Although Bone morphogenetic protein-2 (BMP-2) is a known mediator of bone regeneration and vascular calcification, to date no study has investigated the relationship between BMP-2 and type 2 diabetes mellitus (T2DM) and its possible role in coronary artery disease (CAD). The purpose of this study is to evaluate the relationship of BMP-2 with atherosclerosis and calcification in patients with T2DM. 124 subjects were enrolled in this study: 29 patients with T2DM and CAD; 26 patients with T2DM and without CAD; 36 patients with CAD and without T2DMand 34 without T2DM or CAD (control group). Severity of coronary lesions was assessed using coronary angiography and intravascular ultrasound (IVUS). Plasma BMP-2 levels were quantified using a commercially available ELISA kit. Compared to the control group, the mean plasma BMP-2 level was significantly higher in T2DM patients with or without CAD (20.1 ± 1.7 or 19.3 ± 1.5 pg/ml, vs 17.2 ± 3.3 pg/ml, P <0.001). In a multivariable linear regression analysis, both T2DM and CAD were significantly and positively associated with BMP-2 (Estimate, 0.249; standard error (SE), 0.063; p <0.0001; Estimate, 0.400; SE, 0.06; p <0.0001). Plasma BMP-2 was also strongly correlated with glycosylated hemoglobin A1c (HbA1c) (Spearman ρ = −0.31; p = 0.0005). SYNTAX score was also significantly associated with BMP-2 (Spearman ρ = 0.46; p = 0.0002). Using the results from IVUS, plasma BMP-2 levels were shown to positively correlate with plaque burden (Spearman ρ = 0.38, P = 0.002) and plaque calcification (Spearman ρ =0.44, P = 0.0003) and to negatively correlate with lumen volume (Spearman ρ =0.31, P = 0.01). Our study demonstrates that patients with T2DM had higher circulating levels of BMP-2 than normal controls. Plasma BMP-2 levels correlated positively with plaque burden and calcification in patients with T2DM.

Fibroblast growth factor 21 (FGF21), a hormone with multiple metabolic properties, has proven to be pleiotropic biological effects and may play pivotal role in numerous cardiovascular and metabolic diseases in the future. Vascular calcification (VC) is a concomitant pathological process of various cardiovascular and metabolic diseases. However, the effects of FGF21 on VC remain unclear. Therefore, in this research, we aimed to explore the roles and mechanisms of FGF21 in VC induced by vitamin D₃ plus nicotine (VDN) treatment rats. After 28 days VDN treatment, the calcium overload was confirmed by blood pressure, ultrasound imaging, calcium content, ALP activity and aortic pathological characteristics. In terms of FGF21, exogenous FGF21 can ameliorate the elevation of blood pressure, aortic calcification and related injury in VC rats. To investigate the mechanisms of FGF21 on VC, the endoplasmic reticulum stress (ERS) mediated apoptosis pathways were tested. As a method to detect apoptosis, the increased positive TUNEL staining cells were alleviated by FGF21 treatment. Furthermore, exogenous FGF21 can suppress the increased ERS chaperone, GRP78, in the calcified aortas. In the three pathways of ERS mediated apoptosis, we found CHOP pathway and caspase-12 pathway were involved in the treatment of FGF21, but not p-JNK/JNK pathway. Our study proved for the first time that FGF21 can inhibit the progress of VC by alleviating ERS mediated apoptosis in rats. FGF21 might be a new target for preventing and treating VC.

Objectives: Vascular calcification is a dysfunction of the vasculature. Recent findings indicate that fibroblast growth factor21 (FGF21), a protector of the cardiovascular system, is related to the mineral deposition of bone and enhances the osteogenic activity of bone morphogenic protein (BMP)-2. In this study, we explored whether FGF21 suppresses vascular calcification. Methods: A calcifying model was established by culturing primary rat vascular aortic smooth muscle cells (VSMCs) in a beta-glycerophosphate (BGP)-containing calcifying medium for 14 days. In addition, recombinant human FGF21 was applied to protect against VSMC calcification. Results: In the presence of BGP, the expression levels of osteoblastic genes, including alkaline phosphatase (ALP), BMP-2 and runt-related transcription factor (RUNX)-2, were significantly upregulated on day 3, an effect that was maintained through day 14 (P < 0.001). A concomitant increase in ALP protein expression was observed through day 9 (P < 0.05). The incubation of VSMCs with calcifying medium for 14 days increased ALP activity (P < 0.05) and led to the formation of visible calcium nodules over the course of the protocol. β-klotho expression was unaltered in BGP-induced VSMCs for the 14-day culture period. The culturing of VSMCs with calcifying medium led to opposing trends in the expression of FGFRs, namely, an increase in FGFR1 and FGFR4 mRNA levels (P < 0.001) and a decrease in FGFR2 and FGFR3 mRNA levels (P < 0.01). Reduced mineral deposition, in combination with decreased ALP activity (P < 0.001) and ALP protein expression (P < 0.001), was noted in VSMCs treated with varying doses of FGF21 and BGP in a dose-dependent manner. In addition, FGF21 downregulated osteoblastic-promoting gene expression, including ALP (P < 0.001), BMP-2 (P < 0.001) and RUNX-2 (P < 0.001). Furthermore, FGF21 enhanced β-klotho expression (P < 0.05) and increased FGFR1 and FGFR3 mRNA levels (P < 0.001). FGFR-1 inhibitor SU5402 blocked partial inhibition of FGF21 on the expression of BMP-2 (P < 0.001) and RUNX-2 (P < 0.05). Furthermore, FGF21 suppressed the phosphorylation of P38, while P38 inhibitor, SB203580, attenuated the downregulation of RUNX-2 (P < 0.05). Conclusions: These data demonstrate FGF21 attenuates VSMC calcification in vitro via an FGF21/FGFR1/3/β-klotho/P38MAPK/RUNX-2 signalling pathway.

