Vascular calcification is a life-threatening clinical condition in chronic kidney disease (CKD) and is associated with reduced zinc serum levels. Anemia is another frequent complication of CKD. Hypoxia-inducible factor (HIF) stabilizers, also known as HIF prolyl hydroxylase inhibitors (PHI), are promising candidates to treat CKD-associated anemia by increasing erythropoietin synthesis. Recent evidence suggests that HIFs play a pivotal role in vascular calcification. Our study explored feasible impacts of HIF PHI on phosphate (Pi)-induced calcification of vascular smooth muscle cells (VSMCs) and tested whether zinc might inhibit this mineralization process. Treatment of VSMCs with PHI aggravated Pi-induced calcium deposition and Pi uptake. PHI promoted Pi-induced loss of smooth muscle cell markers (ACTA-2, MYH11, SM22α) and enhanced osteochondrogenic gene expression (Msx-2, BMP-2, Sp7) triggering osteochondrogenic phenotypic switch of VSMCs. These effects of PHI paralleled with increased pyruvate dehydrogenase kinase 4 (PDK4) expression, decreased Runx2 Ser451 phosphorylation, and reduced cell viability. Zinc inhibited Pi-induced mineralization of VSMCs in a dose-dependent manner and also attenuated the procalcification effect of PHI in Pi-induced mineralization. Zinc inhibited osteochondrogenic phenotypic switch of VSMCs reflected by lowering Pi uptake, decreasing the expressions of Msx-2, BMP-2, and Sp7 as well as the loss of smooth muscle cellspecific markers. Zinc preserved phosphorylation state of Runx2 Ser451, decreased PDK4 level, and restored cell viability. PHI alone reduced the expression of smooth muscle markers without inducing mineralization, which was also inhibited by zinc. In addition, we observed a significantly lower serum zinc level in CKD as well as in patients undergoing carotid endarterectomy compared to healthy individuals. Conclusion-PHI promoted the loss of smooth muscle markers and augmented

Vascular calcification is a frequent complication of atherosclerosis, diabetes and chronic kidney disease. In the latter group of patients, calcification is commonly seen in tunica media where smooth muscle cells (SMC) undergo osteoblastic transformation. Risk factors such as elevated phosphorus levels and vitamin D3 analogues have been identified. In the light of earlier observations by our group and others, we sought to inhibit SMC calcification via induction of ferritin. Human aortic SMC were cultured using β‐glycerophosphate with activated vitamin D3, or inorganic phosphate with calcium, and induction of alkaline phosphatase (ALP) and osteocalcin as well as accumulation of calcium were used to monitor osteoblastic transformation. In addition, to examine the role of vitamin D3 analogues, plasma samples from patients on haemodialysis who had received calcitriol or paricalcitol were tested for their tendency to induce calcification of SMC. Addition of exogenous ferritin mitigates the transformation of SMC into osteoblast‐like cells. Importantly, pharmacological induction of heavy chain ferritin by 3H‐1,2‐Dithiole‐3‐thione was able to inhibit the SMC transition into osteoblast‐like cells and calcification of extracellular matrix. Plasma samples collected from patients after the administration of activated vitamin D3 caused significantly increased ALP activity in SMC compared to the samples drawn prior to activated vitamin D3 and here, again induction of ferritin diminished the osteoblastic transformation. Our data suggests that pharmacological induction of ferritin prevents osteoblastic transformation of SMC. Hence, utilization of such agents that will cause enhanced ferritin synthesis may have important clinical applications in prevention of vascular calcification.

A rendszeres dialíziskezelésre szoruló vesebetegek körében a halálozási ok leggyakrabban valamilyen cardiovascularis megbetegedés. A cardiovascularis események egyik előidézője a vascularis kalcifi káció, amelynek kialakulási esélye a krónikus vesebetegek körében extrém magas. A kalcifi káció nemcsak az évtizedek óta dialízisterápiában részesülő idősebb korosztályban jelentkezik, hanem a fi atal korosztályt is érinti. Az érrendszerben megjelenő masszív, nagy kiterjedésű kalcifi káció aktív, jól szabályozott komplex folyamat eredményeként alakul ki. Előidézői között szerepel az oxidatív stressz, amely a beteg szervezetében a vese működési zavara következtében nagymértékben fokozódik. A megemelkedett oxidatív terhelést tovább fokozzák a képződő oxidált LDL-formák, amelyek előidézői az endothelialis diszfunkciónak és az érben található simaizomsejtek csontszerű sejtté történő transzdifferenciációjának. Az oxidált hemoglobinból kiszabaduló szabad hem is képes az LDL oxidációjára és ezzel hozzájárul az atherosclerosis kialakulásához. A hemoxigenáz-1/ferritin rendszer indukciója mérsékli a szabad hem ezen káros hatásait. Orv. Hetil., 2015Hetil., , 156(47), 1926Hetil., -1931 Kulcsszavak: vascularis kalcifi káció, krónikus veseelégtelenség, oxidatív stressz, oxidált LDL Oxidative stress: one of the major causes of vascular calcifi cation in chronic kidney disease patientsThe leading cause of high mortality in dialyzed patients is cardiovascular disease. One of the main contributors of cardiovascular event is vascular calcifi cation, which occurs even in very young patients. Multiple factors and complex mechanisms are involved in the formation of robust vascular calcifi cation which affects a large vascular area observed in chronic kidney diseases. Patients on dialysis are exposed to enhanced oxidative stress as a result of increased prooxidant activity and reduced anti-oxidant systems. The oxidation of lipoprotein particles is implicated in the development of vascular damage representing oxidative threat, which leads to endothelial dysfunction. Moreover, in a prooxidant environment osteoblastic trans-differentiation of smooth muscle cells was shown to occur. Heme derived from oxidized hemoglobin might contribute to the formation of reactive lipid metabolites. This oxidative burden contributes to the development of atherosclerosis and vascular calcifi cation. Heme oxygenase-1 and ferritin may serve as intracellular defense mechanisms against such an insult.Keywords: vascular calcifi cation, renal insuffi ciency, oxidative stress, oxidized LDL Nyitrai, M., Balla, Gy., Balla, J. [Oxidative stress: one of the major causes of vascular calcifi cation in chronic kidney disease patients].

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