[Effect of ischemic postconditioning on activation of p38 mitogen activated protein kinase and cardiac myocyte apoptosis in rats].

OBJECTIVE: To explore the change of phospho-p38 (P-p38) mitogen activated protein kinase(MAPK) and its influence on myocardial apoptosis in reperfusion injury in postconditioning. METHODS: Totally 60 rats were equally and randomly divided into six groups: Sham group,reperfusion injury (R/I) group, postconditioning (Post) group, SB203580 (I_p38) group, anisomycin plus postconditioning (Ani+post) group,and anisomycin (Ani) group. After the model of acute myocardial infarction was established,placebo solution (DMSO), SB203580 (1 mg/kg), or anisomycin (2 mg/kg) was injected through jugular vein 5 minutes before reperfusion. Six hours later, 3 rats in each group were executed and the hearts were separated to measure the signaling molecules including phospho-p38,tumor necrosis factor-alpha (TNF-α), Caspase-8, Bcl-2/Bax, and cytochrome-c (Cyt-c). Twenty-four hours later,the hemodynamic data were measured in the remaining rats,and then blood was collected to determine the serum markers of cardiac damage. After that,hearts were separated to measure the infarction area and apoptosis. RESULTS: Six hours after reperfusion,the expressions of P-p38 in Post and I_p38 group were significantly lower than those in R/I group (P<0.05), significantly higher in Ani+post and Ani group than in Post group (P<0.05), and significantly lower in Ani+post group than in R/I group (P<0.05). The expressions of TNF-α and Caspase-8 were significantly lower in Post and I_p38 group than in R/I group (P<<.05) and significantly higher in Ani+post and Ani group than in Post group (P<0.05). The expression of TNF-α was significantly lower in Ani+post group than in R/I group (P<0.05). The expression of Bcl-2 was significantly higher in Post and I_p38 groups than in R/I group (P<0.05) and significantly lower in Ani+post and Ani groups than in Post group (P<0.05). The expression of Bax was significantly lower in Post and I_p38 groups than in R/I group (P<0.05) and were significantly higher in Ani+post and Ani group than in Post group (P<0.05). The expression of Cyt-c after the removal of the cytoplasm mitochondria was significantly lower in Post and I_p38 group than in R/I group (P<0.05) and was significantly higher in Ani+post and Ani group than in Post group (P<0.05). Twenty-four hours after reperfusion,the values of rate-pressure product and ± delta pressure/delta time max were significantly lower in R/I group than in Post and I_p38 groups (P<0.05) and was significantly higher in Post group than in Ani+post and Ani group (P<0.05). The apoptotic index (AI) was significantly lower in Post and I_p38 groups than in R/I group (P<0.05) and was significantly higher in Ani+post and Ani groups than in Post group (P<0.05). The values of creatine kinase and creatine kinase-MB were significantly lower in Post,Ani+post, and I_p38 groups than in R/I group (P<0.05) and were significantly higher in Ani+post and Ani group than in Post group (P<0.05). The area of necrosis/area at risk ratio was significantly lower in Post and I_p38 groups than in R/I group (P<0.05) and was significantly higher in Ani+post and Ani groups than in Post group (P<0.05). CONCLUSION: Postconditioning can inhibit the phosphorylation of p38 MAPK,through which it can attenuate cardiac myocyte apoptosis by both extrinsic and mitochondria pathways.

[Gradual algorithm of postconditioning reduced reperfusion injury through mitochondrion pathway in rats].

