摘要：
Atherosclerosis (AS) remains the leading cause for global cardiovascular disease morbidity and mortality, and a major cause of cardiopathy, myocardial infarction and peripheral vascular diseases. Macrophages serve a critical role in atherosclerotic plaque stabilization and rupture, and the selective removal of macrophages may be beneficial in improving plaque stability. Autophagy is a process of self-feeding, during which cytoplasmic proteins or organelles are packaged into vesicles and fused with the lysosome to form an autophagosome. The newly formed autophagosome can degrade internalized proteins, and this process may be used to serve the metabolic and self-renewal requirements of the cell. Autophagy serves an important role in maintaining cell homeostasis and promoting cell survival, and therefore an imbalance in autophagy is closely associated with multiple diseases.
作者机构：
[Willer, Cristen J.; Zhang, Jifeng; Zhu, Tianqing; Fan, Yanbo; Guo, Yanhong; Lu, Haocheng; Chen, Y. Eugene] Univ Michigan, Med Ctr, Dept Internal Med, Ctr Cardiovasc, North Campus Res Complex Bldg 26,Room 361S, Ann Arbor, MI 48109 USA.;[Garcia-Barrio, Minerva T.] Morehouse Sch Med, Cardiovasc Res Inst, Atlanta, GA 30310 USA.;[Jiang, Zhisheng] Univ South China, Key Lab Arteriosclerol Hunan Prov, Inst Cardiovasc Dis, Hengyang, Peoples R China.;[Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.;[Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA.
通讯机构：
[Chen, Y. Eugene] U;Univ Michigan, Med Ctr, Dept Internal Med, Ctr Cardiovasc, North Campus Res Complex Bldg 26,Room 361S, Ann Arbor, MI 48109 USA.
关键词：
*Gene Regulation;*Lipid Disorder;*Membrane Proteins;*Translational Research
摘要：
Background & Aims The rs58542926 C>T variant of the transmembrane 6 superfamily member 2 gene (TM6SF2), encoding an E167K amino acid substitution, has been correlated with reduced total cholesterol (TC) and cardiovascular disease. However, little is known about the role of TM6SF2 in metabolism. We investigated the long-term effects of altered TM6SF2 levels in cholesterol metabolism. Methods C57BL/6 mice (controls), mice that expressed TM6SF2 specifically in the liver, and mice with CRISPR/Cas9-mediated knockout of Tm6sf2 were fed chow or high-fat diets. Blood samples were collected from all mice and plasma levels of TC, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol, and triglycerides were measured. Liver tissues were collected and analyzed by histology, real-time polymerase chain reaction, and immunoblot assays. Adenovirus vectors were used to express transgenes in cultured Hep3B hepatocytes. Results Liver-specific expression of TM6SF2 increased plasma levels of TC and LDL-c, compared with controls, and altered liver expression of genes that regulate cholesterol metabolism. Tm6sf2-knockout mice had decreased plasma levels of TC and LDL-c, compared with controls, and consistent changes in expression of genes that regulate cholesterol metabolism. Expression of TM6SF2 promoted cholesterol biosynthesis in hepatocytes. Conclusions TM6SF2 regulates cholesterol metabolism in mice and might be a therapeutic target for cardiovascular disease.
作者机构：
Institute of Cardiovascular Disease, University of South China, Key Laboratory for Arteriosclerology of Hunan Province;[Li Lanfang] Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study;[Li Lanfang; Xu Jin; Chen Linxi] Hunan Province Learning Key Laboratory for Pharmacoproteomics, Hengyang, 421001;Institute of Pharmacy and Pharmacology, University of South China, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study;Institute of Cardiovascular Disease, University of South China, Key Laboratory for Arteriosclerology of Hunan Province, Hengyang, 421001
通讯机构：
[Chen, L.] H
关键词：
Receptor-mediated;reticulophagy;diseases
摘要：
Autophagy is a highly conserved self-digestion process raging from lower eukaryotes to mammals. Autophagy involves in the degradation of misfolded protein aggregates and damaged organelles, which are subsequently reused. Upon autophagy is initiated, a membrane structure termed the phagophore, the precursor of autophagosome, gradually expands and engulfs misfolded protein or damaged organelles and delivers them to the vacuole/lysosome for degradation. Autophagy contributes to the process of survival and death. Basic autophagy is essential for maintaining cellular homeostasis. During normal physiology, specialized cellular function requires the regulation of autophagy by scavenging misfolded protein or damaged organelles. However, excessive and dysregulated autophagy may induce apoptosis and even cell death due to enzymes leaking from lysosomes [1].
