Iron-induced calcification in human aortic vascular smooth muscle cells through interleukin-24 (IL-24), with/without TNF-alpha

Abstract

In CKD patients, arteriosclerotic lesions, including calcification, can occur in vascular smooth muscle cells in a process called Moenckeberg’s medial arteriosclerosis. Iron overload induces several complications, including the acceleration of arteriosclerosis. However, the relationship between Moenckeberg’s arteriosclerosis in vascular smooth muscle cells and iron accumulation has remained unknown. We tested the accelerated effect of iron on calcification in cultured human aortic vascular smooth muscle cells (HASMCs). After establishment of this model, we performed a microarray analysis using mRNA from early stage culture HASMCs after iron stimulation with or without TNF-alpha stimulation. The role of interleukin-24 (IL-24) was confirmed from candidate genes that might contribute to calcification. HASMCs demonstrated calcification induced by iron and TNF-alpha. Calcification of HASMCs was synergistically enhanced by stimulation with both iron and TNF-alpha. In the early phase of calcification, microarray analysis revealed up-regulation of IL-24. Stimulation of HASMCs by IL-24 instead of iron induced calcification. The anti-IL-24 antibody reversed the effect of IL-24, supporting the important role of IL-24 in HASMCs calcification. In conclusion, iron-induced calcification in vascular smooth muscle cells occurred via IL-24, IL-24 was increased during the calcification process induced by iron, and IL-24 itself caused calcification in the absence of iron.

Red Blood Cells and Hemoglobin in Human Atherosclerosis and Related Arterial Diseases

“…As in the early stages of atheroma, lipid accumulation in the fibrosa can promote the development of angiogenesis within the valves, a process always associated with aortic valve diseases. In this context, microcalcifications develop in the fibrosa and could cause neovascularization tears and hemorrhages, which accelerate the calcification process [94], because hemoglobin and its derivatives (heme, ferrous iron, free radicals and NF-kB activation) promote the release of exosomes and the osteoblastic differentiation of valvular interstitial cells [95] as well as of SMCs in the arterial wall [96]. Therefore, there is a vicious circle between calcifications and RBC/iron which promotes exponential development of both valvular and vascular calcifications in association with CV risk factors: aging, tobacco, dyslipidemia, etc.…”

Protective Role of Histidine Supplementation Against Oxidative Stress Damage in the Management of Anemia of Chronic Kidney Disease

“…Atherosclerosis caused by oxidative damage, and evidenced by increased circulating mononuclear superoxide production and vascular cell adhesion molecule-1 (VCAM-1) and triggered by NADPH oxidase (NOx) and NF-kB activation in CKD patients, is associated with IV iron administration [67,68,69,70]. Against this evidence, some studies on the role of iron in CKD pathogenesis showed contradictory results [71]. Iron deposition in the liver of both humans [72] and rats [73] did not develop into cirrhosis, possibly because of iron sequestration into innocuous ferritin L and H subunits.…”

“…Another mechanism that was proposed as a process that prevents iron overload in tissues such as the liver is the secretion of iron-loaded ferritin [74], possibly by an iron-regulated exocytosis efflux process [75] into blood circulation. However, other evidence revealed that high doses of iron were associated with high mortality due to iron-induced oxidative stress [68,71].…”

Blockade of angiotensin AT1 receptors prevents arterial remodelling and stiffening in iron‐overloaded rats

“…In this regard, some reports have indicated that increased iron in vitro enhances calcification of both endothelial (Nanami et al, 2005) and smooth muscle cells (Kawada et al, 2018) through inflammation and oxidative stress. In addition, it has been proposed that aortic calcification may be causally linked to arterial stiffness and increased PWV in humans (Guo et al, 2017;Sekikawa et al, 2012;Tsao et al, 2014) and a rat model of vascular disease (Ng et al, 2011).…”