Thoughts
They corroborate the theory that Fe+2 will make it through the VGCCs. Many used to talk about trying calcium channel blockers to deal with nnEMF effects. They cause my blood pressure to spike and the need to go on oxygen so I won’t be trying this anytime soon. Maybe a low dose natural CCB? Really I would rather get the Fe out of the cell with TTFD. Especially because the paper says this only occurs in cells that express many LVDCCs.
If the CCBs are reducing Fe levels in the cardiac myocytes then what is all that Fe doing in the blood and elsewhere? Still need to address getting it out of the body.
The ability for CCB to block Fe+2 uptake depends on the frequency of the membrane. This is very interesting especially given Fe uptake doesn’t seem to depend on voltage or density.
“L type means it’s long lasting. They are responsible for the excitation-contraction coupling of skeletal, smooth, cardiac muscle, and for aldosterone secretion in endocrine cells of the adrenal cortex. They are also found in neurons, and with the help of L-type calcium channels in endocrine cells, they regulate neurohormones and neurotransmitters. They have also been seen to play a role in gene expression, mRNA stability, neuronal survival, ischemic-induced axonal injury, synaptic efficacy, and both activation and deactivation of other ion channels.”
“The most predominant way of autoinhibition of L-type calcium channels is with the Ca+2/Cam complex. As the pore opens and causes an influx of Calcium, calcium binds to calmodulin and then interacts with the loop that connects the adjacent EF-hand motifs {bind Ca+2} and causes a conformational change in the EF-hand motif so it interacts with the pore to cause quick inhibition in the channel. It is still debated on where and how the pore and EF-hand interact. Hydrophobic pockets in the Ca+2/Cam complex will also bind to three sections of the IQ domain known as the “aromatic anchors”. The CA+2/Cam complex has a high affinity towards L-type calcium channels, allowing it to get blocked even when there are low amounts of calcium present in the cell. The pore eventually closes as the cell repolarizes and causes a conformational change in the channel to put it in the closed conformation.”
https://en.m.wikipedia.org/wiki/L-type_calcium_channel
Given the organs that express the most LVDCCs, Morleys thoughts about Fe buildup causing what we term diseases is along the right path. Though it’s interesting that liver cells don’t express functional ones. Maybe Fe isn’t the cause of liver and liver related issues.
NTBI is non-transferrin bound iron – this is unbound iron.
Highlights
hypothesize that in iron-overload disorders, iron accumulation in the heart depends on ferrous iron (Fe2+) permeation through the L-type voltage-dependent Ca2+ channel (LVDCC), a promiscuous divalent cation transporter. results indicate that cardiac LVDCCs are key transporters of iron into cardiomyocytes under iron-overloaded conditions, and potentially represent a new therapeutic target to reduce the cardiovascular burden from iron overload.
The prevalence of primary (hereditary) hemochromatosis and sec- ondary iron overload (hemosiderosis) is reaching epidemic levels worldwide1–5. Primary hemochromatosis is the most common genetic disorder in white individuals of European ancestry, with an allele fre- quency >10% (refs. 2,6). Iron overload leads to excessive iron deposi- tion in a wide variety of tissues, including the heart and endocrine tissues7–9. Iron-overload cardiomyopathy is the main determinant of survival in patients with secondary iron overload10–12. Although liver dysfunction and cirrhosis are the main causes of death in patients with primary hemochromatosis3,13, iron-induced cardiac dysfunction is also a leading cause of morbidity and mortality in these patients13–16. Elevated cardiac iron causes marked diastolic dysfunction, increased propensity for arrhythmias and late-stage dilated cardiomyopa- thy12,14–19. In addition to cardiac dysfunction, iron-overloaded patients routinely suffer from a range of endocrinopathies, including diabetes mellitus and anterior pituitary dysfunction3,8,20,21. The cur- rent mainstays of therapy for excessive iron deposition in patients with primary and secondary hemochromatosis are phlebotomy and iron chelation, respectively, which are designed to promote whole-body iron removal. Unfortunately, patients with primary hemochromatosis are often treated only after iron overload becomes advanced13,15,22, and chelation therapy is cumbersome and associated with toxic side effects, with only a limited impact on clinical outcome in patients suf- fering from secondary iron overload.
