摘要：
Hydrogen sulfide (H(2)S) exerts an anti‑atherosclerotic effect and decreases foam cell formation. Lipoprotein‑associated phospholipaseA2 (Lp‑PLA(2)) is a key factor involved in foam cell formation. However, the association between H(2)S and Lp‑PLA(2) expression levels with respect to foam cell formation has not yet been elucidated. The present study investigated whether H(2)S can affect foam cell formation and potential signalling pathways via regulation of the expression and activity of Lp‑PLA(2). Using human monocytic THP‑1 cells as a model system, it was observed that oxidized low‑density lipoprotein (ox‑LDL) not only upregulates the expression level and activity of Lp‑PLA(2), it also downregulates the expression level and activity of Cystathionine γ lyase. Exogenous supplementation of H(2)S decreased the expression and activity of Lp‑PLA(2) induced by ox‑LDL. Moreover, ox‑LDL induced the expression level and activity of Lp‑PLA(2) via activation of the p38MAPK signalling pathway. H(2)S blocked the expression levels and activity of Lp‑PLA(2) induced by ox‑LDL via inhibition of the p38MAPK signalling pathway. Furthermore, H(2)S inhibited Lp‑PLA(2) activity by blocking the p38MAPK signaling pathway and significantly decreased lipid accumulation in ox‑LDL‑induced macrophages, as detected by Oil Red O staining. The results of the present study indicated that H(2)S inhibited ox‑LDL‑induced Lp‑PLA(2) expression levels and activity by blocking the p38MAPK signalling pathway, thereby improving foam cell formation. These findings may provide novel insights into the role of H(2)S intervention in the progression of atherosclerosis.
摘要：
Atherosclerosis is a chronic inflammatory vascular disease. Atherosclerotic cardiovascular disease is the main cause of death in both developed and developing countries. Many pathophysiological factors, including abnormal cholesterol metabolism, vascular inflammatory response, endothelial dysfunction and vascular smooth muscle cell proliferation and apoptosis, contribute to the development of atherosclerosis and the molecular mechanisms underlying the development of atherosclerosis are not fully understood. Ubiquitination is a multistep post-translational protein modification that participates in many important cellular processes. Emerging evidence suggests that ubiquitination plays important roles in the pathogenesis of atherosclerosis in many ways, including regulation of vascular inflammation, endothelial cell and vascular smooth muscle cell function, lipid metabolism and atherosclerotic plaque stability. This review summarizes important contributions of various E3 ligases to the development of atherosclerosis. Targeting ubiquitin E3 ligases may provide a novel strategy for the prevention of the progression of atherosclerosis.
摘要：
Cardiovascular diseases are the leading cause of death and morbidity worldwide. Atherosclerotic cardiovascular disease (ASCVD) is affected by both environmental and genetic factors. Microenvironmental disorders of the human gut flora are associated with a variety of health problems, not only gastrointestinal diseases, such as inflammatory bowel disease, but also extralintestinal organs. Hydrogen sulfide (H2S) is the third gas signaling molecule other than nitric oxide and carbon monoxide. In the cardiovascular system, H2S plays important roles in the regulation of blood pressure, angiogenesis, smooth muscle cell proliferation and apoptosis, anti-oxidative stress, cardiac functions. This review is aiming to explore the potential role of gut microbiota in the development of atherosclerosis through hydrogen sulfide production as a novel therapeutic direction for atherosclerosis.
摘要：
Coronary heart disease (CHD) is closely related to hypercholesterolemia, and lowering serum cholesterol is currently the most important strategy in reducing CHD. In humans, the serum cholesterol level is determined mainly by three metabolic pathways, namely, dietary cholesterol intake, cholesterol synthesis, and cholesterol degradation in vivo. An intervention that targets the key molecules in the three pathways is an important strategy in lowering serum lipids. Statins inhibit 3-hydroxyl-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) to reduce low-density lipoprotein (LDL) by about 20% to 45%. However, up to 15% of patients cannot tolerate the potential side effects of high statin dosages, and several patients also still do not reach their optimal LDL goals after being treated with statins. Ezetimibe inhibits cholesterol absorption by targeting the Niemann–Pick C1-like 1 protein (NPC1L1), which is related to cholesterol absorption in the intestines. Ezetimibe lowers LDL by about 18% when used alone and by an additional 25% when combined with statin therapy. The proprotein convertase subtilisin/kexin type 9 (PCSK9) increases hepatic LDLR degradation, thereby reducing the liver’s ability to remove LDL, which can lead to hypercholesterolemia. Evolocumab, which is a PCSK9 monoclonal antibody, can reduce LDL from baseline by 53% to 56%. The three drugs exert lipid-lowering effects by regulating the three key pathways in lipid metabolism. Combining any with the two other drugs on the basis of statin treatment has improved the lipid-lowering effect. Whether the combination of the three musketeers will reduce the side effects of monotherapy and achieve the lipid-lowering effect should be studied further in the future.
