scholarly journals L-type calcium channel blockers decrease the iron overload-mediated oxidative stress in renal epithelial cells by reducing iron accumulation

2020 ◽  
Vol 886 ◽  
pp. 173513
Author(s):  
Linfeng Sun ◽  
Xiaoding Lin ◽  
Sakorn Pornprasert ◽  
Xiaomei Lü ◽  
Bing Ran ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Iron Overload ◽  
Calcium Channel ◽  
Calcium Channel Blockers ◽  
Iron Accumulation ◽  
Channel Blockers ◽  
Renal Epithelial Cells

scholarly journals Metal-Ion Transporter SLC39A14 Is Required for Cardiac Iron Loading in the Hjv Mouse Model of Iron Overload

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 758-758
Author(s):  
Qingli Liu ◽  
Corbin Azucenas ◽  
Bryan Mackenzie ◽  
Mitchell Knutson
Keyword(s):  
Calcium Channels ◽  
Iron Overload ◽  
Calcium Channel ◽  
Calcium Channel Blockers ◽  
Knockout Mice ◽  
Iron Uptake ◽  
Nonheme Iron ◽  
Channel Blockers ◽  
Iron Loading ◽  
Cardiac Iron

Abstract Although iron overload-related cardiomyopathy is a leading cause of morbidity and mortality in iron-overload disorders (e.g., thalassemia major and hemochromatosis), the molecular mechanisms that mediate cardiac iron uptake and accumulation are incompletely understood. Previous studies using Slc39a14 knockout mice have revealed that SLC39A14 is required for the uptake of non-transferrin-bound iron (NTBI) by the liver and pancreas and is essential for iron loading of hepatocytes and pancreatic acinar cells. To investigate the requirement for SLC39A14 in cardiac iron accumulation, we generated cardiomyocyte-specific Slc39a14 knockout (Slc39a14 hrt/hrt) mice and crossed them with iron-loading hemojuvelin (Hjv) knockout mice to generate Hjv -/-;Slc39a14 hrt/hrt animals. At 12 and 24 weeks of age, cardiac nonheme iron levels were ~340% higher in Hjv -/- mice than in controls. By contrast, cardiac nonheme iron levels in Hjv -/-;Slc39a14 hrt/hrt mice at these ages were only ~60% higher than those than in controls, and ~65% less than those in Hjv -/- mice. Moreover, cardiac nonheme iron levels in Hjv -/-;Slc39a14 +/hrt (heterozygous conditional Slc39a14 knockout) mice were between those of Hjv -/- and Hjv -/-;Slc39a14 hrt/hrt mice, suggesting a gene-dosage effect of Slc39a14 on cardiac iron accumulation. A role for voltage-dependent calcium channels in mediating the uptake of NTBI into cardiomyocytes has been proposed based on observations of the effects of L-type calcium-channel blockers on iron uptake and accumulation in vitro and in vivo. We considered the possibility that these observations could be explained if SLC39A14 were reactive with calcium-channel blockers. To test this hypothesis, we examined the effects of blockers on the activity of SLC39A14 by using radiotracer assays in RNA-injected Xenopus oocytes expressing mouse SLC39A14. We found that 100 µM amlodipine (Amld), nifedipine, and nicardipine each afforded modest inhibition of SLC39A14-mediated 55Fe 2+. Inhibition of iron transport by Amld was dose-dependent, EC 50 = 167 µM ± (SEM) 30 µM. Our findings implicate SLC39A14 in mediating cardiomyocyte NTBI uptake in the mouse and raise doubts about the relative importance of calcium channels as a mechanism by which NTBI gains entry to the heart. Disclosures No relevant conflicts of interest to declare.

Dihydropyridine calcium channel blockers inhibit non-esterified-fatty-acid-induced endothelial and rheological dysfunction

2013 ◽  
Vol 125 (5) ◽  
pp. 247-255 ◽  
Author(s):  
Takanori Yasu ◽  
Mayumi Kobayashi ◽  
Akiko Mutoh ◽  
Ken Yamakawa ◽  
Shin-ichi Momomura ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Calcium Channel ◽  
Transit Time ◽  
Calcium Channel Blockers ◽  
Whole Blood ◽  
Channel Blockers ◽  
Reactive Oxygen Metabolites ◽  
Antihypertensive Properties

Circulating NEFAs (non-esterified fatty acids) from adipose tissue lipolysis lead to endothelial dysfunction and insulin resistance in patients with the metabolic syndrome or Type 2 diabetes mellitus. The aim of the present study was to test the hypothesis that DHP (dihydropyridine) CCBs (calcium channel blockers) prevent NEFA-induced endothelial and haemorheological dysfunction independently of their antihypertensive properties. Using a double-blind cross-over study design, nifedipine, amlodipine, diltiazem or placebo were administered to eight healthy subjects for 2 days before each study day. On the study days, the following were assessed before and after the infusion of lipid and heparin to raise serum NEFAs: endothelial function, by measuring FBF (forearm blood flow) responses to ACh (acetylcholine); leucocyte activation, by ex vivo measurement of plasma MPO (myeloperoxidase) levels, adherent leucocyte numbers and whole blood transit time through microchannels; and oxidative stress, by determining plasma levels of d-ROMs (derivatives of reactive oxygen metabolites). Effects of the CCBs on NF-κB (nuclear factor κB) p65 phospholylation stimulated by NEFAs were assessed in cultured monocytic cells in vitro. Elevated NEFAs reduced the responses to ACh and significantly increased whole blood transit time, adherent leucocyte numbers and d-ROMs. Nifedipine and amlodipine, but not diltiazem, prevented NEFA-induced endothelial dysfunction, leucocyte activation and enhancement of oxidative stress without affecting BP (blood pressure), whereas all these drugs prevented NEFA-induced p65 activation in vitro. These results suggest that DHP CCBs, independent of their antihypertensive properties in humans, prevent NEFA-induced endothelial and haemorheological dysfunction through inhibition of NEFA-induced leucocyte activation, although the sensitivity to drugs of leucocyte Ca2+ channels may differ among cells.

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