OBJECTIVE: The effects of various postconditioning algorithm on reperfusion injury and the role of mitochondrion pathway were investigated in a rat model of reperfusion/injury. METHODS: Rats were divided into 5 groups: sham, reperfusion/injury (R/I group), reverse algorithm of postconditioning (R-Post, 30/10-25/15-15/25-10/30 s of reperfusion/re-occlusion), standard algorithm of postconditioning (S-Post, 4 cycles of 20/20 s of reperfusion/re-occlusion), and gradual algorithm of postconditioning (G-Post, 10/30-15/25-25/15-30/10 s of reperfusion/re-occlusion). RESULTS: The levels of Bax, Cytochrome-c, Caspase-9, serum marker of myocardium and apoptosis index were significantly lower while the level of Bcl-2 was significantly higher in the three postconditioning groups than those in R/I group (all P < 0.05). The levels of Bax (0.35 +/- 0.10 vs. 0.50 +/- 0.02, P < 0.05), Cytochrome-c (0.66 +/- 0.16 vs. 1.68 +/- 0.22, P < 0.05), Caspase-9 (0.61 +/- 0.17 vs. 1.66 +/- 0.55, P < 0.05), serum marker of myocardium [CK: (251.00 +/- 45.16) U/L vs. (388.56 +/- 75.01) U/L, P < 0.05; CK-MB: (146.00 +/- 60.12) U/L vs. (291.16 +/- 52.41) U/L, P < 0.05] and apoptosis index [(4.32 +/- 1.16)% vs. (8.58 +/- 1.12)% , P < 0.05] were all significantly lower while Bcl-2 level (2.00 +/- 0.34 vs. 1.40 +/- 0.18, P < 0.05) was significantly higher in G-Post group than those in S-Post group. Moreover, above mentioned cardiac protective effects were significantly stronger in the G-Post group compared to R-Post group (all P < 0.05). CONCLUSION: In conclusion, gradual algorithm of postconditioning could attenuate reperfusion injury more significantly than standard algorithm, and mitochondrion pathway plays an important role in this cardioprotective process.

[Change of JNK MAPK and its influence on cardiocyte apoptosis in ischemic postconditioning].

OBJECTIVE: To test whether postconditioning could inhibit the expression of phospho-JNK (P-JNK) mitogen activated protein kinase (MAPK) and study its relation to apoptosis of cardiocyte. METHODS: Sixty rats were randomly divided into six groups: sham, reperfusion injury (R/I), postconditioning (Post), SP600125 (I_JNK), anisomycin and postconditioning (Ani+Post) and anisomycin (Ani) groups. After acute myocardial infarction was induced in rats, placebo solution (DMSO), SP600125 (6 mg/kg) or anisomycin (2 mg/kg) was injected through jugular vein 5 min before reperfusion; 6 h later 3 rats of each group were executed and the hearts were separated to measure the signaling molecules (phospho-JNK, TNF alpha, Caspase-8, Bcl-2/Bax, cytochrome-c). Twenty-two hours later hemodynamic data were measured in the left rats, and then blood samples were taken to determine serum markers of cardiac damage, and hearts were separated to measure the infarction area and cardiocyte apoptosis. RESULT: Postconditioning improved +/-DP/DTmax of left ventricle, limited infarct area, relieved apoptosis and necrosis of cardiocytes, and inhibited the expression of P-JNK (1.12 +/-0.21 Compared with 1.90 +/-0.32, P<0.05). At the same time the levels of TNFalpha Caspase-8, Bax and Cyt-c were lower in Post group than those in R/I group, but Bcl-2 expression levels were higher. I_JNK group presented the similar protection effect of postconditioning [TUNEL index: (6.23 +/-2.43)% Compared with (18.22 +/-5.10)%, P<0.05; Infarct area: (23.44 +/-6.34)% Compared with (42.31 +/-8.21)%, P<0.05]. On the other hand, Ani+Post group partially lost cardioprotection effect [TUNEL index: (14.12 +/-2.00)% Compared with (18.22 +/-5.10)%,P>0.05; Infarct area: (35.27 +/-5.28)% Compared with (42.31+/-8.21)%,P>0.05], because of the activation of JNK MAPK. CONCLUSION: Postconditioning can inhibit phosphorylation of JNK MAPK, which attenuates cardiocyte apoptosis by both extrinsic and mitochondria pathway.

Effect of glycosylation at Asn302 of pro-urokinase on its stability in culture supernatant.

