Qiqiang Jie

Rac1b enhances cell survival through activation of the JNK2/c-JUN/Cyclin-D1 and AKT2/MCL1 pathways

Rac1b is a constitutively activated, alternatively spliced form of the small GTPase Rac1. Previous studies showed that Rac1b promotes cell proliferation and inhibits apoptosis. In the present study, we used microarray analysis to detect genes differentially expressed in HEK293T cells and SW480 human colon cancer cells stably overexpressing Rac1b. We found that the pro-proliferation genes JNK2, c-JUN and cyclin-D1 as well as anti-apoptotic AKT2 and MCL1 were all upregulated in both lines. Rac1b promoted cell proliferation and inhibited apoptosis by activating the JNK2/c-JUN/cyclin-D1 and AKT2/MCL1 pathways, respectively. Very low Rac1b levels were detected in the colonic epithelium of wild-type Sprague-Dawley rats. Knockout of the rat Rac1 gene exon-3b or knockdown of endogenous Rac1b in HT29 human colon cancer cells downregulated only the AKT2/MCL1 pathway. Our study revealed that very low levels of endogenous Rac1b inhibit apoptosis, while Rac1b upregulation both promotes cell proliferation and inhibits apoptosis. It is likely the AKT2/MCL1 pathway is more sensitive to Rac1b regulation.

Persistent lipid abnormalities in statin-treated coronary artery disease patients with and without diabetes in China

BACKGROUND We evaluate the prevalence of persistent lipid abnormalities and statin use in Chinese coronary artery disease patients with and without diabetes. METHODS AND RESULTS In this cross-sectional observational study, 8965 outpatients from 200 clinical departments of 122 hospitals in 27 provinces nationwide of China who had coronary artery disease and were taking a statin were consecutively enrolled and divided into two groups based on diabetes status. The European Society of Cardiology/European Arthrosclerosis Society Guidelines for the management of dyslipidemias and the Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults were used to compare the control rates of low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, and triglycerides (TG). Among the 8965 participants, 33.3% had been diagnosed with diabetes mellitus. According to the ESC Guidelines, the percentage of patients with not at goal LDL cholesterol did not differ significantly between patients with diabetes and those without diabetes (71.9% vs. 72.7%, P=0.46). The percentages of patients with not-at-goal levels of HDL and TG were 42.9% vs. 34.4% (P<0.001) and 39.1% vs. 34.3% (P<0.001) among patients with diabetes and those without, respectively. Only approximately 10% of patients in both groups had optimal LDL-C, HDL-C, and TG levels. Compared with patients without diabetes, patients with diabetes were more likely to have mixed dyslipidemia. Atorvastatin (47.0%) and simvastatin (34.4%) were the two most frequently used statins, and the average statin dosage was 29.09mg/day (simvastatin equivalent). Less than 1% of patients were treated with another lipid-lowering drug in combination with a statin. CONCLUSIONS Although international guidelines highly recommend intensive lipid modulation in patients with coronary artery disease, persistent dyslipidemia is still prevalent among these patients in China, even with statin treatment.

The Protective Effect of Lacidipine on Myocardial Remodeling Is Mediated by the Suppression in Expression of GPR78 and CHOP in Rats

Lacidipine (LAC) is now widely used for the treatment of hypertension and further can prevent cardiac hypertrophy and remodeling. However, the underlying mechanism has not been fully understood. In this study, we examined the protective effects of LAC on cardiac remodeling in spontaneously hypertensive rats (SHR) and investigated the possible mechanism. Four weeks after administration of the designated drugs, blood pressure, left ventricular mass index (LVMI), and rterial pressure (MAP) were measured. The endoplasmic reticulum stress (ERS) parameters such as GRP78 and CHOP expressions in cardiomyocytes were also detected by immunohistochemistry. Results showed that the MAP in 0.36 and 0.72 mg/kg LAC groups was markedly lowered compared with that of the SHR control group (P < 0.01 or P < 0.05). Moreover, 0.72 mg/kg LAC could also significantly decrease the LVMI (P < 0.05). Simultaneously, the results of immunohistochemistry demonstrated that the expression of GRP78 and CHOP was significantly decreased by 0.72 mg/kg LAC (P < 0.05), respectively. Our present study suggested that LAC could lower blood pressure and could prevent left ventricular hypertrophy accompanied by inhibiting expression of GRP78 and CHOP in ERS.