Generally, cellular iron uptake into cells is tightly regulated and occurs through a combination of transferrin-dependent and trans- ferrin-independent (non-transferrin-bound iron, or NTBI) path- ways3,27–29. Under conditions of iron overload, the trans- ferrin-dependent system becomes inhibited and excessive iron accu- mulation occurs predominantly through the NTBI pathway3,27–31. Iron uptake through the NTBI pathway activates a positive feedback system whereby the uptake of iron is further enhanced27,28,30. Several metal transport systems such as LVDCCs, which show promiscuous permeation by divalent metal ions32,33, and the divalent metal trans- porter-1 (DCT-1/DMT-1) can contribute to NTBI uptake in heart and other tissues. The DCT-1/DMT-1 system is expressed weakly in the heart and, like the transferrin system, its expression is negatively regulated by iron levels29,31,34, suggesting a limited role in NTBI uptake in the heart. In contrast, cardiac sarcolemmal LVDCCs are expected to be especially important for the excessive NTBI uptake under conditions of iron overload for several reasons. First, NTBI uptake involves the transport of the reduced form of iron (Fe2+), which is the iron species permeating LVDCCs in cardiomy- ocytes28,30,32,33 and Langendorff hearts32. Second, as with NTBI uptake, LVDCC currents can be increased when the concentration of Fe2+ is elevated32. Third, a common feature of cells susceptible to iron overload, such as cardiac myocytes, pancreatic β-cells and anterior pituitary cells, is the large number and activity of LVDCC
specific analysis of the collagen volume fraction, using picrosirius red–stained sections, revealed a sixfold increase in the iron + vehicle group (0.53 ± 0.18 for placebo + vehicle versus 3.4 ± 1.2% for iron + vehicle; n = 4; P < 0.01). Moreover, in mice injected with iron and treated with verapamil, the colla- gen volume fraction was markedly reduced
significant increases (P < 0.01) in cardiomyocyte apoptosis in mice injected with iron (Fig. 2f), suggesting that the increased fibrosis in these mice resulted in part from increased myocyte loss. As with the functional changes, treatment with CCBs reduced the composite index of myocardial damage and inflammation and the degree of apoptosis by similar amounts
CCBs selectively reduced the iron deposition in myocytes without affecting extramyocyte iron accu- mulation (Fig. 2c,d,g). Analytical electron microscopy coupled with X-ray microscopic analysis confirmed iron accumulation in cardiomyocytes and showed that iron is deposited throughout the sarcoplasm, particularly in the perinuclear and subsarcolemmal regions as iron-containing electron dense bodies
hepatic iron levels were unaffected by treatment with CCBs. hepatocytes do not express functional LVDCCs.
strongly implicate LVDCCs in NTBI accumulation into the myocardium during iron overload. Previous results have shown that the DCT-1/DMT-1 and transferrin transport systems are downregulated in their expression and activity in iron overload conditions. In contrast, one key estab- lished and unique feature of NTBI transport is the lack of downregula- tion in iron-overload tissues. Indeed, there was no difference in the density and voltage dependence (Fig. 4e) or kinetic properties (Fig. 4f) of LVDCC currents in cardiomyocytes from placebo-injected com- pared with iron-injected mice, suggesting that iron-mediated uptake through the LVDCC is not under a negative feedback control mecha- nism.
The DCT-1/DMT-1 and transferrin iron transport systems are regu- lated in a negative-feedback manner by both transcriptional (iron- responsive elements) and translational mechanisms3,29,31. In contrast, NTBI uptake into excitable cells such as cardiomyocytes is accelerated in iron-overload conditions27,28,30 and requires reduction of ferric iron (Fe3+) to ferrous iron (Fe2+) by a membrane-associated ferri- reductase system28–30,53,54. The heart and certain endocrine tissues (endocrine pancreas and anterior pituitary) are particularly suscepti- ble to secondary iron overload and possess a high abundance and activity of LVDCCs35,36,38,39. Because previous studies have shown that cardiac LVDCCs can transport Fe2+ ions in myocytes and Langendorff hearts32,33 and that cardiac LVDCC current increases in the presence of elevated reduced iron32, we hypothesized that NTBI uptake by the heart in vivo occurs mainly through LVDCCs in car- diomyocytes. Consistent with our hypothesis, myocardial iron deposi- tion is reduced, while survival, myocardial ultrastructure and cardiac function are improved, by treating iron-overloaded mice with amlodipine or verapamil at dosages yielding therapeutic plasma levels similar to those reported in patients treated with these drugs41,48–50. Moreover, peak plasma levels of CCBs in our mice inhibit the net car- diac LVDCC current per beat by more than 50%. The crucial role of LVDCCs in cardiac NTBI iron is further supported by our observation that iron injection in transgenic mice overexpressing functional LVDCC in cardiomyocytes35,51 resulted in greater myocardial iron accumulation and oxidative stress and deterioration in cardiac func- tion compared with iron-injected littermate control mice. Moreover, treatment of iron-overloaded transgenic mice with verapamil reduced myocardial iron levels by about 50% and markedly improved cardiac performance. In contrast to the heart, treatment with CCBs had no effect on iron levels in the liver, as expected from our hypothesis because this tissue is devoid of LVDCCs
In addition, unlike other candidate NTBI iron transporters such as DCT- 1/DMT-1 (refs. 29,31,34), no downregulation of LVDCC current was observed in myocytes from iron-overloaded mice. This lack of down- regulation of LVDCC current in iron overload, combined with the ability of elevated Fe2+to increased LVDCC current in cardiomy- ocytes32 is expected to increase cardiac iron transport, as required for the NTBI transport system, under iron-overload conditions
iron-mediated free-radical generation and elevated oxidative stress as major determinants of cardiotoxicity and apoptosis associated with iron-overload44,45,55, as well as in patients with pri- mary hemochromatosis46 and thalassemia47. Consistent with this sug- gestion, free-radical generation, as assessed by tissue aldehyde levels (the end-products of lipid peroxidation56,57), were markedly elevated in iron-overloaded mice and correlated strongly with iron levels as well as the structural and functional changes in the heart. Indeed, iron- overloaded mice showed elevated aldehyde and iron levels associated with impaired structure and function in the heart, all of which were exacerbated in iron-treated transgenic mice with elevated LVDCC current while being improved by CCB treatment.
Kathleen Stewart 