Molecular Mechanisms of Ferroptosis and Relevance to Cardiovascular Disease

Ferroptosis has recently been demonstrated to be a novel regulated non-apoptotic cell death characterized by iron-dependence and the accumulation of lipid peroxidation that results in membrane damage. Excessive iron induces ferroptosis by promoting the generation of both soluble and lipid ROS via an iron-dependent Fenton reaction and lipoxygenase (LOX) enzyme activity. Cytosolic glutathione peroxidase 4 (cGPX4) pairing with ferroptosis suppressor protein 1 (FSP1) and mitochondrial glutathione peroxidase 4 (mGPX4) pairing with dihydroorotate dehydrogenase (DHODH) serve as two separate defense systems to detoxify lipid peroxidation in the cytoplasmic as well as the mitochondrial membrane, thereby defending against ferroptosis in cells under normal conditions. However, disruption of these defense systems may cause ferroptosis. Emerging evidence has revealed that ferroptosis plays an essential role in the development of diverse cardiovascular diseases (CVDs), such as hemochromatosis-associated cardiomyopathy, doxorubicin-induced cardiotoxicity, ischemia/reperfusion (I/R) injury, heart failure (HF), atherosclerosis, and COVID-19–related arrhythmias. Iron chelators, antioxidants, ferroptosis inhibitors, and genetic manipulations may alleviate the aforementioned CVDs by blocking ferroptosis pathways. In conclusion, ferroptosis plays a critical role in the pathogenesis of various CVDs and suppression of cardiac ferroptosis is expected to become a potential therapeutic option. Here, we provide a comprehensive review on the molecular mechanisms involved in ferroptosis and its implications in cardiovascular disease

Aspirin-Mediated Reset of Preeclamptic Placental Stem Cell Transcriptome - Implication for Stabilized Placental Function.

Preeclampsia (PE) is a pregnancy-specific disease, occurring in ~ 2-10% of all pregnancies. PE is associated with increased maternal and perinatal morbidity and mortality, hypertension, proteinuria, disrupted artery remodeling, placental ischemia and reperfusion, and inflammation. The mechanism of PE pathogenesis remains unresolved explaining limited treatment. Aspirin is used to reduce the risk of developing PE. This study investigated aspirin\u27s effect on PE-derived placenta mesenchymal stem cells (P-MSCs). P-MSCs from chorionic membrane (CM), chorionic villi, membranes from the maternal and amniotic regions, and umbilical cord were similar in morphology, phenotype and multipotency. Since CM-derived P-MSCs could undergo long-term passages, the experimental studies were conducted with this source of P-MSCs. Aspirin (1 mM) induced significant functional and transcriptomic changes in PE-derived P-MSCs, similar to healthy P-MSCs. These include cell cycle quiescence, improved angiogenic pathways, and immune suppressor potential. The latter indicated that aspirin could induce an indirect program to mitigate PE-associated inflammation. As a mediator of activating the DNA repair program, aspirin increased p53, and upregulated genes within the basic excision repair pathway. The robust ability for P-MSCs to maintain its function with high dose aspirin contrasted bone marrow (M) MSCs, which differentiated with eventual senescence/aging with 100 fold less aspirin. This difference cautions how data from other MSC sources are extrapolated to evaluate PE pathogenesis. Dysfunction among P-MSCs in PE involves a network of multiple pathways that can be restored to an almost healthy functional P-MSC. The findings could lead to targeted treatment for PE

Mesenchymal Stem Cell-Secreted Extracellular Vesicles Instruct Stepwise Dedifferentiation of Breast Cancer Cells into Dormancy at the Bone Marrow Perivascular Region

In the bone marrow (BM), breast cancer cells (BCC) can survive in dormancy for decades as cancer stem cells (CSC), resurging as tertiary metastasis. The endosteal region where BCCs exist as CSCs poses a challenge to target them, mostly due to the coexistence of endogenous hematopoietic stem cells. This study addresses the early period of dormancy when BCCs enter BM at the perivascular region to begin the transition into CSCs, which we propose as the final step in dormancy. A twostep process comprises the Wnt-b-catenin pathway mediating BCC dedifferentiation into CSCs at the BMperivascular niche. At this site, BCCs responded to two types of mesenchymal stem cell (MSC)-released extracellular vesicles (EV) that may include exosomes. Early released EVs began the transition into cycling quiescence, DNA repair, and reorganization into distinct BCC subsets. After contact with breast cancer, the content of EVs changed (primed) to complete dedifferentiation into a more homogeneous population with CSC properties. BCC progenitors (Oct4alo), which are distant from CSCs in a hierarchical stratification, were sensitive to MSC EVs. Despite CSC function, Oct4alo BCCs expressed multipotent pathways similar to CSCs. Oct4alo BCCs dedifferentiated and colocalized with MSCs (murine and human BM) in vivo. Overall, these findings elucidate a mechanism of early dormancy at the BM perivascular region and provide evidence of epigenome reorganization as a potential new therapy for breast cancer