Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, Reduces Rho Kinase Activity in Atherosclerosis.

PURPOSE: Increased lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and Rho kinase activity may be associated with atherosclerosis. The principal aim of this study was to examine whether darapladib (a selective Lp-PLA2 inhibitor) could reduce the elevated Lp-PLA2 and Rho kinase activity in atherosclerosis. MATERIALS AND METHODS: Studies were performed in male Sprague-Dawley rats. The atherosclerosis rats were prepared by feeding them with a high-cholesterol diet for 10 weeks. Low-dose darapladib (25 mg·kg⁻¹·d⁻¹) and high-dose darapladib (50 mg·kg⁻¹·d⁻¹) interventions were then administered over the course of 2 weeks. RESULTS: The serum levels of triglycerides, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), high-sensitivity C-reactive protein (hs-CRP), and Lp-PLA2, significantly increased in atherosclerosis model groups, as did Rho kinase activity and cardiomyocyte apoptosis (p<0.05 vs. sham group), whereas nitric oxide (NO) production was reduced. Levels of TC, LDL-C, CRP, Lp-PLA2, and Rho kinase activity were respectively reduced in darapladib groups, whereas NO production was enhanced. When compared to the low-dose darapladib group, the reduction of the levels of TC, LDL-C, CRP, and Lp-PLA2 was more prominent in the high-dose darapladib group (p<0.05), and the increase of NO production was more prominent (p<0.05). Cardiomyocyte apoptosis of the high-dose darapladib group was also significantly reduced compared to the low-dose darapladib group (p<0.05). However, there was no significant difference in Rho kinase activity between the low-dose darapladib group and the high-dose darapladib group (p>0.05). CONCLUSION: Darapladib, a Lp-PLA2 inhibitor, leads to cardiovascular protection that might be mediated by its inhibition of both Rho kinase and Lp-PLA2 in atherosclerosis.

[Association of Cystatin C and metabolic syndrome].

OBJECTIVE: To explore the correlation between serum levels of Cystatin C and metabolic syndrome. METHODS: This study was randomly conducted in 506 persons, including 191 patients with metabolic syndrome (MS), 210 with metabolic disorder (MD) and 105 persons in normal control (NC) group. According to serum levels of Cys C, the clinical data were also divided into 3 groups of lower tertile (T1, n = 165), middle tertile (T2, n = 172) and upper tertile (T3, n = 169). Body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), fasting plasma glucose (FPG), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), high density lipoprotein (HDL), creatinine (Cr), estimated glomerular filtration rate (eGFR), microalbuminuria (MAU), systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) were measured and their mutual relations evaluated. RESULTS: Statistically significant differences (all P < 0.01) existed among T1, T2 and T3 groups in the mean values of BMI, waist circumference, WHR, FPG, LDL-C, TG, Cr, eGFR, MAU, SBP, DBP and PP. As tertile levels of Cys C increased, MS morbidity rates became all remarkably augmented (P < 0.01). The MS component scores had significant statistical differences among the patients of T1, T2 and T3 groups (P < 0.01). As the MS component scores increased, the level of Cys C rose in these patients. The higher MS marks were, the higher serum concentration of Cys C was in these patients. The plasma concentration of Cys C in MS patients was closely related with WC, LDL-C, FBG and blood pressure (all P < 0.05), not related with TG levels and negatively correlated with HDL-C levels (r = -0.352, P = 0.01). WC, Cys C, LDL-C, MAU and PP were significantly associated with MS. And the value of OR between Cys C and MS was 2.943 (95% CI 1.276-3.914). CONCLUSION: Cys C is significantly associated with MS. As MS scores rise, the level of Cys C increases.

The role of TWEAK/Fn14 in cardiac remodeling.

The pathophysiological basis of heart failure is cardiac remodeling, a process that comprises structural and functional changes including cardiomyocyte proliferation, hypertrophy, necrosis, apoptosis, autophagy, interstitial fibrosis, contractile dysfunction and ventricular dilatation. Accumulating evidence demonstrate that tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is involved in the process by binding its receptor fibroblast growth factor-inducible molecule 14 (Fn14). In this review, we will discuss the potential role of the TWEAK/Fn14 axis in cardiac remodeling, elucidate its possible mechanisms and explore new therapeutic targets for heart failure.

TWEAK/Fn14 promotes the proliferation and collagen synthesis of rat cardiac fibroblasts via the NF-кB pathway.

We wished to elucidate a potential role of the tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible molecule 14 (Fn14) axis in myocardial fibrosis. Stimulation of neonatal rat cardiac fibroblasts (CFs) with TWEAK could increase CFs numbers and collagen synthesis. Conversely, when CFs were pretreated with siRNA against Fn14, induction of cell proliferation and collagen synthesis by TWEAK were inhibited. Pretreatment with TWEAK on CFs induced activation of the nuclear factor-kappaB (NF-кB) pathway and subsequently increased the production of metalloproteinase-9 (MMP-9). Cell treatment with siRNA against Fn14 led to inhibition of the NF-кB pathway. Additionally, after stimulation of cell with ammonium pyrrolidine dithiocarbamate, cell proliferation and collagen synthesis induced by NF-кB and the upregulation of MMP-9 production were inhibited. The present study suggested that the TWEAK/Fn14 axis increased cell proliferation and collagen synthesis by activating the NF-кB pathway and increasing MMP-9 activity. This axis may be important for regulating myocardial fibrosis.