Background: Acute coronary syndrome (ACS) is closely related to unstable plaques and secondary thrombosis. The inflammatory cells in plaques and their inflammatory products may be the cause for plaque instability and ruptures. The study aimed to disclose the changes of inflammatory factors including serum intracellular adhesion molecule-1 (ICAM-1), chitinase-3-like protein 1 (YKL-40), and lipoprotein-associated phospholipase A2 (Lp-PLA2) in patients with ACS and its clinical significance. Methods: A total of 120 patients with coronary heart disease (CHD) were categorized into 2 groups: 69 with ACS and 51 with stable angina pectoris (SAP); 20 patients with chest pain and normal angiography served as a control group. The 120 patients with CHD were categorized into single-vessel disease group, double-vessel disease group, and three-vessel disease group based on the number of coronary artery stenosis. The severity of coronary artery stenosis was quantified based on coronary angiography using Gensini score. They were further divided into mild CHD group with its Gensini score <26 (n = 36), moderate CHD group with its Gensini score being 26–54 (n = 48) and severe CHD group with its Gensini score >54 (n = 36). Serum levels of ICAM-1, YKL-40, and Lp-PLA2 of different groups were determined by enzyme-linked immunosorbent assay. Correlation between ICAM-1, YKL-40, Lp-PLA2, and Gensini score was analyzed. Results: The levels of serum inflammatory factors ICAM-1, YKL-40, and Lp-PLA2 were significantly higher in the ACS group than those in control group and SAP group (all P < 0.05); and compared with control group, no significant difference was observed in terms of the serum ICAM-1, YKL-40, and Lp-PLA2 levels in the SAP group (P > 0.05).The levels of serum ICAM-1, YKL-40, and Lp-PLA2 were not significantly different among control group, single-vessel disease group, double-vessel disease group, and three-vessel disease group (all P > 0.05). The levels of serum ICAM-1, YKL-40, and Lp-PLA2 were not significantly different among control group, mild CHD group (Gensini score <26), moderate CHD group (Gensini score 26–54), and severe CHD group (Gensini score >54) (all P > 0.05). Nonparametric Spearman correlation analysis showed that the levels of serum ICAM-1, YKL-40, and Lp-PLA2 were not correlated with the Gensini score in CHD patients (r = 0.093, r = –0.149, and r = –0.085, all P > 0.05; respectively). Conclusions: The serum levels of ICAM-1, YKL-40, and Lp-PLA2 were correlated with different clinical types of CHD, but not well correlated the severity and extent of artery stenosis, suggesting that ICAM-1, YKL-40, and Lp-PLA2 might be involved in occurrence of instability of atherosclerotic plaque, and might reflect the severity of CHD mostly through reflecting the plaque stability. 急性冠状动脉综合征与相关炎性因子的临床研究 摘要 背景：探讨急性冠状动脉综合征（ACS）患者相关炎性因子可溶性细胞间粘附分子（ICAM-1）、几丁质酶-3样蛋白-1（YKL-40）、脂蛋白相关磷脂酶A2(Lp-PLA2)的变化及其临床意义。 方法：入选冠心病（CHD）患者120例，分为ACS组69例和稳定型心绞痛（SAP）组51例。另选同期有胸痛症状冠状动脉造影正常的患者20例为对照组。再将120例CHD患者按病变血管支数分为单支病变组（45例）、双支病变组（38例）和三支病变组（37例）。采用Gensini评分系统评定冠脉血管病变狭窄程度，按Gensini积分分为轻度病变组（<26分）36例、中度病变组（26~54分）48例和重度病变组（>54分）36例。用酶联免疫吸附试验（ELISA）法分别检测血清ICAM-1、YKL-40、Lp-PLA2水平，对各组进行比较分析，并分别与Gensini积分进行相关性分析。 结果：与对照组和SAP组相比，ACS组血清炎性因子ICAM-1、YKL-40、Lp-PLA2均明显升高（P均<0.05），SAP组与对照组比较，ICAM-1、YKL-40、Lp-PLA2差异均无统计学意义（P均>0.05）。单支病变组、双支病变组、三支病变组血清炎性因子ICAM-1、 Lp-PLA2、 YKL-40差异均无统计学意义（P均> 0.05）。轻度病变组、中度病变组和重度病变组血清炎性因子ICAM-1 、Lp-PLA2、 YKL-40差异均无统计学意义（P均> 0.05）。非参数Spearman相关分析显示血清炎性因子ICAM-1 、YKL-40、Lp-PLA2水平与Gensini积分均无明显相关性（r=0.093，r=-0.149, r=-0.085，P均>0.05）。 结论：血清炎性因子ICAM-1、YKL-40、Lp-PLA2与CHD的临床类型有关，ACS组患者ICAM-1、YKL-40、Lp-PLA2较SAP组和对照组明显升高，提示三种炎症因子可能参与斑块不稳定性的发生，成为预测CHD患者发生ACS风险和病情严重程度的临床指标。CHD患者血清炎性因子ICAM-1、YKL-40、Lp-PLA2水平与冠状动脉病变狭窄的范围和程度相关性不明显，提示其反映冠心病患者病情严重程度主要与反映斑块的稳定性有关。