Inflammation, dysregulated iron metabolism, and cardiovascular disease

Abstract

Iron is an essential trace element associated with both pathologic deficiency and toxic overload. Thus, systemic and cell iron metabolism are highly controlled processes regulated by protein expression and localization, as well as turnover, through the action of cytokines and iron status. Iron metabolism in the heart is challenging because both iron overload and deficiency are associated with cardiac disease. Also associated with cardiovascular disease is inflammation, as many cardiac diseases are caused by or include an inflammatory component. In addition, iron metabolism and inflammation are closely linked. Hepcidin, the master regulator of systemic iron metabolism, is induced by the cytokine IL-6 and as such is among the acute phase proteins secreted by the liver as part of the inflammatory response. In an inflammatory state, systemic iron homeostasis is dysregulated, commonly resulting in hypoferremia, or low serum iron. Less well characterized is cardiac iron metabolism in general, and even less is known about how inflammation impacts heart iron handling. This review highlights what is known with respect to iron metabolism in the heart. Expression of iron metabolism-related proteins and processes of iron uptake and efflux in these cell types are outlined. Evidence for the strong co-morbid relationship between inflammation and cardiac disease is also reviewed. Known connections between inflammatory processes and iron metabolism in the heart are discussed with the goal of linking inflammation and iron metabolism in this tissue, a connection that has been relatively under-appreciated as a component of heart function in an inflammatory state. Therapeutic options connecting inflammation and iron balance are emphasized, with the main goal of this review being to bring attention to alterations in iron balance as a component of inflammatory diseases of the cardiovascular system.

Interleukin-mediated therapies in liver diseases and comorbidity effects

“…Heart disease has been linked to abnormal iron levels, both low and overloaded[ 22 ]. Systemic iron metabolism is regulated by hepcidin itself induced by IL-6.…”

“…Hepcidin is an acute-phase protein released by the liver in response to inflammation. During inflammation, the homeostasis of systemic iron is dysregulated, which may lead to low blood iron levels[ 22 ]. Thus, the underlying mechanisms of iron regulation and inflammatory processes are linked, and these processes occur in the cardiovascular system, particularly in heart diseases.…”

Application of 4D printing and bioprinting in cardiovascular tissue engineering

“…Thus, it is worth emphasizing what is understood about cells of the heart and cardiac disease relating to inflammation and iron handling, with the hope of bringing attention to iron metabolism as a therapeutic target for cardiovascular disease. 74 Stimulus materials that respond to pH pH-responsive materials, commonly referred to as pH-sensitive or pH-responsive gels, exhibit unique properties that can be modulated in response to changes in the pH value of their environment. These materials are typically composed of hydrogel networks, which are three-dimensional crosslinked polymer structures capable of swelling or shrinking in response to pH variations.…”

“…Thus, it is worth emphasizing what is understood about cells of the heart and cardiac disease relating to inflammation and iron handling, with the hope of bringing attention to iron metabolism as a therapeutic target for cardiovascular disease. 74…”

Calcium and IL-6 regulate the anterograde trafficking and plasma membrane residence of the iron exporter ferroportin to modulate iron efflux

“…The abluminal space in the brain and the heart are protected from circulating iron, whether transferrin-bound iron (TBI) or nontransferrin-bound iron (NTBI), by an impermeable endothelial cell barrier. Dysregulated iron metabolism within these tissues is a key factor in both neurodegenerative and cardiovascular diseases, therefore iron handling at these barriers needs to be precisely controlled ( 3 , 4 ).…”