A Handbook of Mouse Models of Cardiovascular Disease

The availability of well-defined genetic strains and the ability to create transgenic and knockout mice makes mouse models extremely valuable biomedical tools. Their suitability as an experimental system for cardiovascular research depends on the individual investigator’s ability to manipulate the mice surgically. Many mouse models require microsurgical techniques, which hitherto could not be performed without practical training. This comprehensive handbook enables scientists to develop these models in their own laboratories.

A Handbook of Mouse Models of Cardiovascular Disease is the first book to address pathology in mouse models of heart disease, providing the reader with essential information on technical assays in artificially created models. It includes background information on individual cardiovascular diseases, describes detailed methods and materials used for establishing each mouse model, discusses the problems that may appear in the experiments, and provides examples of applications of the model.

A Handbook of Mouse Models of Cardiovascular Disease:

• Describes mouse models of all important cardiovascular diseases, including atherosclerosis, atrial fibrillation and thrombosis
• Features videos of key experimental procedures on the accompanying CD, allowing researchers to learn the techniques by directly watching the whole operational procedure
• Describes how to establish each experimental model with detailed protocols and tips on dealing with common operational problems
• Highlights potential applications of each model in areas such as pathogenesis, gene transfer, therapy and pathophysiology

This handbook is an invaluable resource for researchers in cardiovascular disease, pathology, physiology, interested in the mechanism of vascular disorders and therapeutic approaches. It is also relevant to clinicians seeking to understand the pathology of cardiovascular disease and the rationale for interventions, and of interest to the pharmaceutical industry and all those involved in drug discovery/development for cardiovascular disease.

Preface xi

List of Contributors xiii

1 Mice – general information 1
Hermann Dietrich

Historical perspective of house mice as laboratory animals 1

Maintaining and breeding of mice 3

Mouse genetics 5

Blood and bone marrow collection methods 7

Anesthesia and analgesia 7

Euthanasia 14

References 14

2 Naturally occurring variation among mouse strains 19
Weibin Shi and Aldons J. Lusis

Introduction 19

Mapping genes underlying quantitative traits 20

Dissecting QTLs using congenic strains 22

Testing candidate genes in QTL regions 24

Functional tests of candidate genes 26

From mouse to man 28

References 28

3 Transgenic and gene-targeted mice in the study of hyperlipidemia 33
Yadong Huang

Introduction 33

Generation of transgenic mouse models 34

Generation of gene-targeted mouse models 36

Application of transgenic and gene-targeted mouse models in hyperlipidemia research 38

Acknowledgments 39

References 40

4 Bone marrow transplantation: the methodology and its application in atherosclerosis research 43
Menno P.J. de Winther and Marten H Hofker

Introduction 43

Methods 45

Discussion and application 48

Conclusions 50

References 51

5 Hyperlipidemia-induced atherosclerosis 53
Alan Daugherty and Debra L. Rateri

Introduction 53

Induction of hyperlipidemia in mice 54

Mouse strain 56

Environmental factors 57

Gender 57

Analysis of atherosclerotic lesions 57

Determination of lesion composition 62

Statistical analysis 63

Conclusions 64

Acknowledgments 64

References 64

6 Magnetic resonance imaging evaluation of atherosclerotic plaque 67
Martina A. McAteer, Jürgen E. Schneider and Robin P. Choudhury

Introduction 67

Imaging atherosclerosis with MRI 68

Mouse MRI 68

Materials and methods 69

Discussion 75

Application 76

Acknowledgments 76

References 76

7 Plaque rupture 79
Christopher L. Jackson

Introduction 79

Animals 79

Husbandry and welfare 81

Termination 81

Tissue processing 82

Morphological analysis 83

Morphometric analysis 84

Study design considerations 85

Summary 85

Acknowledgment 86

References 86

8 Perivascular cuff-, electronic and chemical injury-induced stenosis 89
Nuno M.M. Pires, Margreet R. de Vries, Abbey Schepers, Daniel Eefting, Jan-Willem H.P. Lardenoye and Paul H.A. Quax

Introduction 89

Materials and methods 92

Discussion 93

Application 94

References 100

9 Flow-induced vascular remodeling 103
Vyacheslav A. Korshunov and Bradford C. Berk

Introduction 103

Materials and methods 104

Discussion 107

Applications 108

References 110

Movie legends 111

10 Vein graft atherosclerosis 113
Yanhua Hu and Qingbo Xu

Introduction 113

Materials and methods 114

Discussion 119

Applications 120

Acknowledgments 122

References 122

11 Angiotensin II-induced aortic aneurysms 125
Yi-Xin Wang, Lisa A. Cassis and Alan Daugherty

Introduction 125

Methods 126

Discussion 133

Acknowledgments 133

References 134

12 Carotidojugular fistula 137
Yves Castier, Alain Tedgui and Stéphanie Lehoux

Introduction 137

Creation of the AVF 138

Hemodynamic and structural data 142

References 144

13 Applications to the study of stroke 147
Jacques Seylaz and Elisabeth Pinard

Introduction 147

Experimental preparation of mice 148

Methods 153

Applications 155

References 157

14 Identifying congenital heart defects in embryos using high-resolution magnetic resonance imaging 159
Jürgen E Schneider and Shoumo Bhattacharya