Low protein Z plasma level is a risk factor for acute myocardial infarction in coronary atherosclerosis disease patients

OBJECTIVES To examine plasma protein Z (PZ) levels in acute myocardial infarction (AMI) and chronic coronary atherosclerosis disease (CCAD) patients without history of AMI and explore its potential clinical significance. METHODS Plasma PZ concentrations were measured in 90 AMI patients (Group A), 87 CCAD patients without AMI history who remained free of major clinical events at least one year (Group B), and 88 clinically healthy controls (Group C). RESULTS PZ was found to be significantly lower (P<0.001) in Group A (1508.5±486.2ng/mL) compared with Group B (1823.0±607.8ng/mL) and C (2001.7±733.0ng/mL) and in Group A+B compared with Group C (Group A+B 1663.1±570.0 ng/mL, P<0.001). No statistically significant difference was reached between Group B and C (P=0.081). PZ level was significantly correlated with concentration of creatine kinase MB, high sensitive-cardiac troponin T, high sensitive C reactive protein, D-dimer and coagulation factor II and may be a useful predictor for AMI (OR: 1.38, 95% CI: 1.13-1.77, P=0.03). Subgroup analysis showed PZ concentration below the lowest tertile (<1398ng/mL) had a significantly increased risk for AMI and CCAD (OR: 3.39; 95% CI: 1.12-10.31; P=0.03 and OR: 7.39; 95% CI: 2.62-20.79; P<0.001 respectively). CONCLUSIONS PZ deficiency is found in AMI patients and could potentially reflect the myocardium injury, local coagulation activation and inflammation response during the acute phase of coronary atherosclerosis disease.

The role of mAKAPβ in the process of cardiomyocyte hypertrophy induced by angiotensin II

Angiotensin II (AngII) is the central product of the renin-angiotensin system (RAS) and this octapeptide contributes to the pathophysiology of cardiac hypertrophy and remodeling. mAKAPβ is an A-kinase anchoring protein (AKAP) that has the function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. In this study, we aimed to investigate the role of mAKAPβ in AngII-induced cardiomyocyte hypertrophy and the possible mechanisms involved. Cultured cardiomyocytes from neonatal rats were treated with AngII. Subsequently, the morphology of the cardiomyocytes was observed and the expression of mAKAPβ and cardiomyocyte hypertrophic markers was measured. mAKAPβ-shRNA was constructed for RNA interference; the expression of mAKAPβ and hypertrophic markers, the cell surface area and the [3H]Leucine incorporation rate in the AngII-treated rat cardiomyocytes were detected following RNA interference. Simultaneously, changes in the expression levels of phosphorylated extracellular signal-regulated kinase (p-ERK)2 in the cardiomyocytes were assessed. The cell size of the AngII-treated cardiaomyocytes was significantly larger than that of the untreated cardiomyocytes. The expression of hypertrophic markers and p-ERK2, the cell surface area and the [3H]Leucine incorporation rate were all significantly increased in the AngII-treated cells. However, the expression of mAKAPβ remained unaltered in this process. RNA interference simultaneously inhibited the protein expression of mAKAPβ and p-ERK2, and the hypertrophy of the cardiomyocytes induced by AngII was attenuated. These results demonstrate that AngII induces hypertrophy in cardiomyocytes, and mAKAPβ is possibly involved in this process. The effects of mAKAPβ on AngII-induced cardiomyocyte hypertrophy may be associated with p-ERK2 expression.

The influence of individual socioeconomic status on the clinical outcomes in ischemic stroke patients with different neighborhood status in Shanghai, China

Objective: Socioeconomic status (SES) is being recognized as an important factor in both social and medical problems. The aim of present study is to examine the relationship between SES and ischemic stroke and investigate whether SES is a predictor of clinical outcomes among patients with different neighborhood status from Shanghai, China. Methods: A total of 471 first-ever ischemic stroke patients aged 18-80 years were enrolled in this retrospective study. The personal SES of each patient was evaluated using a summed score derived from his or her educational level, household income, occupation, and medical reimbursement rate. Clinical adverse events and all-cause mortality were analyzed to determine whether SES was a prognostic factor, its prognostic impact was then assessed based on different neighborhood status using multivariable Cox proportional hazard models after adjusting for other covariates. Results: The individual SES showed a significant positive correlation with neighborhood status (r = 0.370; P < 0.001). The incidence of clinical adverse events and mortality were significantly higher in low SES patients compared with middle and high SES patients (P = 0.001 and P = 0.037, respectively). After adjusting other risk factors and neighborhood status, Kaplan-Meier analysis showed clinical adverse events and deaths were still higher in the low SES patients (all P < 0.05). Multivariate Cox regression analysis demonstrated that both personal SES and neighborhood status are independent prognostic factors for ischemic stroke (all P < 0.05). Besides, among patients with low and middle neighborhood status, lower individual SES was significantly associated with clinical adverse events and mortality (all P < 0.05). Conclusion: Both individual SES and neighborhood status are significantly associated with the prognosis after ischemic stroke. A lower personal SES as well as poorer neighborhood status may significantly increase risk for adverse clinical outcomes among ischemic stroke patients.