摘要：
Proprotein convertase subtilisin/kexin type-9 (PCSK9), a member of the proprotein convertase family, is an important drug target because of its crucial role in lipid metabolism. Emerging evidence suggests a direct role of localized PCSK9 in the pathogenesis of vascular diseases. With this in our consideration, we reviewed PCSK9 physiology with respect to recent development and major studies (clinical and experimental) on PCSK9 functionality in vascular disease. PCSK9 upregulates low-density lipoprotein (LDL)-cholesterol levels by binding to the LDL-receptor (LDLR) and facilitating its lysosomal degradation. PCSK9 gain-of-function mutations have been confirmed as a novel genetic mechanism for familial hypercholesterolemia. Elevated serum PCSK9 levels in patients with vascular diseases may contribute to coronary artery disease, atherosclerosis, cerebrovascular diseases, vasculitis, aortic diseases, and arterial aging pathogenesis. Experimental models of atherosclerosis, arterial aneurysm, and coronary or carotid artery ligation also support PCSK9 contribution to inflammatory response and disease progression, through LDLR-dependent or -independent mechanisms. More recently, several clinical trials have confirmed that anti-PCSK9 monoclonal antibodies can reduce systemic LDL levels, total nonfatal cardiovascular events, and all-cause mortality. Interaction of PCSK9 with other receptor proteins (LDLR-related proteins, cluster of differentiation family members, epithelial Na(+) channels, and sortilin) may underlie its roles in vascular disease. Improved understanding of PCSK9 roles and molecular mechanisms in various vascular diseases will facilitate advances in lipid-lowering therapy and disease prevention.
摘要：
Atherosclerosis is a chronic inflammatory response that increases the risk of cardiovascular diseases. An in-depth study of the pathogenesis of atherosclerosis is critical for the treatment of atherosclerotic cardiovascular disease. The development of atherosclerosis involves many cells, such as endothelial cells, vascular smooth muscle cells, macrophages, and others. The considerable effects of macrophages in atherosclerosis are inextricably linked to macrophage polarization and the resulting phenotype. Moreover, the significant impact of macrophages on atherosclerosis depend not only on the function of the different macrophage phenotypes but also on the relative ratio of different phenotypes in the plaque. Research on atherosclerosis therapy indicates that the reduced plaque size and enhanced stability are partly due to modulating macrophage polarization. Therefore, regulating macrophage polarization and changing the proportion of macrophage phenotypes in plaques is a new therapeutic approach for atherosclerosis. This review provides a new perspective for atherosclerosis therapy by summarizing the relationship between macrophage polarization and atherosclerosis, as well as treatment targeting macrophage polarization.
摘要：
Fibroblast growth factor (FGF)21, a member of the family of FGFs, exhibits protective effects against myocardial ischemia and ischemia/reperfusion injury; it is also an enhancer of autophagy. However, the mechanisms underlying the protective role of FGF21 against cardiomyocyte hypoxia/reoxygenation (H/R) injury remain unclear. The present study aimed to investigate the effect of FGF21 on H9c2 cardiomyocyte injury induced by H/R and the mechanism associated with changes in autophagy. Cultured H9c2 cardiomyocytes subjected to hypoxia were treated with a vehicle or FGF21 during reoxygenation. The viability of H9c2 rat cardiomyocytes was measured using Cell Counting Kit8 and trypan blue exclusion assays. The contents of creatine kinase (CK) and creatine kinase isoenzymes (CKMB), cardiac troponin I (cTnT), cardiac troponin T (cTnI) and lactate dehydrogenase (LDH) in culture medium were detected with a CK, CKMB, cTnT, cTnI and LDH assay kits. The protein levels were examined by western blot analysis. Autophagic flux was detected by AdmCherryGFPLC3B autophagy fluorescent adenovirus reagent. The results indicated that FGF21 alleviated H/Rinduced H9c2 myocardial cell injury and enhanced autophagic flux during H/R, and that this effect was antagonized by cotreatment with 3methyladenine, an autophagy inhibitor. Furthermore, FGF21 increased the expression levels of Beclin1 and Vps34 proteins, but not of mechanistic target of rapamycin. These data indicate that FGF21 treatment limited H/R injury in H9c2 cardiomyocytes by promoting autophagic flux through upregulation of the expression levels of Beclin1 and Vps34 proteins.