OBJECTIVE: To investigate the effect of glycosylation at Asn302 of pro-urokinase (pro-UK) on the stability in culture supernatant. METHODS: Nonglycosylated pro-UK was constructed by site-directed mutagenesis of Asn302 to Ala302. The pro-UK mutant and native pro-UK were transfected into dhfr(-)-CHO cells, and serum-free culture supernatant was harvested and incubated at 4 degrees C and 37 degrees C, respectively. The pro-UK activity in culture supernatant was measured by the optical density (OD) increase with time (12 hours) at 405 nm. Without thermolysin activation, the percentage of single chain pro-UK was measured. RESULTS: After 48 hours of incubation at 4 degrees C, the activities of pro-UK mutant and native pro-UK decreased 3.7% and 2.9% respectively, and at 37 degrees C decreased 37.9% and 23.5%, respectively. The total activity of native pro-UK was significantly higher than that of nonglycosylated mutant at 37 degrees C. The single-chain percentage of native pro-UK was higher than that of nonglycosylated mutant at both 4 degrees C and 37 degrees C. CONCLUSION: Higher temperature increases the proteolysis of pro-UK. The glycosylation site on Asn302 is beneficial to pro-UK stability in culture supernatant.

[Chronic effects of spironolactone in conjunction with an angiotensin-converting enzyme inhibitor enalapril on circulating procollagen marker P III NP and vascular resistance in patients with essential hypertension].

OBJECTIVE: Disturbances of the synthesis and breakdown of the extracellular matrix of arterial walls have emerged as key features of the atherosclerotic process. We observed the changes of circulating procollagen marker for type III collagen turnover rate, the N-terminal propeptide P III NP and vascular resistance in hypertensive patients treated with various antihypertensive regimens. METHOD: A total of 130 light to moderate hypertensive patients were randomly assigned to receive enalapril (group B, n = 43), enalapril + spirolactone (20 mg/d, group A, n = 44) and anti-hypertensive drugs not directly affecting RAAS (calcium antagonist, beta-blocker, group C, n = 43) for 1 year. Target blood pressure is < 130/80 mm Hg. RESULTS: Target blood pressure was reached in all treated patients and was similar among various groups. Under the same blood pressure controlling precondition, serum P III NP were similar at baseline among various groups and remained unchanged in group B [(3.4 +/- 0.3) microg/L vs. (3.7 +/- 0.3) microg/L, P > 0.05] and significantly decreased in group A [(2.3 +/- 0.2) microg/L vs. (3.8 +/- 0.2) microg/L, P < 0.05] while significantly increased in group C [(3.9 +/- 2.0) microg/L vs. (3.2 +/- 1.5) microg/L, P < 0.05]. Vascular resistance was similar among groups before therapy and all significantly decreased after 1 year antihypertensive therapy and the decrease was more significant in group A [(1064.3 +/- 158.6) dyn.s(-1).cm(-5)] than that in group B [(1200.8 +/- 298.7) dyn.s(-1).cm(-5)] and group C [(1205.1 +/- 206.4) dyn.s(-1).cm(-5)]. CONCLUSION: Spironolactone in conjunction with enalapril is a more favorable antihypertensive regimen in decreasing P III NP and improving vascular resistance than enalapril alone or antihypertensive drug regimens not directly affecting RAAS.

Aggressive plaque modification with rotational atherectomy and cutting balloon for optimal stent expansion in calcified lesions.

OBJECTIVE: To evaluate the factors affecting optimal stent expansion in calcified lesions treated by aggressive plaque modification with rotational atherectomy (RA) and a cutting balloon (CB). METHODS: From January 2014 to May 2015, 92 patients with moderate to severe coronary calcified lesions underwent rotational atherectomy and intravascular ultrasound imaging at Chinese PLA General Hospital (Beijing, China) were included in this study. They were divided into a rotational artherectomy combined with cutting balloon (RACB) group (46 patients treated with RA followed by CB angioplasty) and an RA group (46 patients treated with RA followed by plain balloon angioplasty). Another 40 patients with similar severity of their calcified lesions treated with plain old balloon angioplasty (POBA) were demographically matched to the other groups and defined as the POBA group. All patients received a drug-eluting stent after plaque preparation. Lumen diameter and lumen diameter stenosis (LDS) were measured by quantitative coronary angiography at baseline, after RA, after dilatation, and after stenting. Optimal stent expansion was defined as the final LDS < 10%. RESULTS: The initial and post-RA LDS values were similar among the three groups. However, after dilatation, the LDS significantly decreased in the RACB group (from 54.5% ± 8.9% to 36.1% ± 7.1%) but only moderately decreased (from 55.7% ± 7.8% to 46.9% ± 9.4%) in the RA group (time × group, P < 0.001). After stenting, there was a higher rate of optimal stent expansion in the RACB group (71.7% in the RACB group, 54.5% in the RA group, and 15% in the POBA group, P < 0.001), and the final LDS was significantly diminished in the RACB group compared to the other two groups (6.0% ± 2.3%, 10.8% ± 3.3%, 12.7% ± 2.1%, P < 0.001). Moreover, an LDS ≤ 40% after plaque preparation (OR = 2.994, 95% CI: 1.297-6.911) was associated with optimal stent expansion, which also had a positive correlation with the appearance of a calcified ring split (r = 0.581, P < 0.001). CONCLUSIONS: Aggressive plaque modification with RA and CB achieve more optimal stent expansion. An LDS ≤ 40% after plaque modification was a predictive factor for optimal stent expansion in calcified lesions. This parameter was also associated with the presence of calcified ring split.

