2015 Vol. 29, No. 6
2015, 29(6): 429-436. doi: 10.7555/JBR.29.20150052
Pro-protein convertase subtilisin-kexin 9 (PCSK9) is known to affect low-density lipoprotein (LDL) metabolism,but there are indications from several lines of research that it may also influence the metabolism of other lipoproteins, especially triglyceride-rich lipoproteins (TRL). This review summarizes the current data on this possible role of PCSK9. A link between PCSK9 and TRL has been suggested through the demonstration of (1) a correlation between plasma PCSK9 and triglyceride (TG) levels in health and disease, (2) a correlation between plasma PCSK9 and markers of carbohydrate metabolism, which is closely related to TG metabolism, (3) an effect of TG-lowering fibrate therapy on plasma PCSK9 levels, (4) an effect of PCSK9 on postprandial lipemia, (5) an effect of PCSK9 on adipose tissue biology, (6) an effect of PCSK9 on apolipoprotein B production from the liver and intestines, (7) an effect of PCSK9 on receptors other than low density lipoprotein receptor (LDLR) that are involved in TRL metabolism, and (8) an effect of anti-PCSK9 therapy on serum TG levels. The underlying mechanisms are unclear but starting to emerge.
Platelets are small anucleate cells generated from megakaryocytes in the bone marrow. Although platelet generation, maturation, and clearance are still not fully understood, significant progress has been made in the last 1-2 decades. In blood circulation, platelets can quickly adhere and aggregate at sites of vascular injury, forming the platelet plug (i.e. the first wave of hemostasis). Activated platelets can also provide negatively charged phosphatidylserinerich membrane surface that enhances cell-based thrombin generation, which facilitates blood coagulation (i.e. The second wave of hemostasis). Platelets therefore play central roles in hemostasis. However, the same process of hemostasis may also cause thrombosis and vessel occlusion, which are the most common mechanisms leading to heart attack and stroke following ruptured atherosclerotic lesions. In this review, we will introduce the classical mechanisms and newly discovered pathways of platelets in hemostasis and thrombosis, including fibrinogen-independent platelet aggregation and thrombosis, and the plasma fibronectin-mediated ‘‘protein wave’’ of hemostasis that precedes the classical first wave of hemostasis. Furthermore, we briefly discuss the roles of platelets in inflammation and atherosclerosis and the potential strategies to control atherothrombosis.
Ischemic heart diseases are the leading cause of death with increasing numbers of patients worldwide. Despite advances in revascularization techniques, angiogenic therapies remain highly attractive. Physiological ischemia training, which is first proposed in our laboratory, refers to reversible ischemia training of normal skeletal muscles by using a tourniquet or isometric contraction to cause physiologic ischemia for about 4 weeks for the sake of triggering molecular and cellular mechanisms to promote angiogenesis and formation of collateral vessels and protect remote ischemia areas. Physiological ischemia training therapy augments angiogenesis in the ischemic myocardium by inducing differential expression of proteins involved in energy metabolism, cell migration, protein folding, and generation. It upregulates the expressions of vascular endothelial growth factor, and induces angiogenesis, protects the myocardium when infarction occurs by increasing circulating endothelial progenitor cells and enhancing their migration, which is in accordance with physical training in heart disease rehabilitation. These findings may lead to a new approach of therapeutic angiogenesis for patients with ischemic heart diseases. On the basis of the promising results in animal studies, studies were also conducted in patients with coronary artery disease without any adverse effect in vivo, indicating that physiological ischemia training therapy is a safe, effective and non-invasive angiogenic approach for cardiovascular rehabilitation. Preconditioning is considered to be the most protective intervention against myocardial ischemia-reperfusion injury to date. Physiological ischemia training is different from preconditioning. This review summarizes the preclinical and clinical data of physiological ischemia training and its difference from preconditioning.