作者机构：
[王程] Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China;[王程] Department of Spine Surgery, the First Affiliated Hospital, University of South China, Hengyang 421001, China;[王文军; 晏怡果; 杨威] Department of Spine Surgery, the First Affiliated Hospital, University of South China, Hengyang 421001, China;[于小华] Life Science Research Center, University of South China, Hengyang 421001, China;[张健] Department of Hand and Micro-surgery, the First Affiliated Hospital, University of South China, Hengyang 421001, China
摘要：
Low shear stress plays a crucial role in the initiation and progression of atherosclerotic lesions. However, the detailed mechanisms of these processes remain unclear. In this study, the effect of low shear stress on endothelial cell autophagy and its potential mechanism were investigated. Results showed autophagy dysfunction and ten-eleven translocation 2 (TET2) protein downregulation during atherosclerotic lesion progression. Autophagic markers BECLIN 1 and LC3II/LC3I under low shear stress (5 dyne/cm(2)) obviously decreased compared with those under physiological shear stress (15 dyne/cm(2)), whereas autophagic substrate p62 increased. TET2 expression was also downregulated under low shear stress. Endothelial cell autophagy was improved with TET2 overexpression but was impaired by TET2 siRNA treatment. Moreover, TET2 overexpression upregulated the expression of endothelial cell nitric oxide synthase (eNOS) and downregulated the expression of endothelin-1 (ET-1). TET2 siRNA further attenuated eNOS expression and stimulated ET-1 expression. Overall, the results showed that low shear stress downregulated endothelial cell autophagy by impaired TET2 expression, which might contribute to the atherogenic process.
作者机构：
[Jiang, Zhisheng; Guo, Fang; He, Hui] Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, Hengyang 421001, Hunan, Peoples R China.;[Li, Yong; Kimmis, Brooks D.; Papasian, Christopher J.; Fu, Mingui; Sandhu, Jeena; He, Hui; Fan, Michelle] Univ Missouri, Sch Med, Dept Basic Med Sci, Shock Trauma Res Ctr, Kansas City, MO 64108 USA.;[Li, Yong] Nanchang Univ, Inst Translat Med, Nanchang 330031, Jiangxi, Peoples R China.;[Fan, Daping; Saaoud, Fatma; Lessner, Susan] Univ South Carolina, Dept Cell Biol & Anat, Sch Med, Columbia, SC 29209 USA.;[Maulik, Dev] Univ Missouri, Dept Obstet & Gynecol, Sch Med, Kansas City, MO 64108 USA.
通讯机构：
[Jiang, Zhisheng; Fu, Mingui] U;Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, Hengyang 421001, Hunan, Peoples R China.;Univ Missouri, Sch Med, Dept Basic Med Sci, Shock Trauma Res Ctr, Kansas City, MO 64108 USA.
摘要：
Adiporedoxin (Adrx) is a recently discovered redox regulatory protein that is preferentially expressed in adipose tissue and plays a critical role in the regulation of metabolism via its modulation of adipocyte protein secretion. We here report that Adrx suppresses endothelial cell activation via inhibiting MAPK and NF-kB signaling pathways. Adrx is constitutively expressed in human vascular endothelial cells, and significantly induced by a variety of stimuli such as TNFα, IL-1β, H2O2 and OxLDL. Overexpression of Adrx significantly attenuated TNFα-induced expression of VCAM-1 and ICAM-1, and thus reduced monocyte adherence to human umbilical vein endothelial cells (HUVECs). Conversely, siRNA-mediated knockdown of Adrx increased TNFα-induced expression of adhesion molecules and monocyte adherence to HUVECs. Furthermore, forced expression of Adrx decreased TNFα-induced activation of ERK1/2, JNK, p38 and IKKs in HUVECs. Adrx mutant in the CXXC motif that lost its anti-redox activity is less efficient than the wild-type Adrx, suggesting that Adrx-mediated inhibition of endothelial activation is partially dependent on its antioxidant activity. Finally, Adrx expression was markedly increased in human atheroma compared with normal tissue from the same carotid arteries. These results suggest that Adrx is an endogenous inhibitor of endothelial activation, and might be a therapeutic target for vascular inflammatory diseases.
摘要：
Autophagy is conserved in nature from lower eukaryotes to mammals and is an important self-cannibalizing, degradative process that contributes to the elimination of superfluous materials. Cardiac hypertrophy is primarily characterized by excess protein synthesis, increased cardiomyocyte size, and thickened ventricular walls and is a major risk factor that promotes arrhythmia and heart failure. In recent years, cardiomyocyte autophagy has been considered to play a role in controlling the hypertrophic response. However, the beneficial or aggravating role of cardiomyocyte autophagy in cardiac hypertrophy remains controversial. The exact mechanism of cardiomyocyte autophagy in cardiac hypertrophy requires further study. In this review, we summarize the controversies associated with autophagy in cardiac hypertrophy and provide insights into the role of autophagy in the development of cardiac hypertrophy. We conclude that future studies should emphasize the relationship between autophagy and the different stages of cardiac hypertrophy, as well as the autophagic flux and selective autophagy. Autophagy will be a potential therapeutic target for cardiac hypertrophy.
