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Aksoy, Z. B.

Publications and source records attributed to Aksoy, Z. B..

3 recordsLinked to original sources
bioRxiv2025

Pretreatment with estrogen enhances the therapeutic efficacy of cardiac progenitor cells and improves cardiac recovery in a failing heart model

BackgroundIn recent years, cardiac progenitor cells (CPCs) are considered as a potential source of cell therapy for the treatment of heart failure. Despite the encouraging results of clinical trials showing that transplantation of CPCs improves function of infarcted hearts, reduced cell survival and inefficient engraftment into host tissue are still challenging issues. MethodsCPCs were isolated from a male mouse heart and incubated with estrogen (10-7M for 48 hours) in vitro. The heart failure model was generated by intraperitoneally isoproterenol (ISO) treatment (200mg/kg for 6 days) in the female mouse. Either estrogen pretreated-CPC (E2-CPC) or untreated-CPCs (Control-CPC) were intramyocardially transplanted into the failure heart. Engraftment of transplanted cells were visualized by in vivo imaging, Y-chromosome staining (by Fluorescence In Situ Hybridization) and SRY gene for expression analysis. Cardiac functions were determined by analyzing electrophysiological changes. Pathological changes following the transplantation were also examined at the molecular level by immunostaining and western blotting from isolated heart samples and on heart tissue sections to address the efficiency of the E2-CPC transplantation. In addition to regenerative outcomes at animal level, the enhancing effect of estrogen on the therapeutic potential of CPC was examined through changes in migration, proliferation and mitochondrial energetics by in vitro experiments. The effects of estrogen in transcriptome profiling was also evaluated by RNA sequencing (RNA-seq) in CPCs. ResultsIn vivo results demonstrated that estrogen pretreatment increased the retention rate of transplanted CPCs in failing heart. E2-CPC transplantation enhanced cardiac function and ameliorated pathological cardiac remodelling via inducing revascularization, proliferation while attenuating collagen formation and hypertrophy in failing heart. Our in vitro results have shown that estrogen treatment promotes migration, angiogenesis and proliferation capacities and adenosine triphosphate (ATP) production of CPCs in vitro. RNA sequencing provided further evidence that the change in the transcriptome profile of CPCs upon estrogen treatment improved their ability to cause reverse cardiac remodelling in the failing heart after transplantation. ConclusionOur data indicated that estrogen-pretreatment significantly improves cardiac recovery in a failing heart through enhancing efficacy of CPC transplantation. This study also emphasized underyling mechanisms of the improvement in function in CPC-based therapies which remain poorly understood.

molecular biology↗
bioRxiv2025

The effects of estrogen on cardiac progenitor cell-derived extracellular vesicles in enhancing cardiac protection through promoting tissue repair and regeneration

Withdrawal StatementThe authors have withdrawn this manuscript because additional data are being incorporated and the manuscript is being substantially revised for resubmission. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

molecular biology↗
bioRxiv2025

Dual GLP-1 and GIP receptor agonist Tirzapetide plays an off-target role in the modulation of the β-adrenoceptors and glucose metabolism in hyperglycemic or senescent cardiac cells

BackgroundA dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP1) receptor agonist Tirzepatide (TZPD) is a novel cardioprotective agent, particularly in metabolic disturbances-related co-morbidities, however, there is no exact study to emphasize its possible off-target action in cardiac cells. ObjectiveTaking into consideration a relationship between the trafficking of incretin receptors in a manner not anticipated by the standard way of cAMP as a primary actor in TZPD action, together with the role of cAMP depression in cardiac dysfunction, here, we aimed to elucidate a pattern of off-target receptor interactions of TZPD and molecular processes underlying the pleiotropic effects of TZPD through modulation of the {beta}-adrenoceptors ({beta}-ARs) signaling in cardiomyocytes. MethodsTo establish the multifaceted cardioprotective function and underlying mechanisms of TZPD against hyperglycemia (HG)- or senescence (SC)-induced cardiac dysfunction, H9c2 cells were treated with and without TZPD. We also used {beta}3-ARs overexpressed H9c2 cells ({beta}3OE) for comparisons. ResultsThe TZPD intervention ameliorated the HG or SC phenotypes in the cardiac cells via alleviation in protein levels of GLP-1R and GIP-R as well as production of cAMP or cGMP even in the presence of these receptor antagonisms. The TZPD also alleviated the depressed levels of the {beta}1- and {beta}2-ARs with a significant decrease in the activated {beta}3-ARs and PKG being parallel to normalizations in the cAMP and cGMP in the presence of the antagonisms of these receptors. The therapeutic effects of TZPD on the similar parameters of the {beta}3OE group of cells can strongly verify its off-target action among multifaceted effects in either HG or SC cells. In addition, molecular dynamics simulations indicated that TZPD binds with the highest affinity to GLP-1R and {beta}3-ARs rather than GIP-R and then relatively lower but almost similar affinities to {beta}1- and {beta}2-ARs. Furthermore, mechanistically, the cardioprotective effect of TZPD includes significant regulation of the cellular Ca2+, at most, modulating the proteins in {beta}-ARs signaling pathways. Moreover, TZPD could significantly increase not only the depressed protein level but also the translocation of GLUT4 on the sarcolemma, promoting glucose uptake in the HG or SC groups independent of its receptor actions. ConclusionsOur findings indicate that TZPD, with its multifaceted role, has beneficial effects on cardiac cells by positively modulating {beta}-ARs signaling and glucose metabolism rather than on-target receptor action. Furthermore, we demonstrated how TZPD can engage the different targets with distinct signaling motifs at the sarcolemma. Highlights- TZPD has direct cardio-therapeutic effects in cardiac cells under hyperglycemia or senescence, at most, through affecting altered {beta}-ARs signaling in cardiomyocytes with the highest affinity to {beta}3-ARs compared to the others. - The multifaceted roles of TZPD in the HG or SC group of cells include modulation of {beta}- ARs signaling, cellular Ca2+ regulation, and glucose metabolism independent from the insulin signaling pathway. - TZPD could induce translocation of GLUT4 on the membrane and increase its protein level in the HG or SC group of cells independent of its receptor actions. - TZDP could also normalize the depressed level of IRS-1in the HG or SC group of cells. - TZPD activates both GLP-1R and GIP-R in cells, particularly with consideration of the in silico finding on the higher binding affinity of TZPD to GLP-1R rather than GIP-R, it seems an activation of GLP-1R by an agonist stimulates insulin secretion predominantly through the GLP-1R, with an additional contribution of GIP-R activation - Overall, these results demonstrate that the same drug engaging the different targets has distinct signaling motifs at the plasma membrane and provides further information on the role of incretins in cardiac cells under hyperglycemia or senescence.

molecular biology↗