作者机构：
[Feng Shu-Jun; Tang Xin-Ying] Univ South China, Peoples Hosp Chenzhou 1, Dept Cardiol, Chenzhou 423000, Peoples R China.;[Tang Zhi-Han; Li Tao-Hua; Tang Wei] Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, Hengyang 421001, Peoples R China.;[Tang Zhi-Han] Univ Calgary, Hlth Sci Ctr, Dept Biochem & Mol Biol, Libin Cardiovasc Inst Alberta, 3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada.;[Wang Ying] Henan Univ Sci & Technol, Dept Cardiol, Affiliated Hosp 2, Luoyang 471000, Peoples R China.;[Tang Wei] Univ South China, Med Coll, Class 2014, Hengyang 421001, Peoples R China.
通讯机构：
[Kuang Ze-Min] C;Capital Med Univ, Dept Hypertens, Beijing Anzhen Hosp, Beijing 100029, Peoples R China.
关键词：
Red yeast rice;Xuezhikang;Atherosclerotic cardiovascular disease;Endothelial cells;Molecular mechanism
摘要：
Atherosclerotic cardiovascular disease (ASCVD) is the deadliest disease in the world, with endothelial injury occurring throughout the course of the disease. Therefore, improvement in endothelial function is of essential importance in the prevention of ASCVD. Red yeast rice (RYR), a healthy traditional Chinese food, has a lipid modulation function and also plays a vital role in the improvement of endothelial reactivity and cardiovascular protection; thus, it is significant in the prevention and treatment of ASCVD. This article reviews the molecular mechanisms of RYR and its related products in the improvement of endothelial function in terms of endothelial reactivity, anti-apoptosis of endothelial progenitor cells, oxidative stress alleviation and anti-inflammation.
摘要：
Proprotein convertase subtilisin/kexin 9 (PCSK9) is the ninth member of the secretory serine protease family. It binds to low-density lipoprotein receptor (LDLR) for endocytosis and lysosome degradation in the liver, resulting in an increasing in circulating LDL-cholesterol (LDL-c) level. Since a PCSK9 induced increase in plasma LDL-c contributes to atherosclerosis, PCSK9 inhibition has become a new strategy in preventing and treating atherosclerosis. However, in addition to the effect of PCSK9 on elevating blood LDL-c levels, accumulating evidence shows that PCSK9 plays an important role in inflammation, likely representing another major mechanism for PCSK9 to promote atherosclerosis. In this review, we discuss the association of PCSK9 and inflammation, and highlight the specific effects of PCSK9 on different vascular cellular components involved in the atherosclerotic inflammation. We also discuss the clinical evidence for the association between PCSK9 and inflammation in atherosclerotic cardiovascular disease. A better understanding of the direct association of PCSK9 with atherosclerotic inflammation might help establish a new role for PCSK9 in vascular biology and identify a novel molecular mechanism for PCSK9 therapy.
