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:
[Linxi Chen *] 2;[Zhisheng Jiang *] 1
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:
[Chen, Lin-xi; Liu, Mei-qing; Chen, Zhe] Univ South China, Inst Pharm & Pharmacol, Hengyang 421001, Peoples R China.
通讯机构:
[Chen, Lin-xi] U;Univ South China, Inst Pharm & Pharmacol, Hengyang 421001, Peoples R China.
关键词:
endoplasmic reticulum stress;unfolded protein response;ischemic cardiomyopathy;atherosclerosis;hypertension;cardiac hypertrophy;heart failure
摘要:
Endoplasmic reticulum is a principal organelle responsible for folding, post-translational modifications and transport of secretory, luminal and membrane proteins, thus palys an important rale in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is a condition that is accelerated by accumulation of unfolded/misfolded proteins after endoplasmic reticulum environment disturbance, triggered by a variety of physiological and pathological factors, such as nutrient deprivation, altered glycosylation, calcium depletion, oxidative stress, DNA damage and energy disturbance, etc. ERS may initiate the unfolded protein response (UPR) to restore cellular homeostasis or lead to apoptosis. Numerous studies have clarified the link between ERS and cardiovascular diseases. This review focuses on ERS-associated molecular mechanisms that participate in physiological and pathophysiological processes of heart and blood vessels. In addition, a number of drugs that regulate ERS was introduced, which may be used to treat cardiovascular diseases. This review may open new avenues for studying the pathogenesis of cardiovascular diseases and discovering novel drugs targeting ERS.
摘要:
Apelin is an endogenous ligand of the apelin receptor(APJ),a seven-transmembrane G protein-coupled receptor.Apelin and APJ exist in a variety of tissues,with special status in the heart,lung and tumors.Furthermore,many research shows that the apelin/APJ system exerts a broad range of activities that affect kidney systems.This review we summarize the role of apelin/APJ system on renal fibrosis,renal ischemia/reperfusion injury and diabetic nephropathy,polycystic kidney disease,hemodialysis.It was found that the level expression of apelin m RNA in the inner stripe of kidney outer medulla was the highest,and the region is significantly correlated with water and sodium balance.In UUO mice model,intraperitoneal injection of Apelin can reduceα-SMA,the expression of TGF-1 and its receptor,and between renal stromal components also significantly decreased.These results show that Apelin can reduce the deposition of ECM and improve renal interstitial fibrosis.In renal ischemia/reperfusion injury studies show that apelin-13 can significantly reduce the damage induced by renal tubularlesions,renal cell death and the normal renal function is not completely lead to large damage.But in diabetic nephropathy,Apelin-APJ system can promote or slow DN disease progression is controversial,still needs further research.Analysis the receiver operating characteristic curve found that in the process of identifying ADPKD disease apelin and copeptin shows good receiver operating characteristic curve(ROC),cox proportional hazards regression model also showed apelin can predict on the progress of kidney disease.In hemodialysis patients the apelin levels and PTH levels were positively correlated,it could prompt apelin can protect bone dialysis patients.Apelin also can reduce Pit-1 inhibition of vascular smooth muscle cell osteoblast calcification and thus improve the aortic calcification,so Apelin may have a potential role in the treatment of vascular calcification in CKD.In kidney disease conditions,Apelin/APJ system plays a variety of biological functions,because of the Apelin protective on kidney,Apelin/APJ may be a potential material for the treatment of chronic kidney disease.
摘要:
The G-protein-coupled receptor APJ and its endogenous ligand apelin are widely expressed in many peripheral tissues and central nervous system, including adipose tissue, skeletal muscles and hypothalamus. Apelin/APJ system, involved in numerous physiological functions like angiogenesis, fluid homeostasis and energy metabolism regulation, is notably implicated in the development of different pathologies such as diabetes and its complications. Increasing evidence suggests that apelin regulates insulin sensitivity, stimulates glucose utilization and enhances brown adipogenesis in different tissues associated with diabetes. Moreover, apelin is also involved in the regulation of diabetic complications via binding to APJ receptor. Apelin improves diabetes-induced kidney hypertrophia, normalizes obesity-associated cardiac hypertrophy and negatively promotes retinal angiogenesis in diabetic retinopathy. In this review, we provide a comprehensive overview about the role of apelin/APJ system in different tissues related with diabetes. Furthermore, we describe the pathogenesis of diabetic complications associated with apelin/APJ system. Finally, agonists and antagonists targeted to APJ receptor are described in the literature. Thus, we highlight apelin/APJ system as a novel therapeutic target for pharmacological intervention in treating diabetes and its complications.
