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 (p0.05). 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.

Bone marrow mesenchymal stem cells to repair the reproductive system of male azoospermia rats / 中华男科学杂志

<p><b>OBJECTIVE</b>To study the ability of bone marrow mesenchymal stem cells (BMSCs) to repair the internal environment of the testis in male azoospermia rats.</p><p><b>METHODS</b>We established azoospermia models in 22 six-week-old male SD rats by intraperitoneal injection of busulfan at 20 mg per kg body weight. We transplanted allogeneic rat BMSCs (rBMSCs) into the testicular seminiferous tubules of the model rats and, 30 days after transplantation, observed the composition and structure of the seminiferous tubular cells by HE staining and detected the expressions of CD44, CD106, and c-kit in the rBMSCs by immunohistochemistry.</p><p><b>RESULTS</b>The number of epididymal sperm was significantly reduced in the model rats as compared with the normal controls (P < 0.01). CD44 and CD106, but not c-kit, were expressed in the isolated rBMSCs. At 30 days after transplantation of rBMSCs, lots of new cells were observed in the seminiferous tubules, some expressing CD106 and some expressing the germ cell surface marker c-kit.</p><p><b>CONCLUSION</b>BMSCs can transdifferentiate into germ cells and repair the damaged seminiferous tubules of sterile rats.</p>

Effect and mechanism of salvianolic acid B on the myocardial ischemia-reperfusion injury in rats

OBJECTIVE@#To investigate the effect of salvianolic acid B on rats with myocardial ischemia-reperfusion injury.@*METHODS@#SD rats were randomly divided into five groups (n=10 in each group): A sham operation group, B ischemic reperfusion group model group, C low dose salvianolic acid B group, D median dose salvianolic acid B group, E high dose salvianolic acid B group. One hour after establishment of the myocardial ischemia-reperfusion model, the concentration and the apoptotic index of the plasma level of myocardial enzymes (CTn I, CK-MB), SOD, MDA, NO, ET were measured. Heart tissues were obtained and micro-structural changes were observed.@*RESULTS@#Compared the model group, the plasma CTn, CK-MB, MDA and ET contents were significantly increased, NO, T-SOD contents were decreased in the treatment group (group C, D, and E) (P<0.05); compared with group E, the plasma CTn I, CK-MB, MDA and ET levels were increased, the NO, T-SOD levels were decreased in groups C and D (P<0.05). Infarct size was significantly reduced, and the myocardial ultrastructural changes were improved significantly in treatment group.@*CONCLUSIONS@#Salvianolic acid B has a significant protective effect on myocardial ischemia-reperfusion injury. It can alleviate oxidative stress, reduce calcium overload, improve endothelial function and so on.

Poly (ADP-ribose) polymerase inhibitor reduces heart ischaemia/reperfusion injury via inflammation and Akt signalling in rats / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Poly (ADP-ribose) polymerase (PARP) has been proposed to play an important role in the pathogenesis of heart ischaemia/reperfusion (I/R) injury. 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ), a potent PARP inhibitor, has cardiac protective effects. Because the underlying mechanisms are not understood, we investigated the effect of DPQ on heart I/R injury and its mechanisms.</p><p><b>METHODS</b>Studies were performed with I/R rats' hearts. DPQ was used to inhibit the activation of PARP. Cardiac function and cellular apoptosis were assessed. The activation of PARP, transcription factor nuclear factor-kappaB (NF-κB), intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9) were evaluated. We also evaluated expression of Akt and two of its downstream targets, glycogen synthase kinase-3β (GSK-3β) and forkhead transcription factor FOXO3a.</p><p><b>RESULTS</b>Administration of DPQ significantly decreased the activation of PARP and cellular apoptosis from (35 ± 5)% to (20 ± 4)% and simultaneously improved the cardiac function. DPQ reduced the expressions of NF-κB, ICAM-1, COX-2 and MMP-9 in rat heart and facilitated the activations of phosphor-Akt, phosphor-GSK-3β and phosphor-FOXO3a.</p><p><b>CONCLUSION</b>The protective effects of DPQ were associated with the suppression of inflammation and the activation of the Akt signalling pathways suggesting that the inhibition of poly (ADP-ribose) polymerase reduced heart I/R injury in rats.</p>

