Inhibition of mitochondrial phosphate carrier prevents high phosphate-induced superoxide generation and vascular calcification

초록

Vascular disease: Phosphate transport protein implicated in blood vessel stiffeningDrugs that block the transport of phosphate ions into mitochondria, the 'powerhouses' of the cell, could prevent life-threatening stiffening of blood vessel walls. Using smooth muscle cells taken from rat aortas, Kyu-Sang Park of Yonsei University Wonju College of Medicine, South Korea, and colleagues showed how mitochondrial uptake of phosphate via phosphate transport proteins triggered toxic metabolite generation, increased activity of bone formation genes and other reactions that collectively drive the deposition of minerals, leading to vascular stiffening. Suppression of the proteins' activity, either using drug-like compounds or by genetic means, reduced these pathological changes in mice. The findings highlight the therapeutic potential of such an approach in people with elevated serum phosphate leading to calcium build-up within their vessel walls, a major risk factor for cardiovascular disease. Vascular calcification is a serious complication of hyperphosphatemia that causes cardiovascular morbidity and mortality. Previous studies have reported that plasmalemmal phosphate (Pi) transporters, such as PiT-1/2, mediate depolarization, Ca2+ influx, oxidative stress, and calcific changes in vascular smooth muscle cells (VSMCs). However, the pathogenic mechanism of mitochondrial Pi uptake in vascular calcification associated with hyperphosphatemia has not been elucidated. We demonstrated that the phosphate carrier (PiC) is the dominant mitochondrial Pi transporter responsible for high Pi-induced superoxide generation, osteogenic gene upregulation, and calcific changes in primary VSMCs isolated from rat aortas. Notably, acute incubation with high Pi markedly increased the protein abundance of PiC via ERK1/2- and mTOR-dependent translational upregulation. Genetic suppression of PiC prevented Pi-induced ERK1/2 activation, superoxide production, osteogenic differentiation, and vascular calcification of VSMCs in vitro and aortic rings ex vivo. Pharmacological inhibition of mitochondrial Pi transport using butyl malonate (BMA) or mersalyl abolished all pathologic changes involved in high Pi-induced vascular calcification. BMA or mersalyl also effectively prevented osteogenic gene upregulation and calcification of aortas from 5/6 subtotal nephrectomized mice fed a high-Pi diet. Our results suggest that mitochondrial Pi uptake via PiC is a critical molecular mechanism mediating mitochondrial superoxide generation and pathogenic calcific changes, which could be a novel therapeutic target for treating vascular calcification associated with hyperphosphatemia.

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