Role Of Inflammation In Arterial Calcification

INFLAMMATION

Atherosclerosis is a chronic inflammatory process characterized by interactions among macrophages, endothelial cells and VSMCs. Inflammation is the key process that links the risk factors of cardiovascular disease with atherogenesis.49) Inflammation is not only important for progression of atherosclerosis but is an important trigger for vascular calcification. Studies have demonstrated that inflammation of the arteries precedes the development of arterial calcification. In a study by Aikawa et al.,50) a strong association between macrophage burden and osteogenic activity was demonstrated in vivo in the arteries of apolipoprotein E−/− mice. Also, in a study by Abdelbaky et al.,51) 137 patients who underwent positron-emission tomography/computed tomography 1–5 years apart were analyzed. The results demonstrated that an increased inflammatory signal at baseline was associated with subsequent vascular calcification at the corresponding segments of the aortic wall. The results of the above-mentioned studies suggest that inflammation is the key driver and precursor of vascular calcification.

As mentioned previously, osteoblastic trans-differentiation of VSMCs is a key process in vascular calcification. Specific knockout of Runx2, the key transcription factor for osteoblastic differentiation, in VSMCs has been shown to be significantly associated with inhibition of vascular calcification.52), 53) Osteoblastic transformation of VSMCs is characterized by loss of SMC markers, such as SM22α and SM α-actin, and gain of osteogenic markers such as Runx2, osteopontin and ALP.10) Matrix vesicles released by osteoblast-like cells are important in hydroxyapatite crystal formation and subsequent calcification.54) In normal states, VSMCs are maintained in contractile phenotype usually in the media layer. However, VSMCs have diverse plasticity and may trans-differentiate into foam cell-like cells, osteoblast-like cells and chondrocyte-like cells in response to various stimuli such as vascular injury and inflammation.10) Inflammation is the key process that mediates osteoblastic trans-differentiation of VSMCs. M1 macrophages, by secreting pro-inflammatory cytokines, promote vascular calcification by inducing osteoblastic trans-differentiation of VSMCs. Cytokines derived from M1 macrophages, such as oncostatin M, interleukin-1β, interleukin-6, and tumor necrosis factor (TNF)-α, induce osteoblastic trans-differentiation.55), 56), 57) In a study by Menini et al.,58) 62 human carotid plaques obtained after carotid endarterectomy were assessed for plaque instability, type of calcification, markers of inflammation and presence of markers of osteogenesis. The study demonstrated higher expression of receptor for advanced glycation end-product (RAGE), interferon-γ and TNF-α in unstable plaques with microcalcification compared to stable plaques with macrocalcification. This suggests that inflammation is the key process that precedes the development of vascular calcification and microcalcification that increases the risk of plaque progression by association with increased inflammation and directly increasing plaque stress.