Poly (ADP-ribose) polymerase inhibition attenuates ischemia/reperfusion induced myocardial injury in rat via reducing myocardial nuclear factor κB activity / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the effect of Poly (ADP-ribose) polymerase (PARP) inhibition on ischemia/reperfusion (I/R) induced myocardial injury in rat and related mechanisms.</p><p><b>METHOD</b>Adult Wistar rats were randomly divided into sham-control (n = 18), I/R (60 min ischemia followed by 180 min reperfusion, n = 18) and I/R + PARP inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ), 10 mg/kg, i.p. injection at 1 h before I/R (n = 18). Myocardial expression of PARP, infarct size, and cardiomyocytes apoptosis were determined. Additionally, myocardial NF-κB activity and the myocardial expressions of ICAM-1, COX-2 and MMP-9 at protein and mRNA level were detected.</p><p><b>RESULT</b>(1) Myocardial expression of PARP was significantly upregulated in I/R group compared to sham-control group, which could be significantly reduced by pretreatment with DPQ (P < 0.05 vs. I/R group). (2) Infarct size [(31.45 ± 5.54)% vs. (45.97 ± 4.22)%] and cardiomyocytes apoptosis [(23.0 ± 3.8)% vs. (34.0 ± 6.2)%] were significantly reduced by pretreatment with DPQ (all P < 0.05 vs. I/R group). (3) Pretreatment with DPQ also significantly decreased the NF-κB activity and the myocardial expressions of ICAM-1, COX-2 and MMP-9 at both protein and mRNA level (all P < 0.05).</p><p><b>CONCLUSION</b>The expression of PARP, NF-κB activity and the myocardial expressions of ICAM-1, COX-2 and MMP-9 are upregulated in I/R induced myocardial injury. PARP inhibitor DPQ could attenuate I/R induced myocardial injury through reducing NF-κB activity and the myocardial expressions of ICAM-1, COX-2 and MMP-9.</p>

Predictors of vulnerable atherosclerotic plaques induced by cholesterol and balloon injury in rabbits / 中华心血管病杂志

<p><b>OBJECTIVE</b>To detect the optimal predictors of vulnerable atherosclerotic plaques.</p><p><b>METHODS</b>Forty New Zealand white rabbits underwent balloon-induced abdominal aortic wall injury and were fed a high cholesterol and saturated fat diet containing 1% cholesterol for 8 weeks. Rabbits were then randomly divided into two groups: group A (n = 20, the aortic segments rich in plaques were incubated transluminally with recombinant adenovirus carrying p53) and group B [n = 20, incubated transluminally with β galactosidase (LacZ) genes]. Two weeks later, rabbits underwent pharmacological triggering with injection of Chinese Russell's viper venom (CRVV) and histamine. Before pharmacologically triggering, concentrations of hs-CRP, sVCAM-1 and sICAM-1 were measured by means of Enzyme-linked-immunosorbent assay (ELISA). Fibrinogen was analyzed by nephelometer. Ultrasound imaging, accuracy densitometry (AD) examination and intravascular ultrasound (IVUS) were performed to analyze the in vivo features of vulnerable plaques. Logistic regression was used to detect the predictors for vulnerable plaques.</p><p><b>RESULTS</b>The ratio of plaque rupture after pharmacological triggering was significantly higher in group A (89.5%, 17/19) than in group B (22.2%, 4/18). Serum hs-CRP level was significantly higher in plaque rupture group than in non-rupture group before pharmacological triggering (P < 0.05). In the meantime, parameters derived from ultrasound imaging [intima-media thickness (IMT) and peak velocity (VP), values of accuracy densitometry], measurements of IVUS [external elastic membrance area (EEMA), plaque area (PA), plaque burden (PB), eccentric index (EI) and remodeling index (RI)] were significantly larger in plaque rupture group than in non-rupture group. Logistic regression showed that EI (OR = 26.917), PA (OR = 19.301), sVCAM-1 (OR = 1.339) and AII-c% (OR = 0.458) were independent predictors for plaque rupture (all P < 0.05).</p><p><b>CONCLUSION</b>The major predictors of vulnerable plaques were eccentric index (EI) and plaque area (PA), sVCAM-1 and AII-c% in this model.</p>