The association of retinol binding protein 4 (RBP4) with atherosclerosis of the carotid artery in type 2 diabetes mellitus (T2DM) remains undefined. We aimed to investigate the correlation of RBP4 expression with atherosclerosis of the carotid artery in T2DM. A total of 1,076 subjects were investigated for intima-media thickness of the bilateral common carotid arteries, and they were divided into three groups: in group I, patients had normal neck vascular ultrasound,in group II, intimal carotid artery media thickness was equal to or more than 1 mm, and in group III, carotid artery plaque was present. Height, weight, blood pressure (BP), fasting plasma glucose (FPG), hemoglobin A1c(HbA1c), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-1 (apoA-1), apolipoprotein B (apoB) and lipoprotein (a) [Lp(a)] were determined by routine laboratory methods. RBP4 and high sensitivity C reactive protein (HsCRP) were measured by an enzyme-linked immuno-sorbent assay, and insulin concentration was measured by an electrochemiluminescence sandwich immunoassay. Duration of diabetes, waist and BP, FPG, HbA1c, TG, TC, LDL-C, APOB, Lp(a), HsCRP, RBP4 and homeostasis model assessment insulin resistance index (HOMA-IR) were significantly lower in group I than in the other two groups (P,0.01, P,0.01). Plasma levels of HbA1c, RBP4, LDL-C, TC, HOMA-IR, HsCRP and Lp(a), waist and BP were significantly increased in group III than in group II (P,0.01). Multivariate logistic regression analysis showed that there were seven factors associated with the occurrence of carotid artery atherosclerosis and its risks in descending order were: high LDL-C, high waist, high HsCRP, duration of diabetes, high HOMA-IR, HbA1c and high RBP4. Our finding supported that RBP4 was positively correlated with carotid atherosclerosis in patients with T2DM and could be used as an early predictor of cardiovascular disease.
The effect of CC-chemokine receptor 7 (CCR7) and CC-chemokine ligand 19 (CCL19) on rheumatic mitral stenosis is unknown. This study aimed to explore the roles of CCR7 and CCL19 in rheumatic mitral stenosis by measuring the expression of CCR7 and CCL19 in human mitral valves from rheumatic mitral stenosis patients.Additionally, we examined their effects on human mitral valve interstitial cells (hMVICs) proliferation, apoptosis and wound repair. CCR7 and CCL19 expression was measured in the mitral valves from rheumatic mitral stenosis patients (n510) and compared to normal mitral valves (n55). CCR7 was measured in cultured hMVICs from rheumatic mitral stenosis patients and normal donors by RT-PCR and immunofluorescence. The cells were also treated with exogenous CCL19, and the effects on wound healing, proliferation and apoptosis were assayed. In the rheumatic mitral valves, valve interstitial cells expressed CCR7, while mononuclear cells and the endothelium expressed CCL19. Healthy mitral valves did not stain positive for CCR7 or CCL19. CCR7 was also detected in cultured rheumatic hMVICs or in normal hMVICs treated with CCL19. In a wound healing experiment, wound closure rates of both rheumatic and normal hMVICs were significantly accelerated by CCL19. These effects were abrogated by a CCR7 neutralizing antibody. The CCR7/CCL19 axis did not influence the proliferation or apoptosis of hMVICs, indicating that wound healing was due to increased migration rates rather than increased proliferation. In conclusion, CCR7 and CCL19 were expressed in rheumatic mitral valves. The CCR7/CCL19 axis may regulate remodeling of rheumatic valve injury through promoting migratory ability of hMVICs.
Recent studies have shown that premature ventricular contractions (PVCs) could enlarge the heart, but its risk factors are incompletely understood as a single 24-hour recording cannot reflect the true PVC burden due to day-to-day variability. Our purpose was to investigate the effect of burden and origin sites on left ventricular (LV) function in patients with PVCs by 7-day Holter electrocardiography (ECG). From May 2012 to August 2013, 112 consecutive patients with PVCs were recruited from the authors’ affiliated hospital. All patients received 2-dimensional transthoracic echocardiography, 12-lead routing ECG and 7-days Holter ECG. Serum N-terminal probrain natriuretic peptide (NT-proBNP) levels were measured. A total of 102 participants with PVCs were included in the final analysis. Origin of PVCs from the tricuspid annulus had the highest burden and NT-proBNP level. LV papillary muscle had a higher LV ejection fraction (EF) level and a lower LV end-systolic dimension (ESD) than other PVC foci (P,0.05). The high burden group had a higher LV end-diastolic dimension (EDD) and LVESD but lower LVEF than the other two groups (P,0.05). Female, older age, physical work, and history of PVCs had a significantly positive correlation with symptoms. Male, older age,physical work, and high burden were positive predictors of enlarged LVEDD, LVESD and higher serum NT-proBNP level, but lower LVEF. Seven-day dynamic ECG Holter monitor showed the true PVC burden on patients with PVCs. PVCs with a lower burden or origin from the LV papillary muscle and the fascicle were relatively benign, while PVCs with a higher burden or origin from the tricuspid annulus may lead to cardiac dysfunction.
