Damaging effects of hyperglycemia on cardiovascular function: spotlight on glucose metabolic pathways
出版年份 2016 全文链接
标题
Damaging effects of hyperglycemia on cardiovascular function: spotlight on glucose metabolic pathways
作者
关键词
-
出版物
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 310, Issue 2, Pages H153-H173
出版商
American Physiological Society
发表日期
2015-10-31
DOI
10.1152/ajpheart.00206.2015
参考文献
相关参考文献
注意:仅列出部分参考文献,下载原文获取全部文献信息。- Cardiomyocyte mitochondrial respiration is reduced by receptor for advanced glycation end-product signaling in a ceramide-dependent manner
- (2015) Michael B. Nelson et al. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
- Protein kinase C promotes cardiac fibrosis and heart failure by modulating galectin-3 expression
- (2015) Xiang Song et al. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
- PKC-β activation inhibits IL-18-binding protein causing endothelial dysfunction and diabetic atherosclerosis
- (2015) Marie-Claude Durpès et al. CARDIOVASCULAR RESEARCH
- Removal of Abnormal MyofilamentO-GlcNAcylation Restores Ca2+Sensitivity in Diabetic Cardiac Muscle
- (2015) Genaro A. Ramirez-Correa et al. DIABETES
- The advanced glycation end product methylglyoxal-derived hydroimidazolone-1 and early signs of atherosclerosis in childhood diabetes
- (2015) Martin Heier et al. Diabetes & Vascular Disease Research
- Decreased levels of soluble receptor for advanced glycation end-products in aortic valve calcification patients
- (2015) H. Zheng et al. GENETICS AND MOLECULAR RESEARCH
- sRAGE, inflammation, and risk of atrial fibrillation: results from the Atherosclerosis Risk in Communities (ARIC) Study
- (2015) Mahmoud Al Rifai et al. JOURNAL OF DIABETES AND ITS COMPLICATIONS
- AKAP150 mobilizes cPKC-dependent cardiac glucotoxicity
- (2014) Chao Zeng et al. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
- PKC-mediated toxicity of elevated glucose concentration on cardiomyocyte function
- (2014) Mark W. Sims et al. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
- Advanced Glycation End Products Promote Heart Failure Through Inducing the Immune Maturation of Dendritic Cells
- (2014) Weiwei Cao et al. APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY
- Circulating Soluble Receptor for Advanced Glycation End Product Identifies Patients With Bicuspid Aortic Valve and Associated Aortopathies
- (2014) Emanuela Branchetti et al. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
- Quinapril treatment abolishes diabetes-associated atherosclerosis in RAGE/apolipoprotein E double knockout mice
- (2014) Anna M.D. Watson et al. ATHEROSCLEROSIS
- The hexosamine biosynthetic pathway induces gene promoter activity of acetyl-CoA carboxylase beta
- (2014) Jamie Imbriolo et al. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
- Cardiac RNAi therapy using RAGE siRNA/deoxycholic acid-modified polyethylenimine complexes for myocardial infarction
- (2014) Jueun Hong et al. BIOMATERIALS
- Effects of Advanced Glycation End Products on Calcium Handling in Cardiomyocytes
- (2014) Dewen Yan et al. CARDIOLOGY
- ROS signalling between endothelial cells and cardiac cells
- (2014) M. Zhang et al. CARDIOVASCULAR RESEARCH
- Dicarbonyl Stress in the Absence of Hyperglycemia Increases Endothelial Inflammation and Atherogenesis Similar to That Observed in Diabetes
- (2014) Chris Tikellis et al. DIABETES
- Ratio of Serum Levels of AGEs to Soluble Form of RAGE Is a Predictor of Endothelial Function
- (2014) Masato Kajikawa et al. DIABETES CARE
- Natural Antisense Transcript for Hyaluronan Synthase 2 (HAS2-AS1) Induces Transcription of HAS2 via ProteinO-GlcNAcylation
- (2014) Davide Vigetti et al. JOURNAL OF BIOLOGICAL CHEMISTRY
- The detrimental effects of acute hyperglycemia on myocardial glucose uptake
- (2014) Danzil Joseph et al. LIFE SCIENCES
- Aminoguanidine inhibits ventricular fibrosis and remodeling process in isoproterenol-induced hypertrophied rat hearts by suppressing ROS and MMPs
- (2014) Arumugam Parthasarathy et al. LIFE SCIENCES
