| dc.description.abstract | Hyperphosphatemia is a significant risk factor for vascular calcification, which is closely linked to increased cardiovascular morbidity and mortality. Recent research indicates that oxidative stress induced by high inorganic phosphate (Pi) levels contributes to calcific changes in vascular smooth muscle cells (VSMCs). However, the specific intracellular signaling pathways responsible for Pi-induced oxidative stress remain poorly understood.
In this study, we investigated the molecular mechanisms underlying Pi-induced oxidative stress in relation to disturbances in intracellular calcium concentration ([Ca2+]i), which is crucial for VSMC calcification. VSMCs isolated from rat thoracic aorta and A7r5 cells were exposed to a high Pi-containing medium. Our results showed that high Pi activates extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin, which are necessary for vascular calcification. High Pi also upregulated the expression of type III sodium-phosphate cotransporters, PiT-1 and -2, and facilitated their trafficking to the plasma membrane.
Interestingly, high Pi increased [Ca2+]i in a manner dependent on extracellular Na+ and Ca2+, as well as PiT-1/2 abundance. This was associated with plasma membrane depolarization mediated by PiT-1/2. Pretreatment with verapamil, a voltage-gated Ca2+ channel (VGCC) blocker, inhibited Pi-induced [Ca2+]i elevation, oxidative stress, ERK activation, and osteogenic differentiation. These protective effects were also observed under conditions of extracellular Ca2+ depletion, intracellular Ca2+ chelation, or oxidative stress suppression. Additionally, mitochondrial superoxide scavengers effectively mitigated ERK activation and osteogenic differentiation induced by high Pi.
In summary, our findings suggest that high Pi activates Ca2+ influx via VGCCs through depolarization, leading to increased [Ca2+]i, oxidative stress, and osteogenic differentiation in VSMCs. | en_US |