作者机构:
[Hong Zhao] Institute of Pharmacy and Pharmacology, Hunan Province Cooperative innovation Center for Molecular Target New Drugs Study, University of South China, Hengyang 421001, China;[Pingbo Yao] Intensive Care Units of the Affiliated Nanhua Hospital, University of South China, Hengyang 421002, China;[Lanfang Li; Linxi Chen] Institute of Pharmacy and Pharmacology, Hunan Province Cooperative innovation Center for Molecular Target New Drugs Study, University of South China, Hengyang 421001, China llfwjl@126.com lxchen6@126.com
通讯机构:
[Lanfang Li; Linxi Chen] 1;1 Institute of Pharmacy and Pharmacology, Hunan Province Cooperative innovation Center for Molecular Target New Drugs Study , University of South China , Hengyang 421001 , China
关键词:
Apelin;mechanism;polarization
摘要:
Cellular polarization is common to many types of cells, such as vascular endothelial cells (ECs), macrophages, and epithelial cells [1]. An individual cell has opposite sides and the directions of imaginary axes connecting opposite sides are highly coordinated. This coordination of the polarization axes is essential for the function of organs, named planar cell polarity (PCP) [2]. It occurs when cell organelles, cytoskeleton, and/or adhesion complexes display unidirectional organization along an axis. The ECs are continuously exposed to shear stress, and they directly exhibit profound morphological adaptations, such as planar cell polarization, elongation, and alignment of microtubules. In addition, the state of cell junctions and dynamic rearrangements of cytoskeleton are important for the establishment of flow-induced EC polarization, which is a significant determinant of maintaining vascular homeostasis.
作者机构:
[Lanfang Li; Di Wu] Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China;[Linxi Chen] Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China lxchen6@126.com
通讯机构:
[Linxi Chen *] I;Institute of Pharmacy and Pharmacology , University of South China , Hengyang 421001 , China
关键词:
应激性疾病;肿瘤转移;治疗;通道;敏感;癌症患者;转移过程;肿瘤细胞
摘要:
Cancer metastasis is a process that cancer cells deviate from the primary site and spread to the other areas to form new colonies, which is the leading cause of death in cancer patients. During metastatic progression, circulating cancer cells lodge within the microvasculature of end organs, where most of them die from mechanical deformation. However, cancer cells can survive from mechanical deformation by unknown mechanisms. Recently, Furlow et al. identified a mutation truncated form of pannexin-1 (Panx-1), PANX1~(1–89), which was significantly enriched in highly metastatic cancer cells. PANX1~(1–89) augmented Panx-1 channel-mediated adenosine triphosphate (ATP) release and enhanced the efficiency of metastasis by promoting metastatic breast cancer cells survival during physical deformation. Additionally, carbenoxolone (CBX), a Panx-1 inhibitor, was proved to reduce the efficiency of breast cancer metastasis. These results suggested that Panx-1 is one of the molecular bases for metastatic cell survival in microvasculature-induced biomechanical trauma.
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.
摘要:
Apelin, the endogenous ligand of APJ which is a member of G protein-coupled receptors, has been shown to be expressed in a variety of tissues in vivo and to exert significant biological effects. Studies have indicated that the apelin/APJ system is involved in the regulation of a variety of physiological functions and pathological processes, and that it is associated with cardiovascular diseases (such as atherosclerosis, hypertension, heart failure and myocardial injury), diabetes with microvascular complications, ischemia reperfusion injury, tumors, pre-eclampsia, as well as others. The occurrence of these diseases is closely related to endothelial dysfunction and the local inflammatory response; however, the occurrence of oxidative stress is related to vascular injury, due to the excessive generation of reactive oxygen species (ROS) and can lead to vascular damage and a series of inflammatory reactions. Therefore, this review summarizes the association between apelin/APJ, oxidative stress and inflammation-related diseases. In addition, drugs targeting the apelin/APJ system are recommended, thus providing a novel therapeutic strategy for oxidative stress-related inflammatory diseases.
作者机构:
[Lu He; Lanfang Li; Jin Xu; Qun Zhou; Di Wu; Meiqing liu; Zhe Chen; Hong Zhou; Linxi Chen] Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China
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, Hengyang, 421001;Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang, 421001;Institute of Cardiovascular Disease, University of South China, Key Laboratory for Arteriosclerology of Hunan Province, Hengyang, 421001;[Li Lanfang] Institute of Cardiovascular Disease,University of South China, Key Laboratory for Arteriosclerology of Hunan Province
通讯机构:
[Linxi Chen *] 2;[Zhisheng Jiang *] 1;2 Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , Institute of Pharmacy and Pharmacology , Learning Key Laboratory for Pharmacoproteomics , University of South China , Hengyang 421001 , China<&wdkj&>1 Institute of Cardiovascular Disease , Key Laboratory for Arteriosclerology of Hunan Province , University of South China , Hengyang 421001 , China
关键词:
initially;identified;closest
摘要:
APJ, which was initially identified as a gene with closest homology to the angiotensin II type 1 receptor, is a seven transmembrane G protein-coupled receptor. Apelin is an endogenous ligand of the APJ originally isolated from bovine stomach extracts. There are several isoforms of apelin. Apelin preproproteins contain 77 amino-acid residues, which can be cleaved to form shorter bioactive isoforms, including apelin-36, apelin-17, apelin-13, apelin-12, and so on. Apelin/APJ receptor is extensively distributed in the central nervous system and peripheral tissues. Apelin/APJ system involves in a wide range of physiological and pathological functions. For example, apelin lowers blood pressure via a NO/cGMP-dependent mechanism. Apelin-13 maintains the Ca~(2+) transient against ischemia/reperfusion in cardiomyocytes. Furthermore, apelin-13 promotes cell proliferation and angiogenesis via PI3K/AKT activation.