Insulin resistance and carotid atherosclerosis in 221 patients with potential hyperglycemia.

OBJECTIVE: To investigate the relationship between insulin resistance and carotid atherosclerosis in patients with potential hyperglycemia. METHODS: A total of 221 patients were recruited among those with potential hyperglycemia. All participants underwent physical examination, medical history interview, and 75 g oral glucose tolerance test. Venous blood was sampled for measurement of insulin and cholesterol levels. The intima-media thickness (IMT) in bilateral common carotid arteries was observed by B-mode ultrasound. Insulin resistance index was calculated by homeostasis model assessment (HOMA-IR). Subjects were stratified in quintiles according to HOMA-IR values. Risk factors and atherosclerotic parameters were analyzed. RESULTS: With HOMA-IR value increase, incidence of impaired glucose tolerance, diabetes mellitus, hypertension, and coronary artery disease increased, the levels of triglyceride (TG), low density lipoprotein cholesterol (LDL-C), fasting plasma glucose, 2 hour plasma glucose, and fasting insulin increased as well, while the level of high density lipoprotein cholesterol (HDL-C) decreased. Meanwhile, all atherosclerotic parameters increased. Multivariate regression analysis showed that TG, total cholesterol, HDL-C, LDL-C levels, and ln(HOMA-IR) were related to IMT, hence were risk factors for IMT increase. CONCLUSION: Insulin resistance is implicated in atherogenesis.

[The impact of different provocations on ERK translocation and c-fos expression in neonatal cultured cardiomyocytes].

OBJECTIVE: To study the nuclear translocation of extracellular signal regulated kinase (ERK) and expression of c-fos mRNA under stimulation of AngII as well as the influence on the nuclear translocation of ERK with different interferences in neonatal cultured cardiomyocytes. METHODS: ERK in the cytoplasm or nucleus was observed by immunocytochemistry using specific antibody and the expression of c-fos was evaluated with RT-PCR technique. RESULTS: AngII (10(-6) mol/L) had the effect in promoting activation of ERK and then appeared in nucleus rapidly. The translocation process of ERK induced by AngII was blocked distinctly by Valsartan (10(-5) mol/L) and PD98059 (5 x 10(-5) mol/L), but not by CGP42112A (10(-5) mol/L). It was also found that Valsartan and PD98059 could inhibit the expression of c-fos in that process. CONCLUSION: The nuclear translocation of ERK might be a precondition for the inducement of c-fos expression.

[Clinical efficacy and safety of emergent percutaneous coronary intervention for vein-grafts in the patients with acute myocardial infarction: comparison between age groups].