Impact of gender on in-hospital death in hospitalized patients with acute myocardial infarction / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate whether gender is an independent predictor of in-hospital death in hospitalized patients with acute myocardial infarction (AMI).</p><p><b>METHODS</b>This retrospective study compared baseline characteristics, therapeutic approaches and the occurrence rate of angina pectoris, reinfarction, heart failure and death during hospitalization between 1501 male and 635 female hospitalized patients with AMI. Multivariate logistic regression analysis was performed to identify risk factors predicting in-hospital death.</p><p><b>RESULTS</b>In-hospital death rate was significantly higher in female than male patients with AMI (11.7% vs. 6.3%, P < 0.01). Female patients with AMI were significantly older than male patients [(67.8 +/- 9.2) years vs. (61.1 +/- 11.9) years, P < 0.01] had a higher incidence of hypertension (52.1% vs. 41.1%, P < 0.01), diabetes mellitus (35.4% vs. 17.3%, P < 0.01), cardiac function > or = Killip class III (11.7% vs. 5.1%, P < 0.01) and TC > 4.68 mmol/L (71.3% vs. 55.0%, P < 0.01). Cigarette smoking, however, was more common in males than in females (69.4% vs. 15.7%, P < 0.01). Reperfusion therapy within the first 24 hours after symptom onset, beta-blockers and statins use during hospitalization were significantly fewer in females compared with males (22.2% vs. 31.5%, P < 0.01; 64.6% vs. 71.2%, P = 0.003; 43.1% vs. 48.0%, P = 0.041, respectively). An increased mortality was demonstrated in females during the hospitalization phase of AMI (11.7% vs. 6.3%, P < 0.01). The results of logistic regression demonstrated that age, diabetes mellitus, hypertension, Killip classification of cardiac function, administration of reperfusion therapy and beta receptor blockers use were significant predictors of in-hospital death in patients with AMI, with odds ratios being 1.06 (95% CI: 1.04 - 1.08), 1.96 (95% CI: 1.32 - 2.90), 1.80 (95% CI: 1.25 - 2.58), 2.86 (95% CI: 2.35 - 3.48), 0.44 (95% CI: 0.30 - 0.66) and 0.51 (95% CI: 0.36 - 0.74), respectively.</p><p><b>CONCLUSIONS</b>The in-hospital mortality of females is significantly higher than that of males in this patient cohort. Older age, higher risk factor rates, less reperfusion therapy and beta-blockers use contributed to the higher in-hospital mortality in female patients with AMI compared to males.</p>

Atrial electrical, contractile and structural remodeling induced by short-term atrial tachycardia in a canine model / 中华心血管病杂志

<p><b>OBJECTIVE</b>To evaluate atrial remodeling induced by short term pacing in a canine model.</p><p><b>METHODS</b>Transvenous lead was inserted into the right atrial appendage of anesthetized mongrel dogs and paced for 5 hours at 450 bpm (n=12). Effective refractory period (ERP) and P-wave duration were measured before and post pacing and left ventricular pressure was monitored during the procedure. Echocardiography was performed to observe the presence or absence of spontaneous echo contrast and to assess the effect of rapid atrial pacing on atrial function. All measurements were obtained in sinus rhythm. Histology of the myocardium in left atrial trabeculae and appendages was examined by electron microscopy.</p><p><b>RESULTS</b>Compared to pre-pacing status, ERP was significantly reduced [(87.27 +/- 16.35) ms vs. (113.27 +/- 11.99) ms, P<0.01] at a cycle length of 300 ms, P-wave duration significantly increased [(56.09 +/- 8.62) ms vs. (52.09 +/- 7.63) ms, P<0.01], the peak velocity of atrial contraction significantly decreased [(48.92 +/- 10.80) cm/s vs. (59.25 +/- 9.37) cm/s, P<0.05] while heart rates and left ventricular pressure were not affected post five hours rapid atrial pacing. Pacing also induced significantly cellular ultrastructures changes including myofibrils loss, glycogen accumulation, mitochondria loss and swelling.</p><p><b>CONCLUSION</b>Short term pacing resulted in atrial electrical, contractile and structural remodeling.</p>

