A soluble receptor for advanced glycation end-products inhibits myocardial apoptosis induced by ischemia/reperfusion via the JAK2/STAT3 pathway.

sRAGE can protect cardiomyocytes from apoptosis induced by ischemia/reperfusion (I/R). However, the signaling mechanisms in cardioprotection by sRAGE are currently unknown. We investigated the cardioprotective effect and potential molecular mechanisms of sRAGE inhibition on apoptosis in the mouse myocardial I/R as an in vivo model and neonatal rat cardiomyocyte subjected to ischemic buffer as an in vitro model. Cardiac function and myocardial infarct size following by I/R were evaluated with echocardiography and Evans blue/2,3,5-triphenyltetrazolium chloride. Apoptosis was detected by TUNEL staining and caspase-3 activity. Expression of the apoptosis-related proteins p53, Bax, Bcl-2, JAK2/p-JAK2, STAT3/p-STAT3, AKT/p-AKT, ERK/p-ERK, STAT5A/p-STAT5A and STAT6/p-STAT6 were detected by western blot analysis in the presence and absence of the JAK2 inhibitor AG 490. sRAGE (100 µg/day) improved the heart function in mice with I/R: the left ventricular ejection fraction and fractional shortening were increased by 42 and 57%, respectively; the infarct size was decreased by 52%, the TUNEL-positive myocytes by 66%, and activity of caspase-3 by 24%, the protein expression of p53 and ratio of Bax to Bcl-2 by 29 and 88%, respectively; protein expression of the p-JAK2, p-STAT3 and p-AKT were increased by 92, 280 and 31%, respectively. sRAGE have no effect on protein expression of p-ERK1/2, p-STAT5A and p-STAT6 following by I/R. sRAGE (900 nmol/L) exhibited anti-apoptotic effects in cardiomyocytes by decreasing TUNEL-positive myocytes by 67% and caspase-3 activity by 20%, p53 protein level and the Bax/Bcl-2 ratio by 58 and 86%, respectively; increasing protein expression of the p-JAK2 and p-STAT3 by 26 and 156%, respectively, p-AKT protein level by 33%. The anti-apoptotic effects of sRAGE following I/R were blocked by JAK2 inhibitor AG 490. The effect of sRAGE reduction on TUNEL-positive myocytes and caspase-3 activity were abolished by PI3K inhibitor LY294002, but not ERK 1/2 inhibitor PD98059. These results suggest that sRAGE protects cardiomyocytes from apoptosis induced by I/R in vitro and in vivo by activating the JAK2/STAT3 signaling pathway.

Cardioprotective effects of adipokine apelin on myocardial infarction.

Angiogenesis plays an important role in myocardial infarction. Apelin and its natural receptor (angiotensin II receptor-like 1, AGTRL-1 or APLNR) induce sprouting of endothelial cells in an autocrine or paracrine manner. The aim of this study is to investigate whether apelin can improve the cardiac function after myocardial infarction by increasing angiogenesis in infarcted myocardium. Left ventricular end-diastolic pressure (LVEDP), left ventricular end systolic pressure (LVESP), left ventricular developed pressure (LVDP), maximal left ventricular pressure development (±LVdp/dtmax), infarct size, and angiogenesis were evaluated to analyze the cardioprotective effects of apelin on ischemic myocardium. Assays of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-bromo-2'-deoxyuridine incorporation, wound healing, transwells, and tube formation were used to detect the effects of apelin on proliferation, migration, and chemotaxis of cardiac microvascular endothelial cells. Fluorescein isothiocyanate-labeled bovine serum albumin penetrating through monolayered cardiac microvascular endothelial cells was measured to evaluate the effects of apelin on permeability of microvascular endothelial cells. In vivo results showed that apelin increased ±LV dp/dtmax and LVESP values, decreased LVEDP values (all p < 0.05), and promoted angiogenesis in rat heart after ligation of the left anterior descending coronary artery. In vitro results showed that apelin dose-dependently enhanced proliferation, migration, chemotaxis, and tube formation, but not permeability of cardiac microvascular endothelial cells. Apelin also increased the expression of vascular endothelial growth factor receptors-2 (VEGFR2) and the endothelium-specific receptor tyrosine kinase (Tie-2) in cardiac microvascular endothelial cells. These results indicated that apelin played a protective role in myocardial infarction through promoting angiogenesis and decreasing permeability of microvascular endothelial cells via upregulating the expression of VEGFR2 and Tie-2 in cardiac microvascular endothelial cells.