OBJECTIVE: To evaluate the efficacy and the safety of emergent primary percutaneous coronary intervention (PCI) in the saphenous vein bypass graft (SVBG) of acute myocardial infarction (AMI), and compare the results between aged -patients with non-aged patients. METHODS: Three hundred and nine consecutive AMI patients with culprit SVBG vessels, were analysed, including aged patients 213 cases(>or=70 years old), non-aged patients 96 cases(<70 years old), underwent the emergent primary PCI after confirmed below TIMI III perfusion(TIMI 0-TIMI II) in coronary angiographies. The immediate results and in-hospital outcomes were compared between two groups. RESULTS: Procedural successful rate, re-occlusion rate, and emergency re-CABG had no significant differences between two groups. The rate of slow-flow/no-reflow and in-hospital mortality rate were significantly higher in elderly group (19.7% vs 10.4%, 9.4% vs 4.2%, both P<0.05), with no difference in the rate of the using of distal protection devices between two groups. The comparison of the rate of direct stenting in slow-flow/no-reflow subgroup with normal-flow subgroup, had not showed statistic difference (73.5% vs 67.3%, P>0.05). There was no statistic difference of heavy hemorrhage between two different age groups. CONCLUSION: The primary PCI for the elderly AMI patients with infarction-related SVBG vessels, has higher risks in slow-flow/no-reflow and the mortality, even with using the distal protection devises and direct stents implantation.

[Effects of atrial excitable period on the stability of atrial fibrillation in goats].

OBJECTIVE: To investigate the effects of atrial excitable period (EP) on the stability of atrial fibrillation (AF) in goats. METHODS: Ten female goats were instrumented with epicardial electrodes patches on the left atrium (LA) free wall. AF was induced and maintained by a home-made stimulator with frequency of 50 Hz at a 1-second duration and a 2-seconds interval. The stimulator was disconnected regularly. AF-induced duration, average AF cycle length (AFCL), and atrial effective refractory period during AF (ERP(AF)) were measured; EP was calculated by AFCL-ERP(AF). RESULTS: Eight goats were studied. Persistent AF (> 24 h) could be induced in all the 8 goats within 6-16 days. When the induced AF lasted for 3-10 min or 24 h, the AFCL was 98.3 ms +/- 11.0 ms and 84.9 ms +/- 5.2 ms (P < 0.05), respectively, ERP(AF) was 90.5 ms +/- 13.2 ms and 63.0 ms +/- 4.8 ms (P < 0.05), respectively, and EP was 7.8 ms +/- 2.4 ms and 21.9 ms +/- 3.5 ms (P < 0.05), respectively. CONCLUSION: The decrease in ERP(AF) is more significant than the shortening in AFCL, resulting in the gradually widening of EP which may contribute to the perpetuation of AF.

RETRACTED: Bosentan attenuates cardiac fibrosis in diabetic mice without affecting blood glucose.

At the request of the authors, 'Bosentan attenuates cardiac fibrosis in diabetic mice without affecting blood glucose' Journal of Renin-Angiotensin-Aldosterone System, published ahead of print August 15, 2011 as doi: 10.1177/1470320311417274 has been retracted. This is due to mistakes in the published data at Figure 3. For clarification: this problem came to the attention of Bo Yang only after publication in the journal. Bo Yang immediately brought it to the attention of the Journal.

[Relationship between the expression of Fas, bcl-2 and apoptosis of cardiomyocytes in experimental myocardial ischemia in rats].

OBJECTIVE: To explore the relationship between expression of Fas, bcl-2 and apoptosis of cardiomyocytes in myocardial ischemia in rats. METHODS: Myocardial ischemia was experimentally induced by ligating the left coronary artery. The rate were killed from 10 minutes to 7 days after the operation. Apoptotic myocardial cells were detected by TUNEL method. The expression of Fas and bcl-2 was studied by ABC immunohistochemistry. RESULTS: Cardiomyocytic apoptosis appeared from 3 to 36 hours after ischemia. This phenomenon however could not be detected by TUNEL method 7 days after ischemia. The expression of Fas could be detected by ABC immunohistochemistry from 3 hours to 7 days after ischemia, and the expression of bcl-2 from 10 minutes to 7 days. Cardiomyocytic apoptosis and Fas / bcl-2 expression appeared in different regions of myocardium: apoptosis in the ischemic regions, while Fas and bcl-2 expression in regions without obvious ischemia. CONCLUSION: In rats, Fas and bcl-2 may not directly regulate apoptosis of cardiomyocytes in case of myocardial ischemia.

[Effects of Ca2+ antagonist on cardiomyocytic apoptosis after experimental myocardial infarction].