Impact of Chinese guidelines for management of patients with acute myocardial infarction on outcomes of hospitalized patients / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The first Chinese guidelines for the diagnosis and management of patients with acute myocardial infarction (AMI) were issued by the Cardiovascular Branch of the Chinese Medical Association, the Editorial Board of the Chinese Journal of Cardiology, and the Editorial Board of the Chinese Circulation Journal in December 2001. However, it is still unclear whether these guidelines have produced a major impact on clinical practice and patient outcomes. The purpose of this study was to evaluate the impact of these guidelines on the management and prognosis of Chinese patients with AMI.</p><p><b>METHODS</b>A retrospective study was carried out in patients with AMI who were admitted to Qilu Hospital of Shandong University from January 1994 to December 2004. Patients were divided into two groups: group A included patients admitted from January 1994 to December 2001, and group B comprised those admitted from January 2002 to December 2004. Therapeutic approaches and the occurrence rate of angina pectoris, reinfarction, heart failure and death during hospitalization were compared between two groups.</p><p><b>RESULTS</b>A total of 1783 patients including 1208 cases in group A and 575 cases in group B were enrolled in this study. No significant difference was found in baseline characteristics between group A and group B patients (all P > 0.05). There were more patients undergoing reperfusion therapy within the first 24 hours after symptom onset in group B than in group A (35.8% vs 21.7%, P < 0.001). Administration of beta-blockers, angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), statins, and heparins were more commonly seen in group B than in group A (P < 0.001). There were no significant differences in the use of nitrates or antiplatelet drugs between groups A and B (98.8% vs. 97.9%, P = 0.172, and 97.4% vs 98.6%, P = 0.113, respectively). In-hospital angina pectoris, heart failure and death were all lower in group B than in group A (32.2% vs 41.2%, P < 0.001; 17.2% vs 26.2%, P < 0.001; and 6.4% vs 9.4%, P = 0.038, respectively). There was no significant difference in the rate of reinfarction between group A and B patients (2.2% vs 1.7%, P = 0.492).</p><p><b>CONCLUSIONS</b>Chinese guidelines for the management of patients with AMI issued in December 2001 resulted in changes in therapy that led to a significant improvement of in-hospital outcomes but not in the rate of reinfarction in patients with AMI.</p>

Effect of Chinese guidelines issued in 2001 on in-hospital management and prognosis of patients with acute myocardial infarction / 中华心血管病杂志

<p><b>OBJECTIVE</b>To evaluate the effect of Chinese guidelines issued on December 2001 on in-hospital management and prognosis of patients with acute myocardial infarction.</p><p><b>METHODS</b>A retrospective study was carried out in patients hospitalized in our hospital with acute myocardial infarction from January 1994 to December 2004.</p><p><b>RESULTS</b>There were 1783 patients enrolled in our study. Reperfusion therapy was undergone in 21.7% of patients hospitalized between 1994 and 2001, and in 35.8% of patients hospitalized between 2002 and 2004 (P < 0.001). Beta-blockers, ACE inhibitors and/or angiotensin receptor blockers, lipid regulating agents and antithrombins were used more extensively between 2002 and 2004 than before (all P < 0.001). There were no significant differences in the usage of nitrates and antiplatelets before and after the guidelines was issued (98.8% vs 97.9%, P = 0.172; 97.4% vs 98.6%, P = 0.113 respectively). After the guidelines issued, the incidence of angina pectoris, heart failure and death in hospital were lower than before (32.2% vs 41.2%, P < 0.001; 17.2% vs 26.2%, P < 0.001; 6.4% vs 9.4%, P = 0.038).</p><p><b>CONCLUSIONS</b>Chinese guidelines issued on December 2001 have great effect on the management and prognosis of patients with acute myocardial infarction. After the guidelines was issued the management became more standardized and the incidence of in-hospital complications was lower than before.</p>

