Induction of lactadherin mediates the apoptosis of endothelial cells in response to advanced glycation end products and protective effects of grape seed procyanidin B2 and resveratrol

Abstract

One of characteristics of diabetes mellitus (DM) is endothelial cell (EC) dysfunction and apoptosis which contributes to the development of vasculopathy. Advanced glycation end products (AGEs) continuously produced in the setting of DM play an important role in causing EC dysfunction and apoptosis. However, the underlying molecular mechanism remains largely elusive. Lactadherin, a secreted glycoprotein of milk-fat globule, is expressed by multiple cell types of arterial wall including ECs. Our previous proteomic studies showed that the expression of lactadherin was significantly increased in the aorta of diabetic rats as compared with control rats and treatment with grape seed procyanidin extracts significantly inhibited the lactadherin expression in diabetic rats. We hypothesized that lactadherin plays a critical role in AGEs-induced EC apoptosis; grape seed procyanidin B2 (GSPB2) and resveratrol protect against AGEs-induced EC apoptosis through lactadherin regulation. Our results showed that AGEs upregulated lactadherin expression and lactadherin RNA interference significantly attenuated AGEs-induced EC apoptosis. Overexpression of lactadherin increased EC apoptosis with up-regulation of Bax/Bcl-2 ratio, cytochrome c release, caspase-9 and caspase-3 activation suggesting the involvement of mitochondria apoptosis pathway. Mechanistically, overexpression of lactadherin reduced the phosphorylation of GSK3beta at baseline. Our study also revealed nine proteins interacting with lactadherin in HUVEC and study of these candidate proteins could unveil further underlying molecular mechanisms. In summary, our study identified lactadherin as a key player responsible for AGEs-induced EC apoptosis and antioxidants GSPB2 and resveratrol protect against AGEs-induced EC apoptosis by inhibiting lactadherin. Targeting lactadherin with antioxidant could be translated into clinical application in the fighting against DM complications.

Quantitative proteomics study of protective effects of grape seed procyanidin B2 on diabetic cardiomyopathy in db/db mice

“…11,12,17) In this study, we observed that GSPB2 significantly prevented the obesity in db/db mice. GSPB2 also prevented the elevation in the levels of serum AGEs observed in db/db mice, suggesting an anti-non-enzymatic glycation effect of GSPB2.…”

“…[8][9][10] Dimeric procyanidin B2 is one of the main components of GSPE, which is more powerful than other polyphenols. Our previous data showed that grape seed procyanidin B2 (GSPB2) could prevent AGEs-induced ROS generation, proliferation and migration of human aortic smooth muscle cells, and alleviate diabetic arterial damage, [11][12][13] but little is known about its protective effects on diabetic cardiomyopathy.…”

Hypericin, a Naphthodianthrone Derivative, Prevents Methylglyoxal-Induced Human Endothelial Cell Dysfunction

“…One of the major AGEs adducts, Nε-(carboxymethyl) lysine, is formed from MGO (Thornalley, 1996). In endothelial cells, increased levels of AGEs cause oxidative stress, mitochondrial dysfunction, cellular dysfunction, and, ultimately, cell death (Li et al ., 2011). That hypericin inhibits the formation of AGEs suggests that it can ameliorate AGEs-related endothelial cell dysfunction.…”

Milk Fat Globule Epidermal Growth Factor VIII Signaling in Arterial Wall Remodeling

“…Recently, not only has MFG-E8 expression emerged as a molecular hallmark of adverse cardiovascular remodeling with aging [2, 3, 13, 14], but MFG-E8 signaling has also been found to mediate the vascular outcomes of cellular and matrix responses to the hostile stresses associated with hypertension, diabetes, and atherosclerosis [15–19]. Increased MFG-E8 signaling promotes endothelial prothrombosis and triggers EC apoptosis, thus contributing to a disruption of the endothelium [20, 21], an enhancement of VSMC proliferation and invasion, as well as the deposition and amyloidization of the extracellular matrix [14, 21–31]. …”