO_LIAge-dependent increase in gut microbial metabolite PAA causally promotes vascular niche senescence C_LIO_LIPAA indirectly accelerates PVAT senescence through endothelial senescence-messaging secretome C_LIO_LISASP upregulates Notch1 signaling, leading to PVAT dysfunction C_LIO_LISenolytic therapy restores PVAT function C_LIO_LIPAA-induced vascular niche senescence contributes to atherosclerosis progression C_LI

cell biology↗

bioRxiv2024

Chromatin Remodeling by the Histone Methyltransferase SETD2 Drives Lipotoxic Injury in Cardiometabolic Heart Failure with Preserved Ejection Fraction

BackgroundCardiometabolic heart failure with preserved ejection fraction (cHFpEF) is highly prevalent and associates with a poor outcome. Pathological gene expression in heart failure is accompanied by changes in active histone marks without major alterations in DNA methylation. Histone 3 trimethylation at lysine 36 (H3k36me3) - a chromatin signature induced by the histone methyltransferase SETD2 - strongly correlates with changes in gene expression in human failing hearts; however, its role is poorly understood. Here we investigate the role of SETD2 in cHFpEF. MethodsMice with cardiomyocyte-specific deletion of SETD2 (c-SETD2-/-) were generated and subjected to high fat diet feeding and L-NAME treatment for 15 weeks to induce cHFpEF. Cardiac function and exercise tolerance were assessed by echocardiography and Treadmill exhaustion test. Chromatin immunoprecipitation assays (ChIP) were performed to investigate SETD2/H3k36me3 enrichment on gene promoters. SETD2 gain- and loss-of-function experiments were performed in cultured cardiomyocytes (CMs) exposed to palmitic acid (PA). SETD2 expression was also investigated in left ventricular (LV) myocardial specimens from patients with cHFpEF and control donors. ResultsSETD2 was upregulated in cHFpEF mouse hearts and its chromatin mark H3k36me3 was enriched on the promoter of sterol regulatory element-binding transcription factor 1 (SREBP1) gene. SETD2 activation in cHFpEF led to SREBP1 upregulation, triglyceride accumulation and lipotoxic damage. Of note, cardiomyocyte-specific deletion of SETD2 in mice prevented HFpEF-related hypertrophy, diastolic dysfunction and lung congestion while improving exercise tolerance. SETD2 deletion blunted H3K36me3 enrichment on SREBP1 promoter thus leading to a marked rewiring of the cardiac lipidome and restoration of autophagic flux. SETD2 depletion in PA-treated CMs prevented SREBP1 upregulation, whereas SETD2 overexpression recapitulated lipotoxic damage. Finally, SETD2 was upregulated in LV specimens from cHFpEF patients and its pharmacological inhibition by EZM0414 attenuated CM stiffness. ConclusionsTherapeutic modulation of SETD2/H3k36me3 axis might prevent lipotoxic injury and cardiac dysfunction in cHFpEF.

physiology↗

bioRxiv2024

AQP1 Differentially Orchestrates Endothelial Cell Senescence

Accumulation of senescent endothelial cells (ECs) with age is a pivotal driver of cardiovascular diseases in aging. However, little is known about the mechanisms and signaling pathways that regulate EC senescence. In this report, we delineate a previously unrecognized role of aquaporin 1 (AQP1) in orchestrating extracellular hydrogen peroxide (H2O2)-induced cellular senescence in aortic ECs. Our findings underscore AQP1s differential impact on senescence hallmarks, including cell-cycle arrest, senescence-associated secretory phenotype (SASP), and DNA damage responses, intricately regulating angiogenesis. In proliferating ECs, AQP1 is crucial for maintaining angiogenic capacity, whereas disruption of AQP1 induces morphological and mitochondrial alterations, culminating in senescence and impaired angiogenesis. Conversely, Aqp1 knockdown or selective blockade of AQP1 in senescent ECs rescues the excess H2O2-induced cellular senescence phenotype and metabolic dysfunction, thereby ameliorating intrinsic angiogenic incompetence. Mechanistically, AQP1 facilitates H2O2 transmembrane transport, exacerbating oxidant-sensitive kinases CaMKII-AMPK. This process suppresses HDAC4 translocation, consequently de-repressing Mef2A-eNOS signaling in proliferating ECs. However, in senescent ECs, AQP1 overexpression is linked to preserved HDAC4-Mef2A complex and downregulation of eNOS signaling. Together, our studies identify AQP1 as a novel epigenetic regulator of HDAC4-Mef2A-dependent EC senescence and angiogenic potential, highlighting its potential as a therapeutic target for antagonizing age-related cardiovascular diseases. Highlights* AQP1 is upregulated in aortic endothelial cells with aging * AQP1 differentially orchestrates H2O2-mediated EC senescence * AQP1 plays a dual role in regulating angiogenesis in proliferating and senescent ECs * AQP1 controls EC function by differentially modulating HDAC4-Mef2A pathway * AQP1 deficiency restores angiogenic capacity in senescent ECs

molecular biology↗