Introduction 159

Identifying mouse cardiac malformations 160

Magnetic resonance imaging 160

Embryo MRI technique and analysis 161

Discussion 166

Applications 166

Pros and cons of ex vivo MRI 169

Acknowledgments 169

References 170

15 Allograft arteriopathy: heterotopic heart transplantation and aortic interposition grafts 173
Koichi Shimizu and Richard N. Mitchell

Introduction 173

Murine models for AA 175

Murine heterotopic cardiac transplantation 177

Murine aortic interposition grafts 183

Translation to clinical investigation 187

References 189

16 Heart preconditioning analysis 193
Guang-Wu Wang, David A Liem, Steven Le and Peipei Ping

Introduction 193

Methods 194

Methodological considerations 198

References 200

17 Myocardial ischemia–reperfusion 203
Bernhard Metzler, Elisabetta Conci and Otmar Pachinger

Myocardial ischemia–reperfusion 203

Ischemia–reperfusion models 206

Measurement of infarction size 210

Electrocardiogram and in vivo left ventricular pressure–volume measurements 214

Different mouse types 215

Conclusion 217

References 217

18 Cardiac hypertrophy 221
David J. Grieve, Alison C. Cave and Ajay M. Shah

Introduction 221

Materials and methods 222

Summary 231

Acknowledgments 231

References 231

19 The retrogradely perfused isolated heart model 235
Mihaela M. Mocanu and Derek M. Yellon

Introduction 235

Langendorff system 235

Preparation of hearts for perfusion 237

Experimental protocol 241

Measurement of infarct size 242

Infarct size computation 243

General comments 244

Acknowledgments 244

References 244

20 Measurement of pulse wave velocity 245
Yi-Xin Wang

Introduction 245

Materials and methods 246

Discussion 249

Application 251

References 252

21 Gene transfer to dyslipidemic mice 255
Kazuhiro Oka, Andrew H. Baker and Lawrence Chan

Introduction 255

Mouse models of dyslipidemia 256

ApoB transgenic mice 263

Vectors for liver-directed gene transfer 263

Route or vector delivery 267

Conclusion 268

Acknowledgments 269

References 269

22 Hypertension 273
Daiana Weiss and W. Robert Taylor

Introduction 273

Pharmacological models of hypertension 275

Renal models of hypertension 278

Genetic models of hypertension 279

Measurement of blood pressure in mice 282

Summary 282

References 283

23 Ischemia-induced neovascularisation 287
Ken-ichiro Sasaki, Christopher Heeschen, Alexandra Aicher and Stefanie Dimmeler

Introduction 287

Materials and methods 288

Discussion 296

Application 296

References 297

24 Angiogenesis in biomatrices and artificial materials 299
Pieter Koolwijk and Victor W.M. van Hinsburgh

Introduction 299

Materials and methods 300

Discussion 305

Application 307

Acknowledgments 308

References 308

25 Venous thrombosis 311
Alberto Smith, James Gossage, Matthew Waltham, Bijan Modarai and Julie Humphries

Background 311

Models of thrombosis 313

The St Thomas’ model 314

References 319

26 Virus-induced vasculitis 321
Philippe Krebs and Burkhard Ludewig

Introduction 321

Materials and methods 322

Discussion 329

Application 329

References 330

27 Surgically induced chronic heart failure 333
Craig A. Lygate and Stefan Neubauer

Introduction 333

Materials and methods 336

Discussion 340

Applications 346

Conclusions 346

References 347

28 Cardiac electrophysiology 349
Sander Verheule, Toshiaki Sato and Jeffrey E. Olgin

Introduction 349

Anesthesia for adult mice 350

ECG recording and analysis 351

Transesophageal stimulation 352

Open chest epicardial measurements 354

Studies on Langendorff perfused hearts 357

Conclusion 360

References 361

29 Ligation- and wire injury-induced stenosis 363
Volkhard Lindner

Introduction 363

Materials and methods 364

Discussion 367

Acknowledgments 370

References 370

Index 373

Professor Xu has an excellent standing in the field of atherosclerosis with an outstanding scientific track record. He is part of a European Network of Excellence on vascular biology, which is a large consortium of experts. He is an expert in mouse models and in microsurgery. His group pioneers the study of heat shock proteins in atherogenesis and has established the first mouse model of vein graft atherosclerosis, which is proven to be powerful in studying the mechanisms of progenitor cells participating in atherosclerosis. Professor Xu’s group also generated the first PKC knockout mice and analysed protein profiles of cardiovascular cells in these mice.