PARP1 interacts with HMGB1 and promotes its nuclear export in pathological myocardial hypertrophy.

High-mobility group box 1 (HMGB1) exhibits various functions according to its subcellular location, which is finely conditioned by diverse post-translational modifications, such as acetylation. The nuclear HMGB1 may prevent from cardiac hypertrophy, whereas its exogenous protein is proven to induce hypertrophic response. This present study sought to investigate the regulatory relationships between poly(ADP-ribose) polymerase 1 (PARP1) and HMGB1 in the process of pathological myocardial hypertrophy. Primary-cultured neonatal rat cardiomyocytes (NRCMs) were respectively incubated with three cardiac hypertrophic stimulants, including angiotensin II (Ang II), phenylephrine (PE), and isoproterenol (ISO), and cell surface area and the mRNA expression of hypertrophic biomarkers were measured. the catalytic activity of PARP1 was remarkably enhanced, meanwhile HMGB1 excluded from the nucleus. PARP1 overexpression by infecting with adenovirus PARP1 (Ad-PARP1) promoted the nuclear export of HMGB1, facilitated its secretion outside the cell, aggravated cardiomyocyte hypertrophy, which could be alleviated by HMGB1 overexpression. PE treatment led to the similar results, while that effect was widely depressed by PARP1 silencing or its specific inhibitor AG14361. Moreover, SD rats were intraperitoneally injected with 3-aminobenzamide (3AB, 20 mg/kg every day, a well-established PARP1 inhibitor) 7 days after abdominal aortic constriction (AAC) surgery for 6 weeks, echocardiography and morphometry of the hearts were measured. Pre-treatment of 3AB relieved AAC-caused the translocation of nuclear HMGB1 protein, cardiac hypertrophy, and heart dysfunction. Our research offers a novel evidence that PARP1 combines with HMGB1 and accelerates its translocation from nucleus to cytoplasm, and the course finally causes cardiac hypertrophy.

mTORC2 facilitates endothelial cell senescence by suppressing Nrf2 expression via the Akt/GSK-3ß/C/EBPα signaling pathway.

Vascular endothelial cell senescence is a leading cause of age-associated and vascular diseases. Mammalian target of rapamycin complex 2 (mTORC2) is a conserved serine/threonine (Ser/Thr) protein kinase that plays an important regulatory role in various cellular processes. However, its impact on endothelial senescence remains controversial. In this study we investigated the role and molecular mechanisms of mTORC2 in endothelial senescence. A replicative senescence model and H2O2-induced premature senescence model were established in primary cultured human umbilical vein endothelial cells (HUVECs). In these senescence models, the formation and activation of mTORC2 were significantly increased, evidenced by the increases in binding of Rictor (the essential component of mTORC2) to mTOR, phosphorylation of mTOR at Ser2481 and phosphorylation of Akt (the effector of mTORC2) at Ser473. Knockdown of Rictor or treatment with the Akt inhibitor MK-2206 attenuated senescence-associated ß-galactosidase (ß-gal) staining and expression of p53 and p21 proteins in the senescent endothelial cells, suggesting that mTORC2/Akt facilitates endothelial senescence. The effect of mTORC2/Akt on endothelial senescence was due to suppression of nuclear factor erythroid 2-related factor 2 (Nrf2) at the transcriptional level, since knockdown of Rictor reversed the reduction of Nrf2 mRNA expression in endothelial senescence. Furthermore, mTORC2 suppressed the expression of Nrf2 via the Akt/GSK-3ß/C/EBPα signaling pathway. These results suggest that the mTORC2/Akt/GSK-3ß/C/EBPα/Nrf2 signaling pathway is involved in both replicative and inducible endothelial senescence. The deleterious role of mTORC2 in endothelial cell senescence suggests therapeutic strategies (targeting mTORC2) for aging-associated diseases and vascular diseases.

[Component Changes of Metabolic Syndrome in Pre-elderly People with Healthy Obese Phenotype].

OBJECTIVE: To determine component changes of metabolic syndrome in pre-elderly people with healthy obese phenotype. METHODS: A total of 1 686 adults aged between 45-59 yr. who underwent health examinations from 2010 to 2016 in West China Hospital of Sichuan University participated in this study. The participants had healthy obese phenotype at the baseline but no history of diabetes,high blood pressure,high cholesterol and cardiovascular disease. Component changes of metabolic syndrome (MS) and associated factors over the seven-year period were analysed using logistic regression modeling. RESULTS: The number of MS components increased over the years in centrally obese individuals,and 11.0% developed MS,including 118 men [(53.29±4.00) years old,66.95% current smokers,5.93% past smokers,24.58% alcohol drinkers] and 67 women [(52.01±4.06) years old,26.87% current smokers,1.49% past smokers,11.94% alcohol drinkers]. The most frequently presented MS components included higher fasting glucose,higher blood pressure and higher triglyceride. Healthy status (0 MS component) resumed in 44 participants who had abdominal obesity (1 MS component) at the baseline: 27 women and 17 men. Age (OR=1.732, 95%CI：1.594-1.882, P<0.000 1),smoking (OR=7.188, 95%CI：4.311-11.986, P<0.000 1) and drinking (OR=3.986, 95%CI：2.283-6.959, P<0.000 1) were identified as risk factors of MS. CONCLUSION: MS components increase over years in both men and women. Smoking and drinking are the main risk factors of MS progression. Regular MS surveillance and behavioral interventions are recommended for pre-elderly people with healthy obese phenotype.

