Mechanosensitivity of the Heart (eBook)

Foreword 5
Contents 7
Editorial 10
MSCs and MGCs 11
Are All MGCs Stretch-Activated Channels? 13
Leak Channels MGCs 14
Molecular Organization of Channels 15
How Mechanical Energy is Transferred to MGC or to MSC 17
Bilayer Model 17
Tethered Model 19
Mechanically Induced Currents and Potentials in Isolated Cardiomyocytes and Cell Tissues 20
Mechano-Electrical Feedback in the Whole Heart 23
Arteries as a Source of Myogenic Contractile Activity 25
Conclusions and Perspectives 25
References 27
Contributors 33
Part I Molecular Mechanisms of Mechanotransduction in Cardiac Cells 38
1 Titin and Titin-Associated Proteins in Myocardial Stress-Sensing and Mechanical Dysfunction 39
1.1 Introduction 39
1.2 The Titin Gene and Tissue Specificity of Titin Expression 41
1.3 Titin Isoform Diversity and Functions in the Heart 42
1.4 Interactions and Properties of Z-Disk Titin 43
1.4.1 Ig-Domains Z1/Z2 and the Z-Disk-Based Mechanosensor 44
1.4.2 Connectivity Provided by Unique Sequence Insertions at Titin0s NH 2 -Terminus 47
1.5 I-Band Titin: Interactions and Multifaceted Roles in Normal and Diseased Heart 48
1.5.1 Extensible Elements in I-Band Titin 48
1.5.2 Novex Domains 49
1.5.3 Cardiac-Specific N2B-Domain: Molecular Spring and Ligand-Binding Site 49
1.5.4 N2A-Domain: A Stress-Sensing Element? 51
1.5.5 PEVK-Domain: Signalling and Mechanical Functions 52
1.5.6 Plasticity of Titin in Cardiac Development 53
1.5.7 Mechanical Function of Titin in Human Heart Disease 54
1.5.8 Regulation of Titin Stiffness by Phosphorylation 56
1.6 The Scaffolding Role of A-Band Titin 56
1.7 Structural and Signalling Complexes of M-Band Titin 57
1.7.1 The Titin-Kinase Region: A Putative Stretch-Sensor Complex 57
1.7.2 Interactions and Function of COOH-Terminal Titin Domains 58
1.8 Human Titin as a Candidate Gene for Hereditary Myopathies 59
1.9 Conclusions and Perspectives 61
References 61
2 Mechanical Stretch-Induced Reorganization of the Cytoskeleton and the Small GTPase Rac-1 in Cardiac Fibroblasts 71
2.1 Introduction 71
2.2 The Cytoskeleton, Rho GTPases and Mechanotransduction 72
2.3 Analysis of the Actin Cytoskeleton and Rac-1 GTPase in Mechanically Stretched Cardiac Fibroblasts 74
2.3.1 Model Systems to Study the Effects of Mechanical Forces 74
2.4 Alterations in Cardiac Fibroblast Morphology in Response to Equibiaxial Stretch 11
2.5 Biochemical Analysis of Rac-1 GTPase Activation by Equibiaxial Stretch 13
2.6 Morphological Alterations in Cytoskeletal Actin and Rac-1 in Response to Equibiaxial Stretch: Fractal Analysis 14
2.7 Morphometric Analysis of Rac-1 in Response to Cellular Activation by Tumor Necrosis Factor-Alpha 15
2.8 Activation of NF-B in Cardiac Fibroblasts by Equibiaxial Stretch and Proinflammatory Cytokines 17
2.9 Conclusions and Perspectives 86
References 27
3 Molecular Signaling Mechanisms of Myocardial Stretch: Implications for Heart Disease 91
3.1 Introduction 92
3.1.1 Extracellular Matrix and Mechanotransduction 92
3.2 Mechanosensors Implicated in Cardiac Pathophysiology 93
3.2.1 Integrins 93
