Biology subjects

Pospiech, E.

Publications and source records attributed to Pospiech, E..

3 recordsLinked to original sources

bioRxiv2026

miR-378a Controls Cardiomyocyte Metabolism and Angiogenic Signaling

AimsWhile the muscle-enriched microRNA-378a (miR-378a) has been implicated in cardiac hypertrophy and stress responses, its role in maintaining cardiomyocyte metabolic homeostasis, mitochondrial function, and angiogenic paracrine signaling under physiological and post-injury conditions remains unclear. This study addresses these gaps by examining the molecular and functional consequences of miR-378a deficiency in murine heart and human cardiomyocytes. Methods and ResultsCardiac structure and function were analyzed in miR-378a-deficient (miR-378a-/-) and wild-type (miR-378a+/+) mice at 12 weeks and 17 months of age, revealing that miR-378a loss promoted myocardial fibrosis, altered IGF1R-AKT signaling, and impaired cardiac performance, with age-dependent effects. Integrated transcriptomic and proteomic analyses in miR-378a-/- and control mice, as well as in human iPSC-derived cardiomyocytes (hiPSC-CM) of both genotypes, revealed deregulated pathways related to translation, metabolism, and cardiomyopathy-associated signaling. In hiPSC-CM, miR-378a knockout (KO) impaired mitochondrial respiration, disrupted mitochondrial morphology, and reduced mitochondrial DNA content, accompanied by altered mitophagy and biogenesis. KO cells also showed increased glucose uptake but reduced glycogen storage, accompanied by changes in key metabolic regulators, and displayed diminished angiogenic potential. Finally, hiPSC-CM overexpressing miR-378a were delivered in a mouse model of acute myocardial infarction, but overexpression did not further enhance their therapeutic effect. ConclusionsThis study broadens our understanding of miR-378as physiological role in murine hearts and human cardiomyocytes, demonstrating its impact on contractility, mitochondrial integrity, glucose metabolism, and angiogenic paracrine signaling. However, overexpression of miR-378a in hiPSC-CM offers limited additional benefit in cell therapy for acute myocardial infarction.

cell biology↗

bioRxiv2023

Diosmetin alleviates liver inflammation by improving liver sinusoidal endothelial cell dysfunction.

Background & AimsTumor necrosis factor-alpha (TNF) induces pro-inflammatory activation in liver sinusoidal endothelial cells (LSEC) and liver inflammation. However, knowledge about whether modulating LSEC activation can alleviate liver inflammation is scarce. This study aimed to establish and validate an animal model mimicking LSEC dysfunction observed in patients with elevated plasma levels of TNF, and explore whether vasoactive flavonoid diosmetin could serve as a therapeutic agent for liver inflammation. Approach & ResultsGenetic deletion of Mcpip1 in myeloid leukocytes (Mcpip1fl/flLysMCre) resulted in the development of systemic and liver inflammation in mice. Symptoms were compared with those in liver samples from obese humans with elevated TNF. Mice were treated with diosmetin, and its effectiveness in alleviating liver inflammation was evaluated. Elevated TNF correlated with reduced Mcpip1 expression in peripheral blood mononuclear cells and LSEC dysfunction in obese patients. Mcpip1 knockout in myeloid cells in mice replicated molecular signs observed in human samples. Diosmetin efficiently reduced LSEC activation and liver inflammation in Mcpip1fl/flLysMCre mice. Diosmetins effects may stem from inhibiting NF-{kappa}B-p50 subunit production in TNF-activated endothelial cells. ConclusionsDiosmetin treatment efficiently restricted liver inflammation, despite ongoing systemic inflammation, by diminishing LSEC dysfunction. Mcpip1fl/flLysMCre mice mimic symptoms of liver inflammation observed in humans and can be useful in studies on new anti-inflammatory therapies for the liver. We show that diosmetin, a vasoactive flavonoid that is successfully used in the clinic to treat chronic venous insufficiency, has also strong anti-inflammatory properties in the liver. This suggests that diosmetin treatment may be tested in humans as a supportive therapy for liver inflammation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=186 HEIGHT=200 SRC="FIGDIR/small/563468v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1c1c841org.highwire.dtl.DTLVardef@1425cb9org.highwire.dtl.DTLVardef@1d583aaorg.highwire.dtl.DTLVardef@b71f40_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2020

Deletion of Mcpip1 in Mcpip1AlbKO mice recapitulates the phenotype of human primary biliary cholangitis

Background & AimsPrimary biliary cholangitis (PBC) is an autoimmune disease characterized by progressive destruction of the intrahepatic bile ducts. The immunopathology of PBC involves excessive inflammation; therefore, negative regulators of inflammatory response, such as Monocyte Chemoattractant Protein-1-Induced Protein-1 (MCPIP1, alias Regnase1) may play important roles in the development of PBC. The aim of this work was to verify whether Mcpip1 expression protects against development of PBC. MethodsGenetic deletion of Zc3h12a was used to characterize the role of Mcpip1 in the pathogenesis of PBC. 6-52-week-old Mcpip1fl/fl and Mcpip1AlbKO mice were used for immunohistochemical, biochemical and molecular tests. ResultsWe found that Mcpip1 deficiency in the liver recapitulates most of the features of human PBC, in contrast to mice with Mcpip1 deficiency in myeloid cells (Mcpip1LysMKO mice), which present with robust myeloid cell-driven systemic inflammation. In Mcpip1AlbKO livers, intrahepatic bile ducts displayed proliferative changes with inflammatory infiltration, bile duct destruction, and fibrosis leading to cholestasis. In plasma, increased concentrations of IgG, IgM, and AMA autoantibodies (anti-PDC-E2) were detected. Interestingly, the phenotype of Mcpip1AlbKO mice was robust in 6-week-old and 52-week-old mice, but milder in 12-24-week-old mice, suggesting early prenatal origin of the phenotype and age-dependent progression of the disease. Hepatic transcriptome analysis of 6-week-old and 24-week-old Mcpip1AlbKO mice showed 812 and 8 differentially expressed genes (DEGs), respectively, compared with age-matched control mice, and revealed a distinct set of genes compared to those previously associated with development of PBC. ConclusionsThe phenotype of Mcpip1AlbKO mice recapitulates most of the features of human PBC, and demonstrates early prenatal origin and age-dependent progression of PBC. Therefore, Mcpip1AlbKO mice provide a unique model for the study of PBC. Lay summaryDeletion of hepatic Mcpip1 in Mcpip1AlbKO mice leads to development of PBC that recapitulates phenotype of human patients. These animals, show early prenatal origin and age-dependent progression of the disease. Thus, Mcpip1AlbKO mice provide a unique model for studying PBC.

pathology↗