The rapidly increasing prevalence of diabetes mellitus worldwide is one of the most serious and challenging health problems in the 21st century. Mammalian sirtuin 1 (SIRT1) has been shown to decrease high-glucose-induced endothelial cell senescence in vitro and prevent hyperglycemia-induced vascular dysfunction. However, a role for SIRT1 in prevention of hyperglycemia-induced vascular cell senescence in vivo remains unclear. We used endothelium-specific SIRT1 transgenic (SIRT1-Tg) mice and wild-type (WT) mice to construct a 40-week streptozotocin (STZ)-induced diabetic mouse model. In this mode, 42.9% of wild-type (WT) mice and 38.5% of SIRT1-Tg mice were successfully established as diabetic. Forty weeks of hyperglycemia induced significant vascular cell senescence in aortas of mice, as indicated by upregulation of expression of senescence-associated markers including p53, p21 and plasminogen activator inhibitor-1 (PAI-1). However, SIRT1-Tg diabetic mice displayed dramatically decreased expression of p53, p21 and PAI-1 compared with diabetic WT mice. Moreover, manganese superoxide dismutase expression (MnSOD) was significantly downregulated in the aortas of diabetic WT mice, but was preserved in diabetic SIRT1-Tg mice. Furthermore, expression of the oxidative stress adaptor p66Shc was significantly decreased in aortas of SIRT1-Tg diabetic mice compared with WT diabetic mice. Overall, these findings suggest that SIRT1-mediated inhibition of hyperglycemia-induced vascular cell senescence is mediated at least partly through the reduction of oxidative stress. SIRT1, hyperglycemia, vascular cell senescence Citation:Chen H Z, Wan Y Z, Zhou S, et al. Endothelium-specific SIRT1 overexpression inhibits hyperglycemia-induced upregulation of vascular cell senescence.
SIRT1, a mammalian ortholog of yeast silent information regulator 2 (Sir2), is an NAD + -dependent protein deacetylase that plays a critical role in the regulation of vascular function. The current study aims to investigate the functional significance of deacetylase activity of SIRT1 in heart. Here we show that the early postnatal hearts expressed the highest level of SIRT1 deacetylase activity compared to adult and aged hearts. We generated transgenic mice with cardiac-specific expression of a dominant-negative form of the human SIRT1 (SIRT1H363Y), which represses endogenous SIRT1 activity. The transgenic mice displayed dilated atrial and ventricular chambers, and died early in the postnatal period. Pathological, echocardiographic and molecular phenotype confirmed the presence of dilated cardiomyopathy. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling analysis revealed a greater abundance of apoptotic nuclei in the hearts of transgenic mice. Furthermore, we show that cardiomyocyte apoptosis caused by suppression of SIRT1 activity is, at least in part, due to increased p53 acetylation and upregulated Bax expression. These results indicate that dominant negative form of SIRT1 (SIRT1H363Y) overexpression in mouse hearts causes cardiomyocyte apoptosis and early-onset heart failure, suggesting a critical role of SIRT1 in preserving normal cardiac development during the early postnatal period. deacetylase, SIRT1, apoptosis, heart failure Citation:
Intercellular adhesion molecule-1 (ICAM-1) plays an important role in the recruitment of leukocytes to the endothelium, which causes inflammation and initiation of atherosclerosis. We have previously shown that endothelium-specific over-expression of class III deacetylase SIRT1 decreases atherosclerosis. We therefore addressed the hypothesis that SIRT1 suppresses ICAM-1 expression in the endothelial cells. Here, we found that expression of SIRT1 and ICAM-1 was significantly induced by PMA and ionomycin (PMA/Io) in human umbilical vein endothelial cells (HUVECs). Adenovirus-mediated over-expression of SIRT1 significantly inhibited PMA/Io-induced ICAM-1 expression in HUVECs. Knockdown of SIRT1 by RNA interference (RNAi) resulted in increased expression of ICAM-1 in HUVECs. Luciferase report assay showed that over-expression of SIRT1 suppressed ICAM-1 promoter activity both in basic and in PMA/Io-induced conditions. We further found that SIRT1 was involved in transcription complex binding on the ICAM-1 promoter by chromatin immunoprecipitation (ChIP) assays. Furthermore, SIRT1 RNAi increased NF-κB p65 binding ability to the ICAM-1 promoter by ChIP assays. Overall, these data suggests that SIRT1 inhibits ICAM-1 expression in endothelial cells, which may contribute to its anti-atherosclerosis effect. SIRT1, ICAM-1, PMA and ionomycin Citation:Jia Y Y, Gao P, Chen H Z, et al. SIRT1 suppresses PMA and ionomycin-induced ICAM-1 expression in endothelial cells .
Recently, with coming of the "omics" era and rapid development of basic research in biology and medicine, huge information about biology and life has been achieved. However, many research results cannot be translated into clinical practice. Under this circumstance, the concept of "translational research" is raised [1-4] and widely spread. "Translational research" is patient-oriented research which connects basic medicine and clinical medicine [2]. It means more directly and quickly raising questions from clinical practice to basic research and translating findings in basic research into clinical practice. The process of translational research can be summarized as follows: first, according to clinical practice, raising clinical problems and refining scientific questions; then, systematic and in-depth research, which integrates diverse disciplines, including epidemic study, basic research and drug discovery, is carried out; last, through research, the potentially effective strategies or methods for diagnosing, treating or preventing diseases are achieved and translated into clinical practice. Translational research has been developed rapidly in recent years. It is used to direct research in cardiovascular diseases (CVD), cancer, infectious diseases, metabolic diseases, etc.Though the concept "translational research" is relatively new, the bedside-to-bench-to-bedside translational strategy is not original. In the past century, especially in the past several decades, many successful studies were done. These studies contributed to human health greatly and are good examples for translational research. In this review, we will choose to talk several of these studies. We hope that these successful examples in the past will facilitate us to deeply understand translational research in the future. We will talk about research in CVD which achieved great progress in the past.In the mid-20th century, CVD was severe and almost accounted for half of all death in the USA [5]. Framingham Heart Study, an epidemiologic study, was carried out to study CVD in the town of Framingham, Massachusetts in 1948, with 5209 adult healthy subjects enrolled [6]. The detailed information for each subject, including diet, exercise, social relationship, physical examination and medical history, was recorded [6]. The study was implemented for about 20 years at its first stage. After that, the second generation and the third generation of subjects were enrolled in 1971 and in 2002 respectively [7,8]. Up to now, the study has lasted more than 60 years. The results from Framingham Heart Study showed that several factors, including high LDL cholesterol level, cigarette smoking, hypertension, obesity, diabetes, menopause, increased the risk of heart diseases, whereas exercise and high HDL cholesterol decreased the risk of heart diseases. It also showed that the social and physiological factors influenced CVD [9][10][11][12]. In recent years, with the development of technology in genetics, such as GWAS technology, some genetic factors contributing to CVD,...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.