Roles of High Mobility Group Box 1 in Cardiovascular Calcification

Abstract

Calcific disease of the cardiovascular system, including atherosclerotic calcification, medial calcification in diabetes and calcific aortic valve disease, is an important risk factor for many adverse cardiovascular events such as ischemic cardiac events and subsequent mortality. Although cardiovascular calcification has long been considered to be a passive degenerative occurrence, it is now recognized as an active and highly regulated process that involves osteochondrogenic differentiation, apoptosis and extracellular vesicle release. Nonetheless, despite numerous studies on the pathogenesis of cardiovascular calcification, the underlying mechanisms remain poorly understood. High mobility group box 1 (HMGB1), a nuclear protein bound to chromatin in almost all eukaryotic cells, acts as a damage-associated molecular pattern (DAMP) when released into the extracellular space upon cell activation, injury or death. Moreover, HMGB1 also functions as a bone-active cytokine participating in bone remodeling and ectopic calcification pathogenesis. However, studies on the roles of HMGB1 in promoting cardiovascular calcification are limited to date, and the mechanisms involved are still unclear. In this review, we summarize recent studies investigating the mechanism of cardiovascular calcification and discuss multiple roles of HMGB1 in its development.

Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

“…TLR ligands including heat shock proteins, and HMGB1 are released from senescent cells via exosomes (65,66). These TLR ligands can be also released from cells which are undergoing necrosis.…”

Lower Serum Irisin Levels Are Associated with Increased Vascular Calcification in Hemodialysis Patients

“…Now, it is believed that vascular calcification involves a tightly regulated transformation of vascular smooth muscle cells to an osteo/chondrocytic cell that expresses Runt-related transcription factor 2 (Runx2) and produces matrix vesicles under hyperphosphate circumstance [26][27][28][29]. Recently, Chen [30], et al reviewed that high mobility group box 1 have a series of pro-calcification effects, such as promoting vascular smooth muscle osteo/chondrogenic differentiation, apoptosis and release of calcific extracellular vesicles, inflammation, oxidative stress and autophagy signaling, these indicated that inhibition of high mobility group box 1 may be a potential therapy for attenuating vascular calcification. Thus a new concept of bone-vascular axis appears.…”

High Mobility Group Box-1 and Diabetes Mellitus Complications: State of the Art and Future Perspectives

“…Once in extracellular space, pro-inflammatory effect of HMGB1 is mediated by its extracellular receptors, in particular receptor for advanced glycation end products (RAGE) and toll-like receptor (TLR)-2, -4, and -9. Recently, other receptors have been studied, such as C-X-C chemokine receptor type 4 (CXCR4), macrophage antigen-1, syndecan-3, CD24, Siglec-10, T cell Igmucin-3 [41], even if their role in the HMGB1 signaling pathway is not completely clear.…”

“…Disulfide HMGB1 induces innate immune response binding TLR-4 and, conversely, fully oxidized HMGB1 has not a pro-inflammatory function, inducing immune tolerance [35,47,48]. In addition, HMGB1 is able to promote vascular calcification, enhancing osteochondrogenic differentiation of cells such as vascular smooth muscle cells (VSMCs), pericytes, myofibroblasts, progenitor cells [41], via TLR4-JNK-NFkB pathway [49]. Moreover, it promotes via RAGE signaling the expression of TGF-β that is associated with fibrosis and calcification [50,51].…”