OBJECTIVE: To explore the effects of Ca(2+) antagonist on apoptosis of cardiomyocytes after myocardial ischemia. METHODS: The model of myocardial infarction was made by ligating left coronary artery in SD rats. In experimental group, the rats were administrated with Adalat through oral cavity (1 mg/kg) before operation and through peritoneal cavity (0.4 mg/kg 3 hours after operation. In ischemic control group the rats were injected with placebo and in normal control group the rats were treated with sham operation (no ligating left coronary artery) and placebo. The rats were killed 6 hours after operation, with their left ventricular function had been measured. Apoptotic myocardial cells were detected by terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling (TUNEL) method, Fas and Bcl-2 proteins by the ABC immunohistochemistry method. Apoptosis indexes were calculated under high magnification field of microscopy. RESULTS: The systolic pressure, end-diastolic pressure and dp/dt of left ventricle in experiment group were not significant different from those in the ischemic control group, they were 76.7+/-7.5/8.0+/-6.1 mm Hg vs. 74.9+/-11.1/11.6+/-8.3 mm Hg (P>0.05) and (777.3+/-128.6)mm Hg/s vs. (761.8+/-136.4)mm Hg/s (P>0.05) respectively; but those in both the experimental group and the ischemic control group were lower than those in the normal control group, they were 94.9+/-7.5/2.8+/-3.2 mm Hg (P<0.001) and (1131.5+/-112.8)mm Hg/s(P<0.001). There were a lot of positive myocytes with TUNEL stain in the ischemic region of left ventricle in both the experimental and the ischemic control group, apoptosis index in the experimental group was lower than that in the ischemic control group (0.201+/-0.053 vs. 0.261+/-0.045, P<0.05). The positive myocytes of Fas and Bcl-2 protein appeared in the region surrounding ischemic myocytes. There were no positive myocytes with the three types of stain in normal control group. CONCLUSION: Ischemia could induce apoptosis of myocytes and expression of Fas and Bcl-2 gene; Ca(2+) antagonist could protect myocytes from apoptosis.

Post-conditioning with gradually increased reperfusion provides better cardioprotection in rats.

BACKGROUND: Rapid and complete reperfusion has been widely adopted in the treatment of patients with acute myocardial infarction (AMI), but this process sometimes can cause severe reperfusion injury. This study aimed to investigate different patterns of post-conditioning in acute myocardial ischemia-reperfusion injury, and to detect the role of mitogen activated protein kinase (MAPK) during the injury. METHODS: RATS WERE RANDOMLY DIVIDED INTO FIVE GROUPS: sham group, reperfusion injury (R/ I) group, gradually decreased reperfusion group (GDR group, 30/10-25/15-15/25-10/30 seconds of reperfusion/ischemia), equal reperfusion group (ER group, 20/20 seconds reperfusion/ischemia, 4 cycles), and gradually increased reperfusion group (GIR group, 10/30-15/25-25/15-30/10 seconds of reperfusion/ischemia). Acute myocardial infarction and ischemic post-conditioning models were established in the rats. Six hours after reperfusion, 3 rats from each group were sacrificed and myocardial tissues were taken to measure the expressions of phosphorylation of extracellular signal-regulated protein kinase (P-ERK), phosphorylated c-Jun N-terminal kinase (P-JNK), mitogen-activated protein kinase p38 (p38 MAPK), tumor necrosis factor-α (TNF-α), caspases-8 in the myocardial tissue, and cytochrome c in the cytosol using Western blot. Hemodynamics was measured at 24 hours after reperfusion, the blood was drawn for the determination of cardiac enzymes, and the heart tissue was collected for the measurement of apoptosis using TUNEL. One-way analysis of variance and the Q test were employed to determine differences in individual variables between the 5 groups. RESULTS: Three post-conditioning patterns were found to provide cardioprotection (P<0.05) compared with R/I without postconditioning. GIR provided the best cardioprotection effect, followed by ER and then GDR. Apoptotic index and serum marker levels were reduced more significantly in GIR than in ER (P<0.05). The enhanced cardioprotection provided by GIR was accompanied with significantly increased levels of P-ERK 1/2 (1.82±0.22 vs. 1.54±0.32, P<0.05), and lower levels of p-JNK, p38 MAPK, TNF-α, caspase-8, caspase-9 and cytochrome in the cytoplasm (P<0.05), compared with ER. The infarct size was smaller in the GIR group than in the ER group, but this difference was not significant (16.30%±5.22% vs. 20.57%±6.32%, P<0.05). All the measured variables were improved more significantly in the GIR group than in the GDR group (P<0.05). CONCLUSION: Gradually increased reperfusion in post-conditioning could attenuate reperfusion injury more significantly than routine method, thereby the MAPK pathway plays an important role in this process.