Effect of blood pressure variability on cardiovascular outcome in diabetic and nondiabetic patients with stroke.

BACKGROUND: The association between blood pressure (BP) variability and stroke outcome is controversial, and there are few studies that have focused on the impact of BP variability in diabetic patients with stroke. Therefore, we aimed to examine the impact of BP variability on cardiovascular outcome in diabetic and nondiabetic patients with stroke. METHODS: A total of 373 ischemic stroke patients with large artery atherosclerosis were recruited and followed up. Ambulatory BP monitoring was performed in all patients and divided according to the 25th and 75th percentiles interval of SD of daytime systolic BP (SBP). Kaplan-Meier analysis and Cox regression were used to assess the relationship between BP variability and cardiovascular outcomes including stroke recurrence, vascular events and cardiovascular death. RESULTS: The 339 patients were included in the final analysis. During an average follow-up of 19.0 ± 5.1 months (.6-26.8 months), 69 (20.4%) cardiovascular events occurred in all patients. Kaplan-Meier analysis found that there were no differences in cardiovascular events-free survival among the different BP variability groups in diabetic patients (P = .995); however, nondiabetic patients with greater BP variability showed a lesser cardiovascular events-free survival (P = .039). Through Cox regression we found the SD of daytime SBP (hazard ratio 1.103; 95% CI 1.011-1.203) was associated with cardiovascular outcomes in nondiabetic patients with stroke. CONCLUSIONS: We show that SBP variability is associated with cardiovascular outcomes in stroke patients without diabetes, but we didn't find a correlation between SBP variability and cardiovascular outcomes in stroke patients with diabetes.

Diagnostic value of combined parameters derived from ambulatory electrocardiography for detecting coronary artery disease in non-active chest pain patients.

BACKGROUND AND OBJECTIVE: The diagnostic value of ST-segment deviation detected by ambulatory electrocardiography (AECG) is controversial in identifying coronary artery disease (CAD) referred for coronary angiography (CAG). Recently, many parameters which evaluate CAD can be derived from AECG. Therefore, we aimed to investigate the diagnostic value of AECG in screening CAD referred for CAG when several parameters were combined. METHODS: We studied the 104 chest pain inpatients. All patients received the CAG and AECG. A lumen diameter reduction of ≥ 50% was considered CAD according to CAG. The parameters derived from AECG included ST-segment deviation, apnea hypopnea index (AHI), QT interval dispersion (QTd) and heart rate variability (HRV). The diagnostic value of AECG in screening CAD was evaluated. RESULTS: Of the 104 patients, 57 (54.8%) had CAD according to CAG. The sensitivity of ST-segment deviation in screening CAD was 64.9%; the specificity was 89.4%; and the Kappa value was 0.528. The sensitivity of at least three combined parameters including ST-segment deviation, AHI, QTd and HRV was 89.5%; the specificity was 87.2%; and the Kappa value was 0.767. CONCLUSION: AECG is very useful in screening CAD referred for CAG, especially while several parameters including ST-segment deviation, AHI, HRV and QTd are combined.

Soluble receptor for advanced glycation end-products positively correlated to kidney injury with coronary heart disease.

AIMS: Coronary heart disease (CHD) patients with changed serum soluble receptor for advanced glycation end products (sRAGE) will experience microalbuminuria and even kidney dysfunction. However, the role of sRAGE for microalbuminuria in CHD is still not established. This study aimed to evaluate the association between sRAGE and early kidney dysfunction in CHD patients. MATERIALS AND METHODS: In this cross-sectional study, sRAGE and urinary albumin-to-creatinine ratio (uACR) were measured in hospitalized CHD patients who have undergone coronary arteriography to evaluate the distinction and correlation between sRAGE and uACR. RESULTS: There were 127 CHD patients (mean age: 63.06 ± 10.93 years, 93 males) in the study, whose sRAGE were 1.83 ± 0.64 µg/L. The sRAGE level was higher in kidney injury group (uACR ≥ 30 mg/g) compared with no kidney injury group (uACR < 30 mg/g) [(2.08 ± 0.70 vs. 1.75 ± 0.61) µg/L, P < 0.05]. Moreover, the positive correlation between serum sRAGE and uACR was significant in CHD patients (r = 0.196, P < 0.05). Binary logistic regression suggests sRAGE as a predictor for microalbuminuria in CHD patients [Odd Ratio = 2.62 (1.12-6.15), P < 0.05)]. The area under the receiver operating characteristic curve (AUC) of sRAGE is higher than that of the traditional indicators of renal function such as creatinine and estimated glomerular filtration rate, indicating sRAGE might have a good performance in evaluating early kidney injury in CHD patients [AUC is 0.660 (0.543-0.778), P < 0.01)]. CONCLUSIONS: Serum sRAGE was positively correlated to uACR and might serve as a potential marker to predict early kidney injury in CHD patients.