- Metformin protects against hyperglycemia-induced cardiomyocytes injury by inhibiting the expressions of receptor for advanced glycation end products and high mobility group box 1 protein
- (2014) Ting Zhang et al. MOLECULAR BIOLOGY REPORTS
- PKC-Dependent Phosphorylation of eNOS at T495 Regulates eNOS Coupling and Endothelial Barrier Function in Response to G+ -Toxins
- (2014) Feng Chen et al. PLoS One
- Receptor for Advanced Glycation End Products - Membrane Type1 Matrix Metalloproteinase Axis Regulates Tissue Factor Expression via RhoA and Rac1 Activation in High-Mobility Group Box-1 Stimulated Endothelial Cells
- (2014) Koichi Sugimoto et al. PLoS One
- Detrimental effects of acute hyperglycaemia on the rat heart
- (2013) R. F. Mapanga et al. Acta Physiologica
- PKCβ Promotes Vascular Inflammation and Acceleration of Atherosclerosis in Diabetic ApoE Null Mice
- (2013) Linghua Kong et al. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
- Oxidized LDL and AGE-LDL in circulating immune complexes strongly predict progression of carotid artery IMT in type 1 diabetes
- (2013) Kelly J. Hunt et al. ATHEROSCLEROSIS
- Relationship between Advanced Glycation End Products and Plaque Progression in Patients with Acute Coronary Syndrome: The JAPAN-ACS Sub-study
- (2013) Yoshifumi Fukushima et al. Cardiovascular Diabetology
- Plasma levels of advanced glycation endproducts are associated with type 1 diabetes and coronary artery calcification
- (2013) Marcelle GA van Eupen et al. Cardiovascular Diabetology
- Advanced glycation end-products impair Na+/K+-ATPase activity in diabetic cardiomyopathy: Role of the adenosine monophosphate-activated protein kinase/sirtuin 1 pathway
- (2013) Qiong Yuan et al. CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
- Hyperglycemia-Induced Protein Kinase C 2 Activation Induces Diastolic Cardiac Dysfunction in Diabetic Rats by Impairing Caveolin-3 Expression and Akt/eNOS Signaling
- (2013) S. Lei et al. DIABETES
- The methylglyoxal-derived AGE tetrahydropyrimidine is increased in plasma of individuals with type 1 diabetes mellitus and in atherosclerotic lesions and is associated with sVCAM-1
- (2013) M. G. A. van Eupen et al. DIABETOLOGIA
- Plasma sRAGE and N-(carboxymethyl) lysine in patients with CHF and/or COPD
- (2013) Piera Boschetto et al. EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
- Exercise training initiated in late middle age attenuates cardiac fibrosis and advanced glycation end-product accumulation in senescent rats
- (2013) Kathryn J. Wright et al. EXPERIMENTAL GERONTOLOGY
- Impairment of Endothelial-Myocardial Interaction Increases the Susceptibility of Cardiomyocytes to Ischemia/Reperfusion Injury
- (2013) Thorsten M. Leucker et al. PLoS One
- Skin Autofluorescence, a Non-Invasive Marker for AGE Accumulation, Is Associated with the Degree of Atherosclerosis
- (2013) Martijn A. M. den Dekker et al. PLoS One
- Glyco-oxidation and cardiovascular complications in type 2 diabetes: a clinical update
- (2012) Francesco Piarulli et al. ACTA DIABETOLOGICA
- The alternative crosstalk between RAGE and nitrative thioredoxin inactivation during diabetic myocardial ischemia-reperfusion injury
- (2012) Yi Liu et al. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
- Effects of glucose-6-phosphate dehydrogenase deficiency on the metabolic and cardiac responses to obesogenic or high-fructose diets
- (2012) Peter A. Hecker et al. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
- Excess protein O-GlcNAcylation and the progression of diabetic cardiomyopathy
- (2012) Eduardo S. Fricovsky et al. AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
- Predictive value of advanced glycation end products for the development of post-infarction heart failure: a preliminary report
- (2012) Sergio Raposeiras-Roubín et al. Cardiovascular Diabetology
- Inhibition of Protein Kinase C β Ameliorates Impaired Angiogenesis in Type I Diabetic Mice Complicating Myocardial Infarction
- (2012) Akihiko Ikeda et al. CIRCULATION JOURNAL