Resistin involved in endothelial dysfunction among preclinical Tibetan male young adults.

INTRODUCTION: Resistin, an adipocyte-derived hormone, was found to be linked to metabolic syndrome and insulin resistance over the past decade. There is growing evidence that resistin plays a potential role in endothelial dysfunction. To the best of our knowledge, few studies have been concerned with the effect of resistin on endothelial function in a Tibetan population. AIMS: To investigate the correlation of resistin and endothelial function among preclinical Tibetan male young adults. MATERIALS AND METHODS: All participants recruited were young adults between 30 and 40 years old of male gender in Lhasa city. All subjects were native Tibetan. A total of 90 healthy subjects were accepted after excluding hypertension, diabetes, hyperlipidemia or coronary artery disease. The subjects were divided into three groups according to flow-mediated dilation (FMD): lower FMD (group A), intermediate FMD (group B) and higher FMD (group C). Body mass index, systolic blood pressure (SBP), diastolic blood pressure (DBP) and cigarette smoking were evaluated. Venous blood was sampled for the measurement of lipid profile, fasting blood glucose (FBG), fasting insulin (FINS), endothelin-1 (ET-1) and plasma resistin quantitation. The non-invasive vascular endothelial function was evaluated through the measurement of FMD with B-mode ultrasound. The insulin resistance was estimated as homeostatic model assessment of insulin resistance (HOMA-IR) = FINS(mu/L)*FBG(mmol/L)/22.5. RESULTS: No statistical significance was found between groups in age, smoking, SBP, DBP, fasting insulin, total cholesterol and HOMA-IR (p>0.05). In the lipid profile, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol in group C were better than in groups A and B (p<0.01). Body mass index, which is an indicator for obesity, was much lower in group C than in group A and B (p<0.05 and 0.01 respectively). Comparison of plasma resistin concentrations: group A > group B > group C (p<0.01). Comparison of plasma ET-1 concentrations had a similar result: group A > group B > group C (p<0.05). The multivariate regression analysis showed that total cholesterol (p<0.05), LDL cholesterol (p<0.01), plasma resistin (p<0.01) and plasma ET-1 (p<0.01) were correlated with FMD. CONCLUSIONS: Resistin is involved in endothelial dysfunction in preclinical male young Tibetan adults.

Deterioration of endothelial function and carotid intima-media thickness in Tibetan male adolescents exposed to second-hand smoke.

INTRODUCTION: It has been commonly accepted that second-hand smoke (SHS) is associated with atherosclerosis and endothelial dysfunction. There is growing evidence that the changes might begin in childhood. Unfortunately, no study has focused on the early atherosclerosis of Tibetan adolescents exposed to SHS. AIMS: We aimed to investigate the endothelial function and carotid atherosclerosis in healthy school-aged Tibetan male adolescents. MATERIALS AND METHODS: All passive smoking participants (SHS) were students were 16 years old and male, and were recruited through middle schools in Lhasa city. In total 624 subjects were accepted after excluding subjects who actively smoked. The adolescents were divided into three groups according to serum cotinine level: high cotinine group (High Group) with 205 boys, intermediate cotinine group (Intermediate Group) with 210 boys, and low cotinine group (Low Group) with 209 boys. Venous blood was sampled for the measurement of cotinine concentration, lipid profile and endothelin-1 (ET-1) quantitation. High-resolution B-mode ultrasonography was performed to evaluate carotid intima-media thickness (cIMT) and intima smoothness. The invasive vascular endothelial function was evaluated through the measurement of flow-mediated dilation (FMD) with B-mode ultrasound and ankle-brachial index (ABI) by using a blood pressure cuff and a Doppler instrument. RESULTS: No statistical significance was found between groups in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, ApoA-I, systolic blood pressure, diastolic blood pressure, and heart rate (p>0.05). In the lipid profile, only apolipoprotein B (ApoB) values were different between groups: ApoB in the High Group was higher than in the Low Group (p=0.0164). Plasma ET-1 concentrations in the High Group were also much higher than in the Intermediate and Low Groups (p=0.0112, p<0.001). The cIMT and intima smoothness had deteriorated in the High Group compared with the Low Group (p<0.001 and p<0.05 respectively). FMD and ABI, which indicate vascular endothelial function, was decreased in the High Group compared with the Intermediate and Low Groups (FMD, p<0.001; ABI, p<0.001). CONCLUSIONS: SHS was associated with sub-clinical carotid atherosclerosis and endothelial dysfunction in Tibetan school-aged male adolescents. Considering the widespread exposure to SHS and the clinical relevance of early atherosclerosis, this result is of public health importance in Tibet, where health education is not satisfactory. Data from our study emphasize the importance of endorsing smoke-free environments for adolescents.