摘要：
Atrial fibrillation (AF) is associated with metabolic stress and induces myocardial fibrosis reconstruction by increasing glycolysis. One goal in the treatment of paroxysmal AF (p-AF) is to improve myocardial fibrosis reconstruction and myocardial metabolic stress caused by the Warburg effect. Adopted male canine that rapid right atrial pacing (RAP) for 6 days to establish a p-AF model. The canines were pre-treated with phenylephrine (PE) or dichloroacetic acid (DCA) before exposure to p-AF or non-p-AF. P-wave duration (P-max), minimum P-wave duration (P-min), P wave dispersion (PWD), atrial effective refractory period (AERP) and AERP dispersion (AERPd) were measured in canine atrial cardiomyocytes. Pyruvate dehydrogenase kinase-1 (PDK-1), PDK-4, lactate dehydrogenase A (LDHA), pyruvate dehydrogenase (PDH), citrate synthase (CS), isocitrate dehydrogenase (IDH), and matrix metalloproteinase 9 (MMP-9) were evaluated by western blotting and reverse transcription polymerase chain reaction (RTPCR), content of adenosine monophosphate (AMP), adenosine triphosphate (ATP), lactic acid and glycogen, and activity of LDHA, PDK-1 and PDK-4 were evaluated by enzyme-linked immunosorbent assay (ELISA), myocardial tissue glycogen content was evaluated by PAS, myocardial fibrosis remodeling was evaluated by hematoxylin and eosin (H&E) and Masson staining. Our findings demonstrated that p-AF increases the Warburg effect-related metabolic stress and myocardial fibrosis remodeling by increasing the expression and activity of PDK-1, PDK-4, and LDHA, content of AMP and lactic acid, and the ratio of AMP/ATP and decreasing the expression of PDH, CS, and IDH, and glycogen content. In addition, p-AF can induce cardiomyocyte fibrosis remodeling and increase MMP-9 expression, and p-AF also increases atrial intracardiac waveform activity by prolonging P-max, P-min, PWD, and AERPd and shortening AERP. PDK isoforms agonists (PE) produce a similar p-AF pathological effect and can produce synergistic effects with p-AF, further increasing Warburg effect-related metabolic stress, myocardial fibrosis remodeling, and atrial intracardiac waveform activity. In contrast, the use of PDK-specific inhibitors (DCA) completely reverses these pathophysiological changes induced by p-AF. We demonstrate that p-AF can induce the Warburg effect in canine atrial cardiomyocytes and significantly improve p-AF-induced metabolic stress, myocardial fibrosis remodeling, and atrial intracardiac waveform activity by inhibiting the Warburg effect. (C) 2019 Elsevier Inc. All rights reserved.
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE,2019年43(5):2055-2063 ISSN：1107-3756
通讯作者：
Liu, Lu-Shan;Wang, Mei-Mei
作者机构：
[Jiang, Zhi-Sheng; Ren, Zhong; Xiao, Jun; Liao, Ling; Tang, Zhi-Han; Zhou, Min; Xiang, Qiong; Peng, Juan; Bai, Xue-Qin; Liu, Lu-Shan] Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, 28 West Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;[Wen, Hong-Yan] Hunan Univ Chinese Med, Med Coll, Changsha 410208, Hunan, Peoples R China.;[Wang, Mei-Mei] Univ South China, Affiliated Nanhua Hosp, Dept Pediat, 28 West Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Liu, Lu-Shan; Wang, Mei-Mei] U;Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, 28 West Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Affiliated Nanhua Hosp, Dept Pediat, 28 West Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.
关键词：
HepG2 cells;Hydrogen sulfide;Lipid metabolism;Low-density lipoprotein receptor;Phosphoinositide 3-kinase/protein kinase B;Proprotein convertase subtilisin/kexin type 9;Sterol regulatory element-binding protein 2
摘要：
Hydrogen sulfide (H2S) is an endogenous gaseous signaling molecule that plays important roles in the cardiovascular system. In our previous studies, we demonstrated that H2S regulates lipid metabolism. In the present study, we aimed to explore the mechanisms through which H2S regulates lipid metabolism in HepG2 cells in vitro. Treatment of the HepG2 cells with H2S inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) and increased the level of lowdensity lipoprotein receptor (LDLR) in a time and dosedependent manner. The knockdown of PCSK9 by siRNA effectively increased the levels of LDLR and 1,1'dioctadecyl3,3,3',3'tetramethylindocarbocyanine perchloratelabeled LDL (DiILDL) uptake in the H2Streated HepG2 cells. Furthermore, the phosphoinositide 3kinase (PI3K)/protein kinase B (Akt)sterol regulatory element binding proteins 2 (SREBP2) signaling pathway was confirmed to be involved in H2Sregulated PCSK9 expression. Notably, the HepG2 cells were incubated with 30% serum and DiILDL for 24 h, and the results revealed that H2S increased lipid uptake, but caused no increase in lipid accumulation. On the whole, the findings of this study demonstrate that H2S is involved in the regulation of lipid metabolism in HepG2 cells through the regulation of the expression of PCSK9 via the PI3K/AktSREBP2 signaling pathway. To the very best of our knowledge, this study is the first to report that H2S can regulate the expression of PCSK9.