- Increased DNA-Glycation in Type 2 Diabetic Patients: The Effect of Thiamine and Pyridoxine Therapy
- (2012) F. Polizzi et al. EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES
- Cellular Dysfunction in Diabetes as Maladaptive Response to Mitochondrial Oxidative Stress
- (2012) Alba Naudi et al. Experimental Diabetes Research
- Exploring LeukocyteO-GlcNAcylation as a Novel Diagnostic Tool for the Earlier Detection of Type 2 Diabetes Mellitus
- (2012) Clare Springhorn et al. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
- Cardiomyocyte Aldose Reductase Causes Heart Failure and Impairs Recovery from Ischemia
- (2012) Ni-Huiping Son et al. PLoS One
- Oleanolic Acid: A Novel Cardioprotective Agent That Blunts Hyperglycemia-Induced Contractile Dysfunction
- (2012) Rudo F. Mapanga et al. PLoS One
- Role of oxidative stress in diabetes-mediated vascular dysfunction: Unifying hypothesis of diabetes revisited
- (2012) Stephen W. Schaffer et al. VASCULAR PHARMACOLOGY
- Aldose Reductase, Oxidative Stress, and Diabetic Mellitus
- (2012) Wai Ho Tang et al. Frontiers in Pharmacology
- Advanced glycation end product cross-link breaker attenuates diabetes-induced cardiac dysfunction by improving sarcoplasmic reticulum calcium handling
- (2012) Allyson L. Kranstuber et al. Frontiers in Physiology
- The hexosamine biosynthetic pathway can mediate myocardial apoptosis in a rat model of diet-induced insulin resistance
- (2011) U. Rajamani et al. Acta Physiologica
- Human Aldose Reductase Expression Accelerates Atherosclerosis in Diabetic Apolipoprotein E−/− Mice
- (2011) Srinivasan Vedantham et al. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
- Cellular bioenergetics is regulated by PARP1 under resting conditions and during oxidative stress
- (2011) Katalin Módis et al. BIOCHEMICAL PHARMACOLOGY
- NADPH oxidase activation by hyperglycaemia in cardiomyocytes is independent of glucose metabolism but requires SGLT1
- (2011) Magali Balteau et al. CARDIOVASCULAR RESEARCH
- Association of soluble receptor for advanced glycation end-product with increasing central aortic stiffness in hypertensive patients
- (2011) Se-Jung Yoon et al. CORONARY ARTERY DISEASE
- Total Soluble and Endogenous Secretory Receptor for Advanced Glycation End Products as Predictive Biomarkers of Coronary Heart Disease Risk in Patients With Type 2 Diabetes: An Analysis From the CARDS Trial
- (2011) H. M. Colhoun et al. DIABETES
- Fibrin(ogen) may be an important target for methylglyoxal-derived AGE modification in elastic arteries of humans
- (2011) Terje Lund et al. Diabetes & Vascular Disease Research
- Emerging role of thiamine therapy for prevention and treatment of early-stage diabetic nephropathy
- (2011) N. Rabbani et al. DIABETES OBESITY & METABOLISM
- Muscle Creatine Kinase Deficiency Triggers Both Actin Depolymerization and Desmin Disorganization by Advanced Glycation End Products in Dilated Cardiomyopathy
- (2011) Nicolas Diguet et al. JOURNAL OF BIOLOGICAL CHEMISTRY
- Circulating soluble receptor for advanced glycation end product (sRAGE) and left ventricular hypertrophy in patients with chronic kidney disease (CKD)
- (2011) D. Leonardis et al. NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES
- Tribulosin protects rat hearts from ischemia/reperfusion injury
- (2010) Shuang Zhang et al. ACTA PHARMACOLOGICA SINICA
- Cardiac contractile dysfunction during acute hyperglycemia due to impairment of SERCA by polyol pathway-mediated oxidative stress
- (2010) Wai Ho Tang et al. AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
- Hyperglycemia-mediated activation of the hexosamine biosynthetic pathway results in myocardial apoptosis
- (2010) Uthra Rajamani et al. AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
- Methylglyoxal increases cardiomyocyte ischemia-reperfusion injury via glycative inhibition of thioredoxin activity
- (2010) Xiao-Liang Wang et al. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
- Oxidative stress: a key contributor to diabetic cardiomyopathyThis review is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease.