3.2.1.1 Structure and Function of Integrins 93
3.2.1.2 Integrin Expression in the Myocardium 94
3.2.1.3 Integrins as Mechanotransducers 95
3.2.2 Angiotensin II Type I (AT1) As a Mechanotransducer 96
3.3 Proximal Effectors of Cardiac Mechanosensing 96
3.3.1 Focal Adhesion Kinase (FAK) 96
3.3.2 Integrin-Linked Kinase (ILK) 98
3.3.3 Rho Family of GTPases 98
3.3.3.1 RhoA and Rac1 99
3.3.4 Protein Kinase C (PKC) 100
3.4 Mechanosensitive Signal Transduction Cascades 101
3.4.1 Mitogen-Activated Protein (MAP) Kinase Cascades 101
3.4.1.1 Extracellular Regulated Kinase (ERK) Cascade 102
3.4.1.2 p38 Cascade 103
3.4.1.3 JNK Cascade 104
3.4.2 Phosphoinositide 3-kinase/AKT/mTOR/FOXO Cascade 104
3.4.2.1 Mechanical Regulation of Akt 104
3.4.2.2 mTOR and Regulation of Cardiac Growth 105
3.4.2.3 Regulation of FOXO Transcription Factors 107
3.4.3 Janus-Associated Kinase (JAK)/Signal Transducers and Activators of Transcription (STATs) 107
3.5 Conclusions and Perspectives 108
References 109
4 Mechanical Stress Induces Cardiomyocyte Hypertrophy Through Agonist-Independent Activation of Angiotensin II Type 1 Receptor 118
4.1 Introduction 118
4.2 Activation of AT1 Receptor in the Development of Cardiac Hypertrophy 119
4.3 Mechanical Stress in the Development of Cardiac Hypertrophy 121
4.4 Mechanical Stress-Induced Activation of AT1Receptor 121
4.5 Conformational Change of AT1Receptor During Mechanical Stress-Induced Activation 123
4.6 Inverse Agonism on Stretch-Induced Activation of AT1 Receptor 124
4.7 Concluding Remarks 126
References 127
Part II Mechanically Induced Potentials and Currents of the Cardiac Cells in Healthy and Diseased Myocardium 131
5 Mechanostransduction in Cardiac and Stem-Cell Derived Cardiac Cells 132
5.1 Introduction 132
5.2 Mechanical Signals Applied In Vitro to Cardiac Cells 133
5.2.1 Direct Stretch 133
5.2.2 Mechanical Indentation 135
5.2.3 Fluid Shear Stress 136
5.2.4 Substrate Elasticity 136
5.3 Patterned Growth and Cell Alignment 136
5.3.1 Contact Guidance 137
5.3.2 Microcontact Printing 137
5.3.3 Microfluidics 137
5.3.4 Dielectrophoresis 138
5.4 Stretch and Shear Stress Effects on Cardiomyocyte Electrophysiology in Culture 138
5.4.1 Direct Stretch 138
5.4.2 Mechanical Indentation 141
5.4.3 Fluid Shear 141
5.4.4 Substrate Stiffness 142
5.5 Myocardial Stress and/or Strain Regulates Cardiac Muscle Growth and Function 143
5.5.1 Fiber and Cross-Fiber Loading 144
5.5.2 Shear Stress and Strain 145
5.5.3 Regulation of Junctional Proteins by Mechanical Load 146
5.6 Role of Mechanics in Stem Cell Differentiation and Maturation of Stem Cell-Derived Cardiomyocytes 146
5.6.1 Mechanical Influences on Differentiation of Cardiac Myocytes from Embryonic Stem Cells 147
5.6.2 Differentiation of Cardiac Myocytes and Mechanical Induction of Differentiation of Other Myocytes from Mesenchymal Stem Cells 149
5.6.3 Mechanical Influences on the Transdifferentiation of Skeletal Myocytes into Cardiac-Like Myocytes 150
5.6.4 Substrate Stiffness 150
5.7 Role of Structural Proteins and Related Signaling Pathways in Mechanotransduction and Heart Failure 151
5.7.1 ECM in Mechanotransduction 151