Cytochrome P450 2J3/epoxyeicosatrienoic acids mediate the cardioprotection induced by ischaemic post-conditioning, but not preconditioning, in the rat.

1. Cytochrome P450 (CYP) epoxygenases and their arachidonic acid metabolites play a protective role against ischaemia-reperfusion injury. In the present study, we investigated whether endogenous CYP2J3/epoxyeicosatrienoic acid (EET) mediates the cardioprotective effects of ischaemic preconditioning (IPC) and ischaemic post-conditioning (IPost). 2. Male Wistar rats were subjected to two cycles of IPC, consisting of 5 min ischaemia and 5 min reperfusion, followed by 45 min occlusion and 2 h reperfusion; IPost consisted of three cycles of 30 s reperfusion and 30 s re-occlusion at the onset of reperfusion. The selective CYP epoxygenase inhibitor N-methylsulphonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH; 3 mg/kg) was administered 10 min before ischaemia or during ischaemia 10 min before reperfusion started. Cardiac function was measured continuously with a angiocatheter connected to a fluid-filled pressure transducer and myocardial infarct size was assessed by triphenyl tetrazolium chloride staining at the end of the experiment. 3. Subjecting rats to IPC and IPost similarly improved cardiac function and reduced myocardial infarct size. Interestingly, IPost, but not IPC, significantly increased CYP2J3 mRNA (1.75 ± 0.22 vs 1.0; P < 0.05) and protein (1.62 ± 0.22 vs 1.0; P < 0.05), as well as 11,12-EET synthesis compared to I/R (6.2 ± 0.2 vs 2.9 ± 0.2 ng/mg wet weight, respectively; P < 0.01). Administration of MS-PPOH before ischaemia significantly decreased 11,12-EET synthesis in both IPC and IPost compared with I/R rats (2.1 ± 0.2, 3.2 ± 0.3 and 2.9 ± 0.2 ng/mg wet weight, respectively; P < 0.01), but decreased the cardioprotective effects, as evidenced by cardiac function and myocardial infarct size, of IPost only. 4. These data indicate that endogenous activation of CYP2J3/EET may be an essential trigger leading to the protective effects of IPost, but not IPC, in the rat heart.

Association of mononucleotide polymorphisms of angiotensinogen gene at promoter region with antihypertensive response to angiotensin receptor blockers in hypertensive Chinese.

INTRODUCTION:: This study aimed to investigate whether mononucleotide polymorphisms of the angiotensinogen gene at promoter were associated with the blood-pressure-lowering response to telmisartan treatment. MATERIALS AND METHODS:: After a two-week single-blind placebo run-in period, 148 patients with mild-to-moderate primary hypertension received monotherapy with 80 mg/day of telmisartan and then were followed up for eight weeks. The -6A/G and -20A/C polymorphisms of the angiotensinogen gene at promoter were determined through polymerase chain reaction and restriction fragment length polymorphsim analysis. The relationship between these polymorphisms and changes in blood pressure was observed and evaluated after eight weeks of treatment. RESULTS:: There were no significant differences between -6A/G, -20A/C polymorphisms of the angiotensinogen gene and blood pressure reductions after treatment, p>0.05. CONCLUSION:: It is suggested that angiotensinogen-6 A/G and angiotensinogen-20 A/C polymorphisms were not associated with the antihypertensive response to telmisartan treatment in Chinese patients with hypertension.

Why is there significant overlap in volume status between hypertensive and normotensive patients on dialysis?