Rac1 promotes the survival of H9c2 cells during serum deficiency targeting JNK/c-JUN/Cyclin-D1 and AKT2/MCL1 pathways

Rac1, known as a “molecular switch”, plays a crucial role in plenty of cellular processes. Rac1 aggravates the damage of myocardial cells in the process of myocardial ischemia-reperfusion during myocardial infarction through activating the NADPH oxidase and bringing about the reactive oxygen species(ROS) generation. Myocardial ischemia and hypoxia are the basic pathogenesis of myocardial infarction and the underlying mechanisms are intricate and varied. Moreover, the regulatory effect of Rac1 on myocardial cells in the condition of serum starvation and the potential mechanisms are still incompletely undefined. Therefore, heart-derived H9c2 cells cultured in 0% serum were used to mimic ischemic myocardial cells and to clarify the role of Rac1 in H9c2 cells and the underlying mechanisms during serum deficiency. After Rac1 was knocked down using specific siRNA, cell apoptosis was assessed by flow cytometry assay and cell proliferation was detected by CCK-8 assay and EdU assay. In addition, the expression and activation of protein in related signaling pathway were detected by Western blot and siRNAs was used to testify the signaling pathways. Our results indicated that Rac1 inhibited apoptosis, promoted proliferation and cell cycle progression of H9c2 cells during serum deficiency. We concluded that Rac1 inhibited apoptosis in an AKT2/MCL1 dependent way and promoted cell proliferation through JNK/c-JUN/Cyclin-D1.

Saponin extract from Panax notoginseng promotesangiogenesis through AMPK‑ and eNOS‑dependent pathways in HUVECs

Panax notoginseng saponins (PNS) are among the most important compounds extracted from Panax notoginseng root, and have long been used in traditional Chinese medicine to control bleeding. PNS have recently garnered attention for the treatment of circulatory system diseases. The present study aimed to evaluate the effects of PNS on angiogenesis in vitro and to explore the molecular mechanisms underlying their actions. The present results demonstrated that the proliferative ability of human umbilical vein endothelial cells (HUVECs) was augmented following treatment with PNS. In addition, wound healing and Boyden chamber assays indicated that PNS may enhance HUVEC motility and increase the number of capillary-like tube branches in HUVECs. These effects were suppressed by 5′ adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) inhibitors. Furthermore, western blot analysis demonstrated that PNS stimulated the phosphorylation of AMPK and eNOS at Thr-172 and Ser-1179, respectively. These results suggested that PNS may promote tube formation in endothelial cells through AMPK- and eNOS-dependent signaling pathways.

Does left atrial appendage (LAA) occlusion device alter the echocardiography and electrocardiogram parameters in patients with atrial fibrillation

BACKGROUND The alterations of echocardiography and electrocardiogram (ECG) in patients received left atrial appendage LAA occlusion therapy are still unclear. The present study was to evaluate the influence of LAA occlusion device on echocardiography and ECG changes in patients with atrial fibrillation (AF). METHODS Seventy-three patients who had undergone Watchman, LAmbre and Lefort were enrolled in this study. Echocardiography and ECG results at pre- and post-operation were collected. Besides, echocardiography was also performed during follow-up visits at 1, 6 and 12months after discharge. RESULTS After LAA occlusion, a slight and measureable movement of QRS electric axis was observed in most patients. The significant differences were also observed in heart rate (HR) and the mean-mean QT interval between pre- and post-operation for all patients. There existed no significant difference in echocardiographic parameters between before and after device implantation. However, a larger left atrial (LA) diameter was detected by echocardiography during follow-up visit at 6months when compared with pre-operation parameters. Similarly, aortic root diameter (ARD) was also larger during follow-up at 12months than the baseline dimension in pre-operation. CONCLUSIONS LAA occlusion device resulted in a slightly movement in QRS axis, reduced HR and increased the mean-mean QT interval duration. In addition, LA diameter and ARD seemed to be larger after device implantation.