Endothelial dysfunction is a crucial event in the early pathogenesis of cardiovascular diseases and is linked to magnesium (Mg) deficiency. Indeed, in endothelial cells, low Mg levels promote the acquisition of a pro-inflammatory and pro-atherogenic phenotype. This paper investigates the mechanisms by which Mg deficiency promotes oxidative stress and affects endothelial behavior in human umbilical vascular endothelial cells (HUVECs). Our data show that low Mg levels trigger oxidative stress initially by increasing NAPDH oxidase activity and then by upregulating the pro-oxidant thioredoxin-interacting protein TXNIP. The overproduction of reactive oxygen species (ROS) activates NF-κB, leading to its increased binding to the inducible nitric oxide synthase (iNOS) promoter, with the consequent increase in iNOS expression. The increased levels of nitric oxide (NO) generated by upregulated iNOS contribute to disrupting endothelial cell function by inhibiting growth and increasing permeability. In conclusion, we provide evidence that multiple mechanisms contribute to generate a pro-oxidant state under low-Mg conditions, ultimately affecting endothelial physiology. These data add support to the notion that adequate Mg levels play a significant role in preserving cardiovascular health and may suggest new approaches to prevent or manage cardiovascular diseases.

Mesenchymal stem cells (MSCs) are multipotent progenitors capable of self-renewal and differentiation into various cell lineages, making them essential for tissue repair and regenerative medicine. However, their regenerative potential is constrained by replicative senescence, an irreversible growth arrest that occurs after a finite number of cell divisions. In this study, we serially passaged human bone marrow-derived MSCs (bMSCs) and compared young, pre-senescent, and senescent cells. The onset of senescence was accompanied by progressive alterations in mitochondrial dynamics, leading to a decline in mitochondrial membrane potential, and increased reactive oxygen species (ROS) production, alongside a diminished cellular antioxidant capacity. These mitochondrial defects play a role in metabolic reprogramming in senescent bMSCs. Our findings underscore the intricate interplay between ROS, mitochondrial dysfunction, and replicative senescence, offering valuable insights to guide the development of therapeutic strategies for preserving MSC functionality in aging and MSC-based therapies.