- (2010) Madhu Khullar et al. CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
- Activation of Protein Kinase C Isoforms and Its Impact on Diabetic Complications
- (2010) Pedro Geraldes et al. CIRCULATION RESEARCH
- Oxidative Stress and Diabetic Complications
- (2010) Ferdinando Giacco et al. CIRCULATION RESEARCH
- Increased Glycation and Oxidative Damage to Apolipoprotein B100 of LDL Cholesterol in Patients With Type 2 Diabetes and Effect of Metformin
- (2010) N. Rabbani et al. DIABETES
- Glycated albumin, a precursor of advanced glycation end-products, up-regulates NADPH oxidase and enhances oxidative stress in human endothelial cells: molecular correlate of diabetic vasculopathy
- (2010) Bruno K. Rodiño-Janeiro et al. DIABETES-METABOLISM RESEARCH AND REVIEWS
- Hyperglycaemia-induced impairment of endothelium-dependent vasorelaxation in rat mesenteric arteries is mediated by intracellular methylglyoxal levels in a pathway dependent on oxidative stress
- (2010) O. Brouwers et al. DIABETOLOGIA
- Aldose Reductase Regulates Vascular Smooth Muscle Cell Proliferation by Modulating G1/S Phase Transition of Cell Cycle
- (2010) Ravinder Tammali et al. ENDOCRINOLOGY
- A PKC-β inhibitor treatment reverses cardiac microvascular barrier dysfunction in diabetic rats
- (2010) Liping Wei et al. MICROVASCULAR RESEARCH
- O-linked β-N-acetylglucosamine During Hyperglycemia Exerts Both Anti-Inflammatory and Pro-Oxidative Properties in the Endothelial System
- (2010) Angana Gupta Rajapakse et al. Oxidative Medicine and Cellular Longevity
- A Reaction-Diffusion Model of ROS-Induced ROS Release in a Mitochondrial Network
- (2010) Lufang Zhou et al. PLoS Computational Biology
- Hexosamine biosynthesis pathway flux promotes endoplasmic reticulum stress, lipid accumulation, and inflammatory gene expression in hepatic cells
- (2009) Andrew T Sage et al. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
- A PKC-β inhibitor protects against cardiac microvascular ischemia reperfusion injury in diabetic rats
- (2009) Liping Wei et al. APOPTOSIS
- Nitric Oxide, Cytochrome C Oxidase, and the Cellular Response to Hypoxia
- (2009) Cormac T. Taylor et al. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
- Peroxisome proliferator-activated receptor-γ activation attenuates cardiac fibrosis in type 2 diabetic rats: the effect of rosiglitazone on myocardial expression of receptor for advanced glycation end products and of connective tissue growth factor
- (2009) Sang-Hyun Ihm et al. BASIC RESEARCH IN CARDIOLOGY
- Irreversibly glycated LDL induce oxidative and inflammatory state in human endothelial cells; added effect of high glucose
- (2009) Laura Toma et al. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
- Structural analyses of enzymes involved in the O-GlcNAc modification
- (2009) Carlos Martinez-Fleites et al. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
- The role of protein O-linked β-N-acetylglucosamine in mediating cardiac stress responses
- (2009) John C. Chatham et al. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
- Prevention of arterial stiffening by pyridoxamine in diabetes is associated with inhibition of the pathogenic glycation on aortic collagen
- (2009) Kuo-Chu Chang et al. BRITISH JOURNAL OF PHARMACOLOGY
- Ischaemic preconditioning improves proteasomal activity and increases the degradation of PKC during reperfusion
- (2009) E. N. Churchill et al. CARDIOVASCULAR RESEARCH
- Protein Kinase Cα, but Not PKCβ or PKCγ, Regulates Contractility and Heart Failure Susceptibility
- (2009) Qinghang Liu et al. CIRCULATION RESEARCH
- S100B Interaction With the Receptor for Advanced Glycation End Products (RAGE)
- (2009) J.N. Tsoporis et al. CIRCULATION RESEARCH
- Inhibition of Protein Kinase C–β by Ruboxistaurin Preserves Cardiac Function and Reduces Extracellular Matrix Production in Diabetic Cardiomyopathy
- (2009) Kim A. Connelly et al. Circulation-Heart Failure
- Blockage of receptor for advanced glycation end products prevents development of cardiac dysfunction in db/db type 2 diabetic mice
- (2009) Jan M. Nielsen et al. EUROPEAN JOURNAL OF HEART FAILURE
- Hyperglycemia Regulates RUNX2 Activation and Cellular Wound Healing through the Aldose Reductase Polyol Pathway
