Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy

Abstract

Excessive body iron or iron overload occurs under conditions such as primary (hereditary) hemochromatosis and secondary iron overload (hemosiderosis), which are reaching epidemic levels worldwide. Primary hemochromatosis is the most common genetic disorder with an allele frequency greater than 10% in individuals of European ancestry, while hemosiderosis is less common but associated with a much higher morbidity and mortality. Iron overload leads to iron deposition in many tissues especially the liver, brain, heart and endocrine tissues. Elevated cardiac iron leads to diastolic dysfunction, arrhythmias and dilated cardiomyopathy, and is the primary determinant of survival in patients with secondary iron overload as well as a leading cause of morbidity and mortality in primary hemochromatosis patients. In addition, iron-induced cardiac injury plays a role in acute iron toxicosis (iron poisoning), myocardial ischemia-reperfusion injury, Friedreich ataxia and neurodegenerative diseases. Patients with iron overload also routinely suffer from a range of endocrinopathies, including diabetes mellitus and anterior pituitary dysfunction. Despite clear connections between elevated iron and clinical disease, iron transport remains poorly understood. While low-capacity divalent metal and transferrin-bound transporters are critical under normal physiological conditions, L-type Ca2+ channels (LTCC) are high-capacity pathways of ferrous iron (Fe2+) uptake into cardiomyocytes especially under iron overload conditions. Fe2+ uptake through L-type Ca2+ channels may also be crucial in other excitable cells such as pancreatic beta cells, anterior pituitary cells and neurons. Consequently, LTCC blockers represent a potential new therapy to reduce the toxic effects of excess iron.

The role of endocytic pathways in cellular uptake of plasma non-transferrin iron

“…3,22 The pathological accumulation of iron in multiple tissues observed in iron overload conditions is thought to be caused by excessive influx of iron into plasma, as well as unbalanced erythrophagocytosis by reticuloendothelial cells in spleen and liver that lead to persistently high circulating NTBI levels which are responsible for the systemic iron dispersal. The hypothesis that tissue iron overload is caused by NTBI is largely based on the assumption that NTBI is randomly transported into cells by unregulated mechanisms, presumably via non-specific divalent cation transporters 23,24 or calcium channels, [25][26][27] subsequent to extracellular reduction of iron(III) to iron(II) by a cell-surface iron reductase such as Dcytb. Chronic exposure of cells in vitro to artificial iron complexes that presumably mimic NTBI (usually ferric citrate) [10][11][12]28,29 has been shown to generate cellular iron overload as indicated by increased ferritin levels, ROS generation, protein and DNA oxidation, and other indicators of cell damage.…”

“…Moreover, in thalassemia or other iron overload disorders, it is not only difficult to experimentally simulate NTBI per se, but also to reproduce the possible chemical modifications of plasma components that become exposed to oxidative stresses due to a rise in labile iron and depletion of antioxidants. 29,30 Despite these limitations, attempts have been made to assess NTBI transport by using NTBI-simulating complexes of radiolabeled iron in protein free settings and by artificial inclusion of reductants in order to render the iron transportable by various voltage activatable Ca channels [25][26][27] or by a putative Zn transporter. 23,24 The pathophysiological significance of such approaches is still a subject of debate, and likewise the effects of Ca-channel blockers on ironassociated cardiac damage.…”

“…As the uptake of rhodamine-dextran added to thalassemia major plasma is not affected by DFO, the contribution of NTBI per se to endocytosis is likely to involve pre-oxidized plasma components, for which there is ample evidence in hypertranfused patients with inadequate chelation treatment. 26 Furthermore, albumin, especially in its oxidized form, has been shown to avidly bind iron 29 and has been suggested to be a possible plasma carrier of NTBI. 29 Considering that the half-life of oxidized human albumin in mice is reduced by almost 50%, mainly due to liver clearance, 30 it is conceivable that oxidized albumin or other plasma components are preferentially endocytosed by macrophages.…”

Iron overload thalassemic cardiomyopathy: Iron status assessment and mechanisms of mechanical and electrical disturbance due to iron toxicity

“…The discrepancy in these findings may be due to differences in the age of animal models. Neonatal myocytes have fewer L-type Ca 2+ channels with a smaller L-type Ca 2+ current than adult myocytes (52). It has been proposed that the Ca 2+ current investigated in cultured neonatal myocytes may be underestimated due to less density in beating cells and more myocyte death (52).…”

“…Oudit et al (51) demonstrated that amlodipine and verapamil reduced intracellular iron accumulation and oxidative stress without disturbing diastolic and systolic function. L-type Ca 2+ channel blockers affect not only cardiomyocytes, but also pancreatic beta cells and anterior pituitary cells, which are important target cells for iron toxicity (52).…”