[The correlation of human serum Lp-PLA2 and hs-CRP and stability of coronary atherosclerotic plaques].

OBJECTIVE: To explore the relationship of serum lipoprotein-associated phospholipase A2 and high sensitive C-reactive protein in vulnerable coronary atherosclerotic plaques. METHODS: Patients undergoing coronary angiography (CAG) were examined for CAD with intravascular ultrasound (IVUS). According to the findings of CAG and IVUS, all the patients were divided into three groups: a control group without plaque, stable plaque group and vulnerable plaque group. The total serum Lp-PLA2 and hs-CRP were measured before angiography and they were valued with T test and Pearson's correlation analysis. RESULTS: (1) Lp-PLA2 level in stable plaque group and vulnerable plaque group was higher than that in control group (P < 0.05). (2) Lp-PLA2 level in the vulnerable plaque group was higher than that in stable plaque group (P < 0.05). (3) hs-CRP level in the vulnerable plaque group is higher than that in the stable plaque group and control group (P < 0.05) and there was significant difference between them. (4) To discriminate vulnerable plaque, the specificity of serum Lp-PLA2 was stronger than that of hs-CRP. CONCLUSIONS: Serum Lp-PLA2 level has higher sensitivity in predicting the vulnerability of the coronary atherosclerotic plaque than hs-CRP. In combination with hs-CRP, we can use Lp-PLA2 as a new biomarker to predict the presence of vulnerable plaque.

Increased plasma osteoprotegerin levels are associated with the presence and severity of acute coronary syndrome.

OBJECTIVE: The objective of this study was to explore the relationship between increased plasma osteoprotegerin (OPG) levels and acute coronary syndrome (ACS). METHODS: Plasma OPG levels from 85 subjects undergoing coronary artery angiography in three different groups, including ACS (n=45), stable angia pectoris (SAP) (n=20) and normal coronary artery (NCA) (n=20), were detected by ELISA. Twenty-two ascending aorta specimens were surgically taken from 8 ACS, 7 SAP and 7 NCA patients, and OPG mRNA expression in the specimens was detected by RT-PCR. In addition, 10 coronary artery sections each were selected from autopsy archives for the presence of vulnerable atherosclerosis plaques (VP), stable plaques (SP) or no plaques (NP) and OPG protein expression in the sections was detected by immunohistochemistry. RESULTS: Plasma OPG concentrations in the ACS group were significantly higher than those in the SAP or NCA group.The levels of plasma OPG in the 1-, 2- and 3-vessel disease subgroups of ACS were increasingly higher (P < 0.05 or 0.01). Multiple logistic regression analyses revealed a significant independent relation between plasma OPG concentration and the presence of ACS (P = 0.032, odd ratio = 1.006).Ascending aorta specimens from the ACS group had a greater OPG mRNA expression than those from the NCA or SAP group (P < 0.01). Sections with VP had a markedly higher OPG expression than sections with SP or NP (P < 0.05 and P < 0.01, respectively). CONCLUSIONS: Increased plasma osteoprotegerin levels are associated with the presence and severity of acute coronary syndrome.

A high association of aortic valve sclerosis detected by transthoracic echocardiography with coronary arteriosclerosis.

OBJECTIVE: To examine whether aortic valve sclerosis (AVS) detected by transthoracic echocardiography (TTE) has a high association with coronary arteriosclerosis. METHODS: Clinical and angiographic features and TTE findings were retrospectively analyzed in a blinded fashion for 138 consecutive patients, of whom 58 had AVS and 80 had non-AVS diseases. Both histological and immunohistochemical studies were performed on frozen aortic valve sections obtained at autopsy from 7 AVS and 3 non-AVS patients. RESULTS: AVS and coronary artery disease (CAD) had similar clinical risk factors. The AVS group had a higher positive rate of coronary angiography and a higher incidence rate of multivessel CAD than the non-AVS group. The sensitivity, specificity, positive predictive value and negative predictive value of AVS in diagnosing CAD were 63.8, 71.3, 61.7 and 73.1%, respectively. Early lesions of AVS were characterized by accumulation of lipid and infiltration of macrophages and T lymphocytes as indicated by immunohistochemical staining. Late lesions were characterized by formation of calcific plaques, proliferation of fibrous connective tissue and immunohistochemical staining identifying a few macrophages or T lymphocytes and little lipid accumulation on the surface of aortic valve leaflets. Late lesions in the basement of aortic valve leaflets were characterized by hyperplastic granulation tissues. Three aortic valve leaflets from the non-AVS group were characterized by nonspecific thickened tips, increased collagen, no calcification, no lipid accumulation and no inflammatory cells. CONCLUSIONS: There were significant similarities in clinical risk factors, histopathological alterations of AVS and coronary atherosclerosis. AVS detected by TTE had a high association with coronary arteriosclerosis.