- (2009) David R. D'Souza et al. JOURNAL OF BIOLOGICAL CHEMISTRY
- NADPH oxidase signaling and cardiac myocyte function
- (2009) Ashwin Akki et al. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
- Plasma Carboxymethyl-Lysine, an Advanced Glycation End Product, and All-Cause and Cardiovascular Disease Mortality in Older Community-Dwelling Adults
- (2009) Richard D. Semba et al. JOURNAL OF THE AMERICAN GERIATRICS SOCIETY
- N-acetylcysteine prevents glucose/glucose oxidase-induced oxidative stress, mitochondrial damage and apoptosis in H9c2 cells
- (2009) Santosh Kumar et al. LIFE SCIENCES
- Therapeutic targets to reduce cardiovascular disease in type 2 diabetes
- (2009) Cyrus DeSouza et al. NATURE REVIEWS DRUG DISCOVERY
- Serum Carboxymethyl-Lysine, an Advanced Glycation End Product, Is Associated With Increased Aortic Pulse Wave Velocity in Adults
- (2008) R. D. Semba et al. AMERICAN JOURNAL OF HYPERTENSION
- Diabetic Cardiomyopathy: Insights into Pathogenesis, Diagnostic Challenges, and Therapeutic Options
- (2008) Ashish Aneja et al. AMERICAN JOURNAL OF MEDICINE
- Valproate Attenuates Accelerated Atherosclerosis in Hyperglycemic ApoE-Deficient Mice
- (2008) Anna J. Bowes et al. AMERICAN JOURNAL OF PATHOLOGY
- Aldose reductase mediates myocardial ischemia-reperfusion injury in part by opening mitochondrial permeability transition pore
- (2008) Radha Ananthakrishnan et al. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
- Upregulation of Aldose Reductase During Foam Cell Formation as Possible Link Among Diabetes, Hyperlipidemia, and Atherosclerosis
- (2008) Christian A. Gleissner et al. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
- Advanced Glycation End-Product of Low Density Lipoprotein Activates the Toll-Like 4 Receptor Pathway Implications for Diabetic Atherosclerosis
- (2008) Conrad P. Hodgkinson et al. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
- Synthesis and biological activity of some new flavonyl-2,4-thiazolidinediones
- (2008) Oya Bozdağ-Dündar et al. BIOORGANIC & MEDICINAL CHEMISTRY
- Selective PKC Beta Inhibition with Ruboxistaurin and Endothelial Function in Type-2 Diabetes Mellitus
- (2008) Nehal N. Mehta et al. CARDIOVASCULAR DRUGS AND THERAPY
- RAGE and Modulation of Ischemic Injury in the Diabetic Myocardium
- (2008) L. G. Bucciarelli et al. DIABETES
- The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes via effects on advanced glycation, oxidative stress and inflammation
- (2008) A. C. Calkin et al. DIABETOLOGIA
- Regulation of the phagocyte NADPH oxidase activity: phosphorylation of gp91phox/NOX2 by protein kinase C enhances its diaphorase activity and binding to Rac2, p67phox, and p47phox
- (2008) Houssam Raad et al. FASEB JOURNAL
- Mice deficient in PKCβ and apolipoprotein E display decreased atherosclerosis
- (2008) Evis Harja et al. FASEB JOURNAL
- Na+/H+ exchanger-1 inhibitors decrease myocardial superoxide production via direct mitochondrial action
- (2008) Carolina D. Garciarena et al. JOURNAL OF APPLIED PHYSIOLOGY
- AGEs-RAGE System Mediates Atrial Structural Remodeling in the Diabetic Rat
- (2008) TAKESHI KATO et al. JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY
- Advanced glycation endproduct (AGE) accumulation and AGE receptor (RAGE) up-regulation contribute to the onset of diabetic cardiomyopathy
- (2008) Heng Ma et al. JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
- The biochemistry, metabolism and inherited defects of the pentose phosphate pathway: A review
- (2008) M. M. C. Wamelink et al. JOURNAL OF INHERITED METABOLIC DISEASE
- NAD+/NADH and NADP+/NADPH in Cellular Functions and Cell Death: Regulation and Biological Consequences
- (2007) Weihai Ying ANTIOXIDANTS & REDOX SIGNALING
- Lipid accumulation in non-adipose tissue and lipotoxicity
- (2007) N.A. van Herpen et al. PHYSIOLOGY & BEHAVIOR
- The discovery of nitric oxide and its role in vascular biology
- (2006) S Moncada et al. BRITISH JOURNAL OF PHARMACOLOGY
Discover Peeref hubs
Discuss science. Find collaborators. Network.
Join a conversationAsk a Question. Answer a Question.
Quickly pose questions to the entire community. Debate answers and get clarity on the most important issues facing researchers.
Get Started