5.7.2 Integrins 152
5.7.3 Sarcolemma in Mechanotransduction 152
5.7.3.1 Phospholipase C 153
5.7.3.2 G-Protein Coupled Receptors 153
5.7.3.3 Stretch Activated Ion Channels 154
5.7.3.4 Na/H Exchanger 154
5.7.4 Cytoskeleton in Mechanotransduction 155
5.7.4.1 Titin 156
5.7.4.2 Muscle LIM Protein 156
5.7.4.3 Four-and-a-Half LIM Domain Protein 157
5.7.4.4 Troponin C 158
5.7.5 The Nucleus in Mechanotransduction 158
5.7.6 Influence of the RhoA/ROCK Pathway in Cardiomyocyte Mechanotransduction 158
5.8 Summary and Conclusion 159
References 160
6 Stretch-Activated Channels in the Heart: Contribution to Cardiac Performance 173
6.1 Introduction 173
6.2 The Cardiac Response to Stretch 175
6.3 Possible Mechanisms of the Slow Force Response 177
6.3.1 Role of the Sarcoplasmic Reticulum in the SFR 177
6.3.2 Stretch-Activation of Na+/H + Exchanger 179
6.3.3 Stretch-Activated Channels and the SFR 179
6.4 Stretch-Sensitive Channels in the Heart 180
6.4.1 Stretch Sensitivity of Voltage-Gated Ion Channels 181
6.4.2 Stretch-Activated Channels Non-selective for Cations (SACNSC) 182
6.4.3 Stretch-Activated Channels Selective for K+ 183
6.4.4 Volume Sensitive Chloride Channels 184
6.4.5 Pharmacological Agents that Block Stretch-Activated Channels 185
6.4.6 Effect of Stretch-Activated Channel Blockers on the SFR 186
6.5 Molecular Candidates for Cardiac SACNSC 187
6.6 Stretch-Induced Arrhythmias 188
6.7 Overview of the Contribution of Stretch to Cardiac Performance: SFR 190
6.8 Conclusion 192
References 193
7 Effects of Applied Stretch on Native and Recombinant Cardiac Na + Currents 200
7.1 Introduction 201
7.2 Effects of Stretch on Na + Currents 202
7.2.1 Modification by Stretch of Na + Current Density and Kinetics 202
7.2.2 Changes in Biophysical Properties of I Na Depend on Amount of Stretch 205
7.3 Pathophysiological Implications 206
7.3.1 Sodium Channels and Stretch-Induced Arrhythmias 206
7.3.2 Mathematical Simulations of the Human Ventricular Action Potential 206
7.3.3 Experimental and Computational Limitations 208
7.3.4 Possible Chamber-Specific Effects of Stretch on I Na , in the Heart 208
7.3.5 Stretch Alters the Kinetics of Reactivation of Cardiac Na + Current 208
7.4 What is the Basis for this Mechanotransduction? 210
References 213
8 Mechanosensitive Alterations of Action Potentials and Membrane Currents in Healthy and Diseased Cardiomyocytes: Cardiac Tissue and Isolated Cell 216
8.1 Introduction 217
8.2 Methods of Direct Mechanical Deformation of Isolated Cardiomyocytes for Electrophysiological Registration 217
8.2.1 Cell Stretch 218
8.2.1.1 Axial Stretch by Two Patch Pipettes 218
8.2.1.2 Axial Stretch by Two Glass Capillaries 219
8.2.1.3 Local Axial Stretch by Glass Stylus and Axial Stretch by Two Glass Styluses 220
8.2.1.4 Local Axial Stretch by Two Thin Carbon Fibers 222
8.2.2 Brick-Like Isolated Cardiomyocyte has Two Different Surfaces 223
8.2.3 Compression of the Cardiomyocytes 225
8.2.4 Simultaneous Recording of Single Channels and Whole-Cell Currents During Direct Deformation of the Whole Cell 226
8.3 Stretch of Freshly Isolated Atrial Cardiomyocytes 227
