| dc.description.abstract | Inorganic phosphate (Pi) is crucial for cellular functions, but excessive Pi can lead to serious complications, including vascular calcification. Recent studies have highlighted the role of oxidative stress in the progression of calcific changes associated with elevated Pi levels. However, the detailed molecular mechanisms behind Pi-induced reactive oxygen species (ROS) generation and its harmful effects are not fully understood.
Type III Na+-dependent Pi cotransporters, PiT-1 and PiT-2, are key players in the uptake of Pi by vascular smooth muscle cells (VSMCs). The influx of Pi through PiT-1 and PiT-2 enhances the abundance of these transporters and facilitates depolarization-activated Ca2+ entry due to their electrogenic properties. This process can lead to overload of both Ca2+ and Pi, contributing to oxidative stress.
Among the suggested mitochondrial Pi transporters, the phosphate carrier (PiC) is primarily involved in mitochondrial Pi uptake. Transport of Pi via PiC may induce mitochondrial hyperpolarization and superoxide generation, resulting in mitochondrial dysfunction and endoplasmic reticulum stress, as well as an increase in cytosolic ROS.
The synergistic increase in intracellular Ca2+ and Pi levels, and their accumulation in the cytosol and mitochondrial matrix, further amplifies oxidative stress and promotes osteogenic differentiation in VSMCs. This detrimental cascade can be mitigated by targeting either Ca2+ or Pi overload.
Overall, our findings suggest that therapeutic strategies aimed at inhibiting plasmalemmal and mitochondrial Pi transporters could offer protection against Pi-induced oxidative stress and vascular calcification. | en_US |
