Iron metabolism is a complex multistep process that begins with dietary uptake into the body. Iron is transported in the circulatory system to target tissues, mainly sites of erythrocyte production ( bone marrow ) and iron storage ( liver ). Extracellular iron exists bound to plasma proteins transferrin and ferritin, and as non-transferrin bound iron. Iron transport across cellular membranes involving transferrin receptors, divalent metal transporter (DMT-1 or Nramp-2), and within cellular matrix of cells is necessary for its incorporation into many cellular haem and non-haem iron-containing proteins. The mechanism and regulation of cellular iron homeostasis also involves other proteins (iron-responsive elements and iron-response element-binding proteins). Iron deficiency or iron overload may arise from defects in any of these processes, and result in various complications.
A current controversy is whether increased amounts of stored iron contribute to cardiac dysfunction, including coronary and ischemic heart disease. It is well established that excess iron accumulation damages the liver, possibly through increased lipid peroxidation and changes to cellular enzyme levels. This mechanism may also underlie the cardiac dysfunction observed in conditions of iron excess.
My research attempts to establish whether excess iron will increase lipid peroxidation and change the levels of crucial enzymes in cardiac tissues. Some of these enzymes are related to myocardial organelle functions, while others are markers for cardiac damage and known antioxidants. The extent of iron loading in the heart is also being investigated. These are some of the questions that the laboratory is trying to answer.
How is the level of iron stores related to the amount of iron in the heart?
Though it is well established that serum ferritin, in particular, is very well
correlated to stored hepatic iron, there is no direct measurement of cardiac
iron for comparison with serum ferritin or liver iron. Another question is that,
since the liver is the main storage organ for iron, does the liver iron need
to reach a certain level before iron starts to appear in other organs, in this
case the organ of interest being the heart? Iron must first accumulate in the
myocardial cells before damage can occur. While in vitro work has shown this
to be true, no in vivo reports has been published. A further question is if
there is iron accumulation in the heart due to iron excess in the body, where
is the iron located?
In many disease states, there are alterations in the level of plasma proteins. These changes may be causative factors in disease, or may result from disease. Various plasma proteins may also interact with each other and with tissues. Of particular interest is that some plasma proteins have anti-oxidant properties while others are pro-oxidants. The level of these proteins at any particular time and their interactions with one another may contribute to the disease state.
Some work on iron excess and its possible consequences in patients with sickle cells anemia, and with iron excess, in particular b-thalassemia patients, had been published. The conclusions of these papers are that in both situations there is a likelihood of excess iron in the cell and the association of these iron with the membrane. The iron can interact with the membrane lipids and can bring about lipid peroxidation, especially since the red cells are constantly exposed to a high oxygen environment. This could then damage the membrane and impair its functions.
These are some of the questions that the laboratory is trying to answer.
Does the presence of increased iron, whether it is inside the cells or in the surrounding environment, contribute to this observation? Does the presence of increased iron create an environment in which the cellular membrane is more prone to lipid peroxidation, weakening the structure of the membrane and thus making the cells more fragile? Is any particular structural protein involved? Are the leukocytes affected? Does plasma protein contribute a protective or causative role to this damage?