8.3.1 Freshly Isolated Atrial Cardiomyocytes from Healthy Animals 228
8.3.2 Stretch of Freshly Isolated Atrial Cardiomyocytes from Patients with Cardiac Hypertrophy 231
8.4 Stretch of Freshly Isolated Ventricular Cardiomyocytes 234
8.4.1 Freshly Isolated Ventricular Cardiomyocytes from Healthy Animals 235
8.4.1.1 Modulation of the Resting Membrane Potential and Action Potential 235
8.4.1.2 Modulation of Basal Membrane Current by Stretch 237
8.4.1.3 I SAC , The Stretch-Activated Current Through Non-selective Cation Channels 240
8.5 Compression of Isolated Ventricular Cardiomyocytes 243
8.6 Freshly Isolated Ventricular Cardiomyocytes from Hearts with Pathology 250
8.6.1 Modulation of Resting Membrane Potential and Action Potential Properties 250
8.6.2 Dependence of Mechanosensitivity of Cardiomyocytes from Age and Presence of Hypertension 252
8.7 From Isolated Cell with Patch-Pipette to Heart Tissue with Microelectrodes 254
8.8 Mechano-Electric Feedback in Atrium from Healthy and Diseased Animals and Human 254
8.8.1 Mechano-Electric Feedback in Right Atrial Tissue in Healthy Rats 254
8.8.2 Mechano-Electric Feedback in Right Atrial Tissue from Animals with Cardiac Hypertrophy After Infarction and Human Atria 255
8.9 Mechano-Electric Feedback in Ventricle from Healthy and Diseased Animals and Human 261
8.9.1 Mechano-Electric Feedback in Left Ventricular Tissue in Healthy Rats 261
8.9.2 Mechano-Electric Feedback in Ventricular Tissue from Animals with Cardiac Hypertrophy After Infarction 262
8.10 Conclusion 265
References 265
9 The Role of Mechanosensitive Fibroblasts in the Heart: Evidence from Acutely Isolated Single Cells, Cultured Cells and from Intracellular Microelectrode Recordings on Multicellular Preparations from Healthy and Diseased Cardiac Tissue 270
9.1 Introduction 271
9.2 Electrical Properties of Single Cardiac Fibroblasts 273
9.2.1 Mechanosensitive Whole-Cell Currents During Compression of the Isolated and Cultured Fibroblasts 274
9.2.2 Mechanosensitive Whole-Cell Currents During Stretch of the Isolated and Cultured Fibroblasts 275
9.2.3 Other Ion Currents of Cardiac Fibroblasts 276
9.2.4 Current-Voltage Relations During Compression and Stretch of the Isolated and Cultured Fibroblasts 276
9.2.5 Single Mechano-Gated Channels in Cardiac Fibroblasts 278
9.3 Electrical Properties of Cardiac Fibroblasts in Heart Tissue 278
9.4 Age Dependence of the Electrical Properties of Cardiac Fibroblasts 282
9.5 Altered Electrical Function of Cardiac Fibroblasts After Myocardial Infarction 283
9.6 Electrical Coupling Between Fibroblasts and Myocytes 284
9.6.1 Electrical Communication Among Cardiac Fibroblasts 285
9.6.2 Electrical Interaction Between Fibroblasts and Myocytes in the Heart 287
9.7 Role of Cardiomyocyte Fibroblast Coupling in Healthy and Diseased Hearts 289
9.8 Conclusions and Perspectives 291
References 292
10 Scanning Ion Conductance Microscopy for Imaging and Mechanosensitive Activation of Selected Areas of Live Cells 298
10.1 Introduction 298
10.2 The Scanning Ion Conductance Microscope 299
10.2.1 