We aimed to investigate the effectiveness and safety of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) on preventing atrial fibrillation in essential hypertensive patients.Systematic literature retrieval was carried out to obtain randomized controlled trials on the effects of ACEI/ARBs on essential hypertensive patients before December, 2013. Data extraction and quality evaluation were performed. Meta-analysis was performed by Review Manager 5.2.3. Ten high quality studies (11 articles) with a total of 42,892 patients (20,491 patients in the ACEI/ARBs group and 22,401 patients in the b-blocker or the calcium antagonist group) met the inclusion criteria and were included in the meta-analysis. The results showed that ACEI/ARBs reduced the incidence of atrial fibrillation (AF) recurrence compared to calcium antagonists (RR50.48; 95%CI, 0.40-0.58; P,0.00001) or b-blockers (RR50.39; 95%CI, 0.20-0.74;P50.005) in long-term follow-up, respectively. Furthermore, ACEI/ARBs reduced the incidence of congestive heart failure (RR50.86; 95%CI, 0.77-0.96; P50.007). However, no significant effects were observed on the incidence of new AF, cardiac death, myocardial infarction, and stroke. Our results suggest that ACEI/ARBs may reduce the incidence of AF recurrence and congestive heart failure, with fewer serious adverse effects.
We sought to investigate the effects of epirubicin-nanogold compounds (EPI-AuNP) on hepatocellular carcinoma xenograft growth in nude mice. EPI-AuNP was prepared and hepatoma xenograft model was established in nude mice. The mice were then randomly divided into four groups: the control group with injection of saline, the AuNP treatment group, the EPI treatment group and the EPI-AuNP treatment group. After two weeks, the hepatoma weight and volume of the xenografts were assessed. Our transmission electron microscopy revealed that epirubicingold nanoparticles caused significantly more structural changes of hepatocellular carcinoma cells HepG2. The tumor weight in the Epi-AuNP treatment group (0.80?.11 g) was significantly lower than that of the control group (2.48?.15 g), the AuNP treatment group (1.67?.17 g), and the EPI treatment group (1.39?.10 g) (P,0.01).Furthermore, the tumor volume of mice in the EPI-AuNP treatment group (0.27?.06 cm3) was significantly smaller than that of the control group (2.23?.34 cm3), the AuNP treatment group (1.21?.25 cm3) and the EPI treatment group (0.81?.11 cm3) (P,0.01). In conclusion, epirubicin-nanogold compounds (EPI-AuNP) have significant inhibitory effects on the growth of hepatocellular carcinoma cells in vivo.
Non-obstructive azoospermia (NOA) is a severe defect in male reproductive health that occurs in 1% of adult men. In a previous study, we identified that rs7099208 is located within the last intron of FAM160B1 at 10q25.3. In this study, we analysed expression Quantitative Trait Loci (eQTL) of FAM160B1, ABLIM1 and TRUB1, the three genes surrounding rs7099208. Only the expression level of FAM160B1 was reduced for the homozygous alternate genotype (GG) of rs7099208, but not for the homozygous reference or heterozygous genotypes. FAM160B1 is predominantly expressed in human testes, where it is found in spermatocytes and round spermatids. From 17 patients with NOA and five with obstructive azoospermia (OA), immunohistochemistry revealed that expression of FAM160B1 is reduced, or undetectable in NOA patients, but not in OA cases or normal men. We conclude that rs7099208 is associated with NOA via a reduction in the expression of FAM160B1
Anterior cervical surgery is commonly used for cervical vertebral body lesions. However, the structure of blood vessels and nerve tissues along the route of anterior cervical surgery is complex. We aimed to measure the data of the longus colli, the sympathetic trunk and the cervical sympathetic trunk (CST) ganglia in Chinese cadaver specimens. A total of 32 adult cadavers were studied. We delineated the surgical anatomy of the CST. The superior and inferior/cervicothoracic ganglia of the sympathetic trunk consistently appeared. The middle ganglion was observed in 28.1% of the specimens and there were 2 cases of unilateral double middle cervical ganglia. The inferior ganglion was observed in 25.0% of the specimens and the cervicothoracic ganglion was observed in the remaining specimens. The distance between the CST gradually decreased from the top to the bottom, and the distance between the medial edges of the longus colli gradually broadened from the top down. The average angle between the bilateral CST and the midline of the vertebra was 11.2°± 1.8°on the left side and 10.3°±1.4° on the right side. The average angle between the medial margins of longus colli of both sides was 11.1°±1.9°. The CST is at high risk when LC muscle is cut transversely or is dragged heavily, especially at the levels of C6 and C7. Awareness of the regional anatomy of the CST could help surgeons to identify and preserve it during anterior cervical surgeries.
Waldenstrom’s macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is a low-grade B-cell non-Hodgkin’s lymphoma with an indolent clinical course. Higher-grade non-Hodgkin lymphoma (NHL) and therapyrelated myelodysplasia/acute leukemia (t-MDS/AML) have been reported in patients with WM/LPL in previous studies. However, only two cases with WM/LPL were reported to develop to Hodgkin lymphoma (HL). Here, we report the first case of WM/LPL who developed classical HL simultaneously 3 years after initial nucleoside analog-based chemotherapy.