BACKGROUND/AIM: Volume overload is believed to play a pivotal role in the pathogenesis of hypertension in dialysis patients. Although the extracellular water (ECW) content in hypertensive dialysis patients was significantly higher than in normotensive dialysis patients on the whole, there was considerable overlap in ECW between the two groups. Little is known about the hemodynamic characteristics in subgroups of patients with normotension but a high volume (HV) status or with hypertension but a normal volume (NV) status. We investigate the overlap in ECW between controlled and uncontrolled hypertension in dialysis patients. METHODS: Fifty-two patients (mean age 62 years, 26 males and 26 females) on peritoneal dialysis were enrolled into this study. The ECW was assessed by bioimpedance analysis and normalized by individual height in meters (NECW). The mean value of NECW in both sexes was arbitrarily set to define NV status (lower than mean value) or HV status (higher than mean value). All patients were thus divided into four subgroups: controlled hypertension with NV (CHT-NV), controlled hypertension with HV (CHT-HV), uncontrolled hypertension with NV (UHT-NV) and uncontrolled hypertension with HV (UHT-HV). The stroke volume, cardiac output and total peripheral resistance were echocardiographically measured and their respective indices were calculated. RESULTS: There were 12 (23%), 8 (15%), 14 (27%) and 18 (35%) patients in the CHT-NV, CHT-HV, UHT-NV and UHT-HV subgroups, respectively. The four subgroups were matched for sex, diabetes and age. The NECW in the CHT-HV group was higher than that in CHT-NV and UHT-NV groups (p < 0.01), but was comparable with that in the UHT-HV group. The stroke volume and cardiac output indices in the CHT-HV group were not significantly different from those in the CHT-NV and UHT-NV groups. The total peripheral resistance index in the CHT-HV group was lower than that in UHT-NV and CHT-NV groups (p < 0.05), but was comparable to that in the UHT-HV group. There was no difference in heart rate among the four groups. CONCLUSIONS: The overlap in ECW between controlled hypertension and uncontrolled hypertension in dialysis patients was related to a significant difference in total peripheral resistance index, but not to significant differences in stroke volume and cardiac output indices. The CHT-HV patients were characterized by lower total peripheral resistance indices.

Peripheral resistance modulates the response to volume overload in peritoneal dialysis patients.

BACKGROUND: Volume overload is thought to be the most important cause of hypertension in peritoneal dialysis (PD) patients. However, there is also evidence that normalization of volume overload is not always accompanied by a drop in blood pressure (BP). In the present study, we hypothesized that dysregulation of peripheral resistance due to endothelial dysfunction would constitute an important determinant of BP response in overhydrated PD patients. METHODS: We performed an observational, prospective cohort study including all prevalent PD patients at the Peking University Third Hospital between 1 June 2006 and 30 November 2006. After baseline measurements, including echocardiography and bioelectrical impedance analysis, patients fulfilling inclusion criteria were reevaluated after 2 months of follow-up. All patients that exhibited significant changes in BP and extracellular water (ECW) between 2 visits were asked to undergo a second ultrasound. These patients were then divided into group A (parallel change between BP and ECW; n = 12) and group B (paradoxical change between BP and ECW; n = 10). RESULTS: The cohort included 22 patients (13 males) with a mean age of 59 +/- 13 years, on dialysis for 23.3 +/- 32.6 months. There were no baseline differences between groups A and B. However, while patients in group A significantly increased their cardiac output, total peripheral resistance remained stable. In group B, cardiac output did not change significantly but total peripheral resistance decreased significantly. CONCLUSION: In PD patients, a significant increase in fluid volume is not necessarily linked to a significant increase in BP. Rather, the change in total peripheral resistance was found to be the most important determinant of the extent to which increased fluid volume affected BP.

The prevalence of left ventricular hypertrophy in Chinese hemodialysis patients is higher than that in peritoneal dialysis patients.