A randomized clinical trial on comparison of weight-adjusted dose with low dose recombinant tissue-type plasminogen activator on Chinese patients with acute myocardial infarction / 中华心血管病杂志

<p><b>OBJECTIVE</b>The aim of the study was to quest appropriate dose of recombinant tissue-type plasminogen activator (rt-PA) on Chinese patients with acute myocardial infarction.</p><p><b>METHODS</b>All enrolled patients were randomized into weight-adjusted dose or low dose rt-PA group, and received a basal treatment with aspirin and heparin. Additionally, after an intravenous bolus of 8 mg rt-PA, patients in weight-adjusted dose group (n = 93) were given an intravenous infusion of 42-92 mg rt-PA (1 mg/kg body weight), while patients in the low dose group (n = 91) were treated with an intravenous infusion of 42 mg rt-PA over 90 minutes. The observational endpoint included reperfusion rate of the infarct-related artery by clinical criteria, left ventricular ejection fraction and major adverse cardiovascular events within 30 days in the two groups.</p><p><b>RESULTS</b>There were 74 patients diagnosed reperfusion by clinical criteria in weight-adjusted dose group and 59 patients in low dose group (79.6% vs 64.8%, P = 0.026). The left ventricular ejection fraction seemed to be better in weight-adjusted dose group than in low dose group (P = 0.259). The major adverse cardiovascular events within 30 days were less in weight-adjusted dose group than in low dose group (P < 0.05).</p><p><b>CONCLUSION</b>There was statistical significant superiority of weight-adjusted dose over low dose rt-PA in the treatment of Chinese patients with acute myocardial infarction.</p>

Establishing an animal model of unstable atherosclerotic plaques / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Atherosclerotic plaque rupture and coronary thrombosis are the main causes of acute coronary syndromes. However, there is no animal model of unstable atherosclerotic plaques. The presence of the p53 gene in advanced atherosclerotic plaques and the sensitivity to p53-induced apoptosis of smooth muscle cells isolated from these plaques prompted us to build an animal model of unstable atherosclerotic plaques using p53 gene transfer.</p><p><b>METHODS</b>Sixty-four New Zealand white rabbits were randomly divided into two groups: group A (n=54) and group B (n=10). Rabbits in group A underwent balloon-induced abdominal aortic wall injury and were then given a diet of 1% cholesterol, while rabbits in group B were given a diet of 1% cholesterol without the induction of aortic wall injury. At the end of the eighth week, rabbits in group A were randomly divided into two subgroups: group A1 (n=27) and group A2 (n=27). Recombinant adenovirus carrying p53 or beta-galactosidase (LacZ) genes were injected through a catheter into the aortic segments rich in plaques in groups A1 and A2, respectively. Two weeks later, 10 rabbits each from groups A1 and A2 were killed to observe the occurrence of spontaneous plaque ruptures, and the remaining rabbits in groups A1, A2, and B all underwent pharmacological triggering with an injection of Chinese Russell's viper venom (CRVV) and histamine.</p><p><b>RESULTS</b>The over expression of p53 in group A1 [(32.4 +/- 10.2)% vs (15.8 +/- 3.6)% in group A2 and (16.2 +/- 6.7)% in group B, P < 0.001, respectively] resulted in a marked increase in cellular apoptosis [(2.5 +/- 0.8)% vs (1.0 +/- 0.3)% in group A2 and (0.9 +/- 0.4)% in group B, P < 0.01, respectively], an accumulation of inflammatory cells within the plaques, and a significant decrease in vascular smooth muscle cells (VSMCs) and in the thickness of the fibrous caps. Although spontaneous plaque rupture was rare in group A1, plaque ruptures and thrombosis occurred in 12 rabbits with a total of 20 lesions after pharmacological triggering. By contrast, pharmacological triggering led to plaque rupture and thrombosis in only 5 rabbits for a total of 7 lesions in group A2 and in none of the rabbits in group B.</p><p><b>CONCLUSION</b>After transfection with human wild-type p53 gene and pharmacological triggering, plaque rupture and thrombosis occur in most atherosclerotic lesions in rabbits, thus offering a reliable model for the further study of unstable atherosclerotic plaques.</p>