Endothelin-1 receptor blockade induces upregulation of renin-angiotensin-aldosterone system expression in terms of blood pressure regulation.

OBJECTIVE: To compare the level of expression of the renin-angiotensin-aldosterone system (RAAS) in mice with or without the endothelin-1 receptor antagonist bosentan and to examine the potential value in blood pressure regulation. MATERIALS AND METHODS: Bosentan (10 mg/kg/d) and placebo were given to two groups of male C57BL/6 mice (n=5) from ages 6 to 12 weeks. The mRNAs of liver, kidney and lung were isolated for Northern blot analysis. A further 15 male C57BL/6 mice were divided into three groups (n=5): mice in group A were given the angiotensin II type 1 receptor blocker valsartan (10 mg/kg/d); mice in group B were given bosentan (10 mg/kg/d); and mice in group C were given both valsartan and bosentan (10 mg/ kg/d for each drug). All mice were administered the drugs from 6 to 12 weeks of age and had their systolic blood pressure (SBP) measured at the end of the drug treatments. RESULTS: Northern blot analysis demonstrated that the expression levels of angiotensinogen in liver (p=0.0126), renin in kidney (p=0.002), and angiotensin-converting enzyme in lung (p=0.0041) were upregulated in mice treated with bosentan. No difference in SBP was found among the groups before drug administration. Six weeks after monotherapy with valsartan, SBP was slightly lowered (126+/-2 vs. 122+/-3 mmHg, p=0.0381). Monotherapy with bosentan also had a small effect on SBP (126+/-2 vs. 122+/-3 mmHg, p=0.0381), whereas dual blockade with valsartan and bosentan significantly lowered SBP (127+/-3 vs. 103+/-3 mmHg, p<0.001). CONCLUSIONS: We conclude that RAAS components are upregulated under endothelin blockade. Dual blockade of the RAAS and endothelin system is beneficial for blood pressure control.

Double-blind, multicenter, active-controlled, randomized clinical trial to assess the safety and efficacy of orally administered nicorandil in patients with stable angina pectoris in China.

BACKGROUND: The efficacy and safety of nicorandil were evaluated in Chinese patients with stable angina pectoris (AP) in a double-blind, multicenter, active-controlled, randomized clinical trial. METHODS AND RESULTS: After a 2-week washout period, 232 patients with stable AP were randomized to receive either nicorandil (5 mg tid; 115 patients) or isosorbide mononitrate (ISMN: 20 mg bid; 117 patients) for 2 weeks. Exercise capacity, number of weekly anginal attacks, nitroglycerin (NTG) consumption, and safety were evaluated. Nicorandil and ISMN significantly prolonged the time to 1 mm ST-segment depression in an exercise tolerance test. Both drugs improved the total exercise time and the time to onset of chest pain. There was no significant difference between the 2 groups. Nicorandil significantly decreased the number of anginal attacks and NTG consumption. ISMN decreased the number of anginal attacks significantly; however, there was no significance in NTG consumption, and the ratio of anginal attack reduction was at least 50% was significantly higher with nicorandil. Nicorandil was well tolerated and there was no safety profile difference compared with ISMN. Thus, nicorandil may have equivalent or better antianginal effect than ISMN. CONCLUSIONS: Nicorandil is beneficial as treatment for AP.