Scuruchi M, et al. Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Oct 28:158545.
Scuruchi M, et al., conducted a review to estimate the present information on the function delivered by proteoglycans (PGs), specifically by biglycan (BGN), in different clinical surroundings distinguished by increased cardiovascular risk.
Role of proteoglycans in the vascular homeostasis
PGs modified regulation is a crucial factor in activating and proceeding atherosclerosis (ATH) and also well-known important molecules in preserving vascular homeostasis. In the extracellular matrix (ECM) of the vascular intima, the main PGs recognized are Versican, decorin and BGN.
The role of BGN under increased cardiovascular risk conditions
Dyslipidemia – As compared to control participants, association of Lipoprotein lipase (LPL) activity with increased generation of small-sized low-density lipoprotein (LDL) was observed which were highly inclined to oxidation and provides a higher affinity for BGN.
Hypertension – In hypertensive patients, BGN-elevated expression may be neutralizing by losartan, thereby enhancing the conception that BGN levels can be pointed.
Cigarette smoking – It is essential to highlight that hypertension, commonly reported in heavy smokers, encourage BGN expression. Additionally, BGN expression could be enhanced by TGF-β, which successively rises in the small airway epithelium of smokers.
Diabetes – In diabetes, it was identified that changed PGs synthesis may be the reason of the elevated levels of TGF-β and not due to to the metabolic factors correlated with the pathological condition.
Chronic Kidney Disease – Certainly, overexpression of BGN can be accounted as a defensive reaction to counteract TGF-ß activity and hence, kidney fibrosis.
Inflammation – The intact molecule of PG, BGN in its soluble form (sBGN), execute as an endogenous ligand for TLR-2 and TLR-4, mediating ex novo or strengthening the inflammatory process by resembling the reaction to gram-positive (via TLR-2) and gram-negative (via TLR-4) pathogens.
BGN in atherosclerosis: a focus on the mechanisms
By ionic interactions, atherogenic lipoproteins penetrate the sub-endothelial space and high affinity bind biglycan. Through the lipolytic/hydrolytic activity of plasma LPL, sPLA2 and SMase on native LDL, small dense LDL get provoked which can easily enter the subendothelial space (bold dotted line) and exhibit the strongest binding affinity for BGN. The composition of such complexes stimulates lipoprotein retention, aggregation and chemical-physical modifications (i.e., oxidation). The removal of modified lipoproteins (browned particles) mediated by tissue-resident or blood monocyte-derived macrophages, which increasingly transforms into foam cells, discharging proinflammatory cytokines and chemokines, and contributes to the atherosclerotic lesion development (Figure 1).
Figure 1: Pro-atherosclerotic processes supported by biglycan. Lp(a), lipoprotein(a); LDL, low density lipoprotein; LPL, lipoprotein lipase; sPLA2, secretory phospholipase A2; SMase, sphingomyelinase; VSMC: vascular smooth muscle cells.
Various cardiovascular risk factors which include cigarette smoking tend to raise BGN expression and secretion (dotted line); in contrast by the stimulation of its AT1 receptor, ang II may raise the expression of TGFβ.
Once secreted, TGFβ may associate with its own receptor in an autocrine fashion, consecutively up-regulating both the expression and secretion of BGN, and its pro-fibrotic pathways. Finally, the upregulation of BGN promotes vascular damage, according to the “response-to-retention” hypothesis (Figure 2).
Figure 2: Cardiovascular risk factors, angII and TGFβ-mediated increased biglycan expression and secretion. CKD, chronic kidney disease; angII, angiotensin II; AT1, angiotensin II receptor type 1; TGFβ, transforming growth factor beta; MAPK, mitogen-activated protein kinase; BGN, biglycan.
Through secreting various cytokines and chemokines, macrophages may react to the biglycan (BGN) stimuli, hence stimulating the inflammatory reaction. BGN, as soluble molecule (sBGN) might get discharged from the extracellular matrix by proteolytic cleavage and, it activates TLR- 2 and TLR-4, mediating ex novo or strengthening inflammatory processes. Moreover, sBGN develop the clustering of TLRs and P2X4/7, which can lead to rise in IL-1β production and secretion, via inflammasome (NLRP3) activation (Figure 3).
Figure 3: Biglycan induces pro-inflammatory cascades in macrophages. IL-1β, interleukin-1 beta; NLRP3, nucleotide-binding domain, leucine-richcontaining family, pyrin domain-containing-3; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; TLRs, Toll-like receptors; CD14, cluster of differentiation 14, P2X4/7, P2X purinoceptor 4/7; TNF-α, tumor necrosis factor alpha; MCP-1, monocyte chemoattractant protein 1 (or chemokine «C-C motif» ligand 2, CCL2); MIP-1α: macrophage inflammatory protein 1-alpha (or chemokine «C-C motif» ligand 3, CCL3); CXCL13, chemokine «C-X-C motif» ligand 13; RANTES, regulated on activation, normal T cell expressed and secreted; SphK1, sphingosine kinase 1.
Thus, the function of BGN in dyslipidemia, hypertension, cigarette smoking, diabetes, chronic kidney disease and inflammatory status is concisely estimated and reviewed in order to provide new highlights on the underlying mechanisms governing the interaction between BGN and ATH.