[Obesity and Osteoporosis in Men Aged Above 50].

OBJECTIVES: To investigate the association between obesity and osteoporosis in men aged above 50 in Chengdu. METHODS: Male participants aged above 50 were recruited from those who visited West China Hospital of Sichuan University for health examinations. Bone mineral density was measured by MetriScan Bone Densitometry. The participants were divided into three groups according to T values: normal, osteopenia and osteoporosis. RESULTS: About 5.75% (525 cases) of the 9 135 male participants had osteoporosis. The three groups had significant different anthropometric parameters, including body mass, waist circumference, hip circumference, body mass index (BMI), waist-hip ratio (WHR), waist-height ratio (WHtR), a body shape index (ABSI), and body roundness index (BRI)( P<0.01). The participants with the highest quartile (Q4) of BMI, BRI, WHtR, WHR, ABSI, waist circumference and height had an age-adjusted odds ratios (OR) of 0.443 [95% confidence interval ( CI): 0.342-0.574), 0.580 (95% CI: 0.454-0.740), 0.587 (95% CI: 0.460-0.751), 0.664 (95% CI: 0.516-0.854], 1.369 (95% CI: 1.069-1.751), 0.634 (95% CI: 0.497-0.809), and 1.357 (95% CI: 1.047-1.758), respectively, for osteoporosis compared with those with the lowest quartile (Q1). The area under cures (AUC) of receiver operator characteristic (ROC) curve of BMI for osteoporosis was 0.606 (95% CI:0.580-0.632). CONCLUSIONS: Large body mass was negatively associated with osteoporosis in middle and old aged men. BMI is the strongest predictor of osteoporosis. Further longitudinal studies are required to verify such asscoiations.

[Obesity and Bone Mineral Density in Menopausal Women].

OBJECTIVES: To determine the association between obesity and bone mineral density in menopausal women. METHODS: We recruited menopausal women aged 50 years and older who undertook health examinations in West China Hospital of Sichuan University in this study. Bone mineral density of the participants was measured by MetriScan Bone Densitometry. The participants were categorized into three groups according to the T value: normal density, osteopenia and osteoporosis. RESULTS: Of the 4 938 participants, 8.55% had obesity [body mass index (BMI)>28 kg/m2]. The three groups of participants were different in BMI, a body shape index (ABSI), body mass, waist circumference, hip circumference and height ( P<0.01). The age-adjusted T values were positively correlated with height, body mass, waist circumference, hip circumference, waist-hip ratio (WHR), waist-height ratio (WHtR) and body roundness index (BRI) ( P<0.05). The areas under curves (AUC) of receiver operator characteristic (ROC) were 0.540 and 0.568, respectively, for waist circumference and BMI in those with osteoporosis. CONCLUSIONS: Obesity in menopausal women is negatively associated with osteoporosis. The clinical significance of such an association requires further studies with a longitudinal design.

The risk of stroke and associated risk factors in a health examination population: A cross-sectional study.

Health examination is an important method for early detection of people with different risk of stroke. This study estimates the risk of stroke and identify risk factors for people who underwent health examinations at the Health Examination Center at West China Hospital, Sichuan University from July 2014 to February 2018.A total of 31,464 people were recruited in this study and divided into 3 groups (low risk, moderate risk, and high risk) according to risk of stroke. We explored possible factors associated with the risk of stroke by using multivariable stepwise logistic regression analysis.Among the participants, 17,959 were at low risk, 11,825 were at moderate risk, and 1680 were at high risk. Age, smoking, alcohol consumption, body mass index, uric acid, diastolic pressure, systolic pressure, triglycerides, low-density lipoprotein cholesterol, glucose, and brachial-ankle pulse wave velocity (baPWV) were independent significant risk factors for stroke, whereas high-density lipoprotein cholesterol was an independent protective factor for stroke. Interestingly, with increasing age, the percentage of people at moderate or high risk of stroke was increased. The percentages of people at moderate and high risk of stroke were also increased with respect to the stages of baPWV.This study showed that >40% of the participants were at moderate or high risk of stroke, especially the older participants. Several factors were related to the risk of stroke, especially baPWV. Some preventive action may be adopted early, and more attention can be paid to the health examination population.