Project description:We used human iPSC-CMs generated from healthy individuals and performed RNA-sequencing after 5 days of trastuzumab treatment to examine the mechanism associated with cardiac dysfunction in iPSC-CMs after iron treatment. Transcriptome analysis revealed broad changes in cardiovascular development and processes.
Project description:We used human iPSC-CMs generated from healthy individuals and performed RNA-sequencing after 7 days of trastuzumab treatment to examine the mechanism associated with contraction dysfunction in iPSC-CMs after trastuzumab treatment. Transcriptome analysis revealed the key role of an altered energy metabolism pathway for cardiomyocytes in the disease pathogenesis.
Project description:To understand the role of MEF2A in iPSC-CMs maturation, we used MEF2A-siRNA to reduce MEF2A transcription in iPSC-CMs and then examined the changes in transcription levels
Project description:Statins prevent cardiovascular disease via their salutary function as inhibitors of cholesterol biosynthesis and mediators of pleiotropic effects on the cardiovascular system. The current study focuses on the class effect of statins on the transcriptome of human iPSC-derived cardiomyocytes (iPSC-CMs), applied at serum peak concentrations. We report a comprehensive transcriptomic analysis of iPSC-CMs derived from four healthy donors and different differentiation batches following treatment with fluvastatin, simvastatin, atorvastatin, and lovastatin. Our data display dynamic transcriptional networks and reveal a statin-induced molecular signature in iPSC-CMs independent of genetic background and technical variability. Finally, in-depth pathway enrichment analysis uncovers that all statins affect mainly metabolic properties of iPSC-CMs and particularly the regulation of cholesterol biosynthesis and fatty acid metabolism. Our study provides a global insight into the cardiomyocyte effects of statins revealing novel aspects of their role on cardiomyocyte metabolic regulation, when applied at clinically relevant concentrations.
Project description:Hereditary hemochromatosis and transfusional iron overload are frequent clinical conditions associated with progressive iron accumulation in parenchymal tissues leading to eventual organ failure. We have discovered a novel mechanism to reverse iron overload by pharmacological modulation of the divalent metal transporter-1 (DMT-1). DMT-1 mediates intracellular iron transport during the transferrin cycle and apical iron absorption in the duodenum. Additional functions in iron handling in the kidney and liver are less well understood. We show that the L- type calcium-channel blocker nifedipine increases DMT-1 mediated cellular iron transport 10-to 100-fold at concentrations between 1-100 uM. Mechanistically, nifedipine causes this effect by prolongation of the activity of DMT-1 to transport iron. We show that nifedipine mobilizes iron from the liver of mice with primary and secondary iron overload, and enhances urinary iron excretion. Modulation of DMT-1 function by L-type calcium-channel blockers emerges a novel pharmacological concept to treat iron overload disorders.<br> <br> In this experiment mice were subjected to dietary iron overload before being treated with nifedipine at 5 ug/g bodyweight, or mock treated with the same volume of solvent.
Project description:Iron overload disorders are an important factor contributing to various pathologies. However, the effects of iron overload on liver transcriptional regulation are largely unknown. To examine the effects of iron overload on liver transcriptome and chromatin accessibility, we fed mice a high-iron diet (HID) for 2 weeks. Then, livers were collected and profiled by RNA-seq and ATAC-seq.
Project description:Iron overload, characterized by accumulation of iron in tissues, induces a multiorgan toxicity whose mechanisms are not fully understood. Using cultured cell lines, Caenorhabditis elegans, and mice, we found that ferroptosis occurs in the context of iron-overload-mediated damage. Exogenous oleic acid protected against iron-overload-toxicity in cell culture and Caenorhabditis elegans by suppressing ferroptosis. In mice, oleic acid protected against FAC-induced liver lipid peroxidation and damage. Oleic acid changed the cellular lipid composition, characterized by decreased levels of polyunsaturated fatty acyl phospholipids and decreased levels of ether-linked phospholipids. The protective effect of oleic acid in cells was attenuated by GW6471 (a PPAR- antagonist), as well as in Caenorhabditis elegans lacking the nuclear hormone receptor NHR-49 (a PPAR- functional homologue). These results highlight ferroptosis as a driver of iron-overload-mediated damage, which is inhibited by oleic acid. This monounsaturated fatty acid represents a potential therapeutic approach to mitigating organ damage in iron overload individuals.