作者机构:
[Li, Lanfang; Jiang, Zhisheng] Univ South China, Postdoctoral Mobile Stat Basic Med, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, Hengyang 421001, Peoples R China.;[Li, Lanfang; He, Lu; Wu, Di; Chen, Linxi] Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Inst Pharm & Pharmacol, Learning Key Lab Pharmacoprote, Hengyang 421001, Peoples R China.
通讯机构:
[Chen, Linxi] U;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Inst Pharm & Pharmacol, Learning Key Lab Pharmacoprote, Hengyang 421001, Peoples R China.
关键词:
Pannexin-1;ATP;arrhythmia;cardiac fibrosis
摘要:
Pannexin-1, Pannexin-2, and Pannexin-3 are three members of the Pannexin family of channel-forming glycoprotein. Their primary function is defined by their ability to form single-membrane channels. Pannexin-1 ubiquitously exists in many cells and organs throughout the body and is specially distributed in the circulatory system, while the expressions of Pannexin-2 and Pannexin-3 are mostly restricted to organs and tissues. Pannexin-1 oligomers have been shown to be functional single membrane channels that connect intracellular and extracellular compartments and are not intercellular channels in appositional membranes. The physiological functions of Pannexin-1 are to link to the adenosine triphosphate efflux that acts as a paracrine signal, and regulate cellular inflammasomes in a variety of cell types under physiological and pathophysiological conditions. However, there are still many functions to be explored. This review summarizes recent reports and discusses the role of Pannexin-1 in cardiovascular diseases, including ischemia, arrhythmia, cardiac fibrosis, and hypertension. Pannexin-1 has been suggested as an exciting, clinically relevant target in cardiovascular diseases.
摘要:
Apelin is highly expressed in rat left ventricular hypertrophy Sprague Dawley rat models, and it plays a crucial role in the cardiovascular system. The aim this study was to clarify whether apelin-13 promotes hypertrophy in H9c2 rat cardiomyocytes and to investigate its underlying mechanism. The cardiomyocyte hypertrophy was observed by measuring the diameter, volume, and protein content of H9c2 cells. The activation of autophagy was evaluated by observing the morphology of autophagosomes by transmission electron microscopy, observing the subcellular localization of LC3 by light microscopy, and detecting the membrane-associated form of LC3 by western blot analysis. The phosphatidylinositol 3-kinase (PI3K) signaling pathway was identified and the proteins expression was detected using western blot analysis. The results revealed that apelin-13 increased the diameter, volume, and protein content of H9c2 cells and promoted the phosphorylation of PI3K, Akt, ERK1/2, and p70S6K. Apelin-13 activated the PI3K-Akt-ERK1/2-p70S6K pathway. PI3K inhibitor LY294002, Akt inhibitor 1701-1, ERK1/2 inhibitor PD98059 attenuated the increase of the cell diameter, volume, protein content induced by apelin-13. Apelin-13 increased the autophagosomes and up-regulated the expressions of beclin 1 and LC3-II/I both transiently and stably. The autophagy inhibitor 3MA ameliorated the increase of cell diameter, volume, and protein content that were induced by apelin-13. These results suggested that apelin-13 promotes H9c2 rat cardiomyocyte hypertrophy via PI3K-Akt-ERK1/2-p70S6K and PI3K-induced autophagy.
摘要:
The APJ is a class A, rhodopsin-like G protein-coupled receptor (GPCR) with high sequence similarity to the angiotensin receptor AT1. APJ has been shown to be widely expressed in humans tissues, including the central nervous system, cardiovascular system, adipocytes and others. APJ plays an important role in the occurrence and development of cardiovascular and metabolic diseases including atherosclerosis (AS), coronary heart disease (CAD), heart failure(HF), pulmonary arterial hypertension (PAH), myocardial hypertrophy and atrial fibrillation, especially hypertension. Previous researchers found that apelin/APJ could induce vasodilation and then reduce blood pressure. Despite APJ is closely associated with many diseases, there are no drugs that can activate or inhibit APJ directly. In the current review, we have summarized recently reported peptides, small molecule agonists and antagonists targeting APJ. Given the role of apelin/APJ in hypertension and other cardiovascular diseases, we believe that the peptides and compounds based on APJ will be developed for treatment of these diseases.
作者机构:
[Xiaowang Liu; Jian Tu; Ping Yu; Lei Xiang; Weike Ding; Kaiqiang Lu; Xiaoyong Lei; Linxi Chen] Institute of Pharmacy and Pharmacology,Learning Key Laboratory for Pharmacoproteomics,University of South China,Hengyang 421001,China;[Zhigang Zhou; Kai Yin] Medical college,University of South China,Hengyang 421001,China;[Zhigang Zhou] the First Affiliated Hospital,University of South China,Hengyang 421001,China