BACKGROUND: Left ventricular hypertrophy (LVH) is common in dialysis patients, and an independent predictor of mortality. While recent studies have shown no differences in mortality between the two most common dialysis modalities, hemodialysis (HD) and peritoneal dialysis (PD), their impact on LVH is controversial. We thus performed cardiac ultrasound studies in prevalent dialysis patients receiving either HD or PD and compared LVH. METHODS: We included 48 HD and 62 PD patients receiving treatment for at least three months in our dialysis center. All patients underwent echocardiographic examination and blood pressure measurements immediately following therapy. Volume status was assessed by bioelectrical impedance analysis. RESULTS: There was no baseline difference in demographics or comorbidities between HD and PD patients. As expected, extracellular water (ECW) in post-HD patients was significantly lower than that in pre-HD and PD patients, while cardiac output (CO) and systolic blood pressure (SBP) were higher in pre-HD than that in post-HD or PD patients. There was no significant difference in CO or SBP between post-HD and PD patients. Left ventricular mass index (LVMI) was markedly higher in HD patients as compared to PD patients. Thus, the prevalence of LVH according to the Framingham criteria was 68.8% in HD patients and 45.2% in PD patients. Subgroup analysis showed similar results in the patients who had been on single-modality dialysis for at least two years and in the anuric patients. Finally, in a linear regression model (r(2) = 0.364, p < 0.001), SBP, treatment modality (to be in HD), and ECW were all independent predictors of LVMI. CONCLUSIONS: In a cross-sectional analysis of prevalent Chinese patients, we found a higher LVMI and a higher prevalence of LVH in HD than in PD patients. As LVMI was associated with high blood pressure and volume overload, we suggest that in these patients, PD may preserve more physiological hemodynamics even during long-term therapy.

[Analysis of the changes in aortic root dimension in patients with anterior cerebral infarction].

OBJECTIVE: To analyze the relationship between aortic root dimension (ARD) and anterior circulation infarction (ACI) by measuring ARD of ACI patients. METHODS: The ARD of 110 ACI patients (56 men and 54 women) were measured with 2-dimensional ultrasonography during ventricular systole. 66 control subjects (32 men and 34 women) without the clinical signs of cerebral infarction or organic heart disease and cardiac insufficiency were selected after carrying out detailed case history inquiring, physical examination, CT or MRI and ultrasonic examination. RESULTS: ARD in men and women was respectively (29.80 +/- 2.35) mm and (28.88 +/- 3.06) mm in the ACI group. While it was (27.64 +/- 1.70) mm and (26.98 +/- 1.60) mm respectively in the control subjects. ARD in men and women was significantly higher in the ACI group as compared with the control subjects (P < 0.01). Logistic regression analysis indicated that the odds ratio (confidence interval) associated with ARD was 1.630 (1.205 - 2.204) in men and 1.494 (1.098 - 2.033) in women for ACI. CONCLUSIONS: There is a close relationship between ARD and ACI. ARD is an important risk factor of ACI.

[A randomized, double-blind, double-dummy study comparing a fixed dose combination of telmisartan 80 mg plus hydrochlorothiazide 12.5 mg to telmisartan 80 mg in Chinese hypertensive patients who failed to respond adequately to telmisartan 80 mg].

OBJECTIVE: To evaluate the efficacy and safety of a fixed dose combination of telmisartan 80 mg plus hydrochlorothiazide (HCTZ) 12.5 mg (TH) to telmisartan 80 mg (T) in Chinese patients who failed to respond adequately to treatment with T. METHOD: This is a multi-center, randomized, double-blind, double-dummy clinical study. A total of 699 eligible hypertensive patients entered a one-week screening phase prior to the eight-week open-label T period. At the end of eight weeks, 345 patients who failed to respond to T (DBP > or = 90 mm Hg, 1 mm Hg = 0.133 kPa) were randomized to receive either TH (175 patients) or T (170 patients) for another eight weeks. Sitting and standing BP were taken 24 hours post-dose and adverse events were documented at visit with 4 weeks interval. Laboratory, ECG and physical examination were performed at screening, at baseline and at the final visit. RESULTS: After 8 weeks treatment, (1) The mean trough reduction in sitting diastolic blood pressure (SiDBP) from baseline in TH group was greater than that in T group (10.1 mm Hg vs 7.7 mm Hg, P = 0.0017). The mean trough reduction in sitting systolic blood pressure (SiSBP) from baseline was 14.2 mm Hg in TH group and 7.4 mm Hg in T group (P < 0.0001). (2) The mean trough reduction in standing DBP and standing SBP from baseline were significantly greater in TH group (8.7 mm Hg and 12.9 mm Hg) compared those in T group (7.3 mm Hg and 7.0 mmHg, P = 0.0350, P < 0.0001). (3) The number and percentage of responders in TH group (129, 74.6%) were significantly higher than in T group (100, 59.2%, P = 0.0016). (4) The incidence of the study drug-related adverse events was similar between TH and T group (3.5% vs. 3.6%, P > 0.05). CONCLUSION: TH was more effective than T in patients not responded adequately to T in Chinese hypertensive patients.

The impact of visit-to-visit systolic blood pressure variability on residual renal function and left ventricular hypertrophy in peritoneal dialysis patients

Background/aim: Blood pressure (BP) variability is more closely associated with adverse outcomes than 'usual' BP in the general population. Residual renal function (RRF) and left ventricular hypertrophy (LVH) are thought to be predictors of poor outcome in dialysis patients. However, only a few studies have focused on BP variation and its link to RRF, LVH, and outcome in peritoneal dialysis (PD) patients. Therefore, we aimed to explore the effect of visit-to-visit BP variability on RRF and LVH in continuous ambulatory PD (CAPD) patients. Materials and methods: We performed an observational study that included all prevalent PD patients between 1 February 2006 and 31 January 2007. All patients underwent BP measurements, pulse wave velocity (PWV), cardiac ultrasound, and biochemical examination during the 1-year observation. Patients were divided into the HBPV group (higher BP variability) and LBPV group (lower BP variability) based on the standard deviation of systolic BP (SBP). Results: There were 70 patients recruited for the final analysis. Patients with HBPV had a higher SBP as compared to patients with LBPV at baseline. Renal Kt/V decreased significantly from 0.50 ± 0.49 to 0.32 ± 0.35 (P < 0.01) in HBPV group (but not in the LBPV group) during follow-up. Patients with HBPV also showed a higher left ventricular mass index (LVMI) and PWV than those with LBPV at the end of follow-up. Conclusion: Our study suggests that BP variability may affect RRF in PD patients. PD patients with HBPV had a faster decline in RRF and higher PWV and LVH.

The standard deviation of extracellular water/intracellular water is associated with all-cause mortality and technique failure in peritoneal dialysis patients.

PURPOSE: The mortality rate of peritoneal dialysis (PD) patients is still high, and the predicting factors for PD patient mortality remain to be determined. This study aimed to explore the relationship between the standard deviation (SD) of extracellular water/intracellular water (E/I) and all-cause mortality and technique failure in continuous ambulatory PD (CAPD) patients. METHODS: All 152 patients came from the PD Center between January 1st 2006 and December 31st 2007. Clinical data and at least five-visit E/I ratio defined by bioelectrical impedance analysis were collected. The patients were followed up till December 31st 2010. The primary outcomes were death from any cause and technique failure. Kaplan-Meier analysis and Cox proportional hazards models were used to identify risk factors for mortality and technique failure in CAPD patients. RESULTS: All patients were followed up for 59.6 ± 23.0 months. The patients were divided into two groups according to their SD of E/I values: lower SD of E/I group (≤0.126) and higher SD of E/I group (>0.126). The patients with higher SD of E/I showed a higher all-cause mortality (log-rank χ (2) = 10.719, P = 0.001) and technique failure (log-rank χ (2) = 9.724, P = 0.002) than those with lower SD of E/I. Cox regression analysis found that SD of E/I independently predicted all-cause mortality (HR  3.551, 95 % CI 1.442-8.746, P = 0.006) and technique failure (HR  2.487, 95 % CI 1.093-5.659, P = 0.030) in CAPD patients after adjustment for confounders except when sensitive C-reactive protein was added into the model. CONCLUSION: The SD of E/I was a strong independent predictor of all-cause mortality and technique failure in CAPD patients.

Soluble receptor for advanced glycation end-products protects against ischemia/reperfusion-induced myocardial apoptosis via regulating the ubiquitin proteasome system.

AIM: Apoptosis participated in the pathological process of myocardial ischemia/reperfusion (I/R) injury. Previous studies have reported that endogenous substance sRAGE protect against I/R injury through inhibiting myocardial apoptosis. But the mechanisms are currently unknown. Prior work has demonstrated that ubiquitin proteasome system (UPS) dysfunction is closely related to apoptosis. We explored the potential role of UPS in the effect of sRAGE inhibition on I/R-induced myocardial apoptosis. METHODS AND RESULTS: Adult male C57BL mice treated with sRAGE (100µg/day, i.p.) or saline were performed to ligate left anterior descending coronary artery (LAD) as an in vivo model. As an in vitro model, primary murine cardiomyocytes pretreated with sRAGE or sRAGE-containing adenovirus were simulated I/R by "ischemia buffer". The TUNEL and caspase-3 activity were assessed. Also the activity and expression of proteasome were detected. sRAGE decreased the number of TUNEL-positive cardiomyocytes and caspase-3 activity, however, the inhibition of sRAGE on I/R-induced apoptosis was abolished by proteasome inhibitor Bortezimb (BTZ). sRAGE inhibited the decreased proteasome activity, also the reduction in protein and gene levels of ß1i and ß5i following I/R. Suppression of STAT3 blocked the inhibition of sRAGE on apoptosis induced by I/R. The chromatin immunoprecipitation (CHIP) results confirmed that sRAGE promoted activating STAT3 binding to ß1i and ß5i promoter. CONCLUSIONS: Our data suggest that the inhibition of sRAGE on I/R-induced apoptosis is associated with activation and expression of proteasome, including improved proteasome activity and elevated ß1i and ß5i expression mediated by STAT3 activation. We predict that sRAGE is a novel intervention to target UPS activation for preventing and treating myocardial apoptosis.

The electrocardiographic changes in acute brain injury patients.

BACKGROUND: Electrocardiographic (ECG) changes occurring during the course of acute brain injury (ABI) have been described frequently, but their significances remain uncertain. The present study was designed to investigate the relation of ECG abnormalities to outcome in the patients with ABI. METHODS: We performed a retrospective, observational study on the ABI patients admitted to the Department of Neurosurgery of the Beijing Tiantan Hospital between December 2005 and December 2007. All the patients accepted 12-lead electrocardiographic examination within 24 hours after injury, then divided into three groups according to the Glasgow coma score (GCS). In-hospital mortality and one-month outcome assessed by the Glasgow outcome score (GOS) were investigated. RESULTS: Of 335 ABI patients (mean ages 32.4 years), 246 patients (73.4%) had abnormal ECGs. The most common abnormality was ST-T changes (41.5%), followed by sinus tachycardia (23.6%). ECG changes had a significant association with the severity and outcome. Logistic regression analysis showed the presence of ST-T changes (OR 2.587, 95%CI 1.009 to 6.629, P = 0.048) and QT dispersion prolongation (OR 4.656, 95%CI 1.956 to 11.082, P = 0.001) significantly associated with short outcomes. CONCLUSIONS: ABI can lead to myocardial damage and ECG changes had a significant association with the severity. ST-T changes and QT dispersion prolongation were the independent prognosis factors for the negative outcome of ABI patients.

Residual renal function and arterial stiffness mediated the blood pressure change during interdialytic weight gain in hemodialysis patients.

Volume overload is thought to be the main cause of hypertension in dialysis patients. However, the effect of interdialytic weight gain (IDWG) in hemodialysis (HD) patients, which was considered as an increase in extracellular water (ECW), on blood pressure (BP) change, was controversial. Our aim was to examine the changes in hemodynamics and arterial stiffness during IDWG in HD patients and attempt to explore the possible mechanism of diverse BP change. Thirty prevalent patients on HD were enrolled. The height, weight, BP, blood chemistry, volume status assessed by bioelectrical impedance analysis, hemodynamic parameters obtained by echocardiography, and pulse wave velocity (PWV) were collected within 1 hour postdialysis and again just before the next dialysis session. Meanwhile, blood samples were drawn to analyze vasoactive hormones, including renin, angiotensin II, catecholamine, and endothelin. The patients' weights and ECWs during the next predialysis were significantly higher than those during the postdialysis. The BP showed no difference between postdialysis and the next predialysis. There was an obvious increase in cardiac output and decrease in total peripheral resistance as a whole during the next predialysis than that during postdialysis. When patients were divided into the BP increase group (BPI group, 13 patients) and BP decrease group (BPD group, 11 patients) according to the change in systolic BP higher than 10 mmHg, both groups displayed a significant increase in weight, ECW, cardiac output, and a decrease in total peripheral resistance. As compared with the BPI group, patients in the BPD group had significantly lower IDWG, shorter time on dialysis treatment, and higher residual renal function. A decrease in catecholamine and endothelin in the next predialysis was obvious in the BPD group. There was a significant decrease in PWV at the next predialysis in the BPD group while the PWV did not change significantly in the BPI group. Our results showed that the diverse BP change during IDWG was significantly affected by residual renal function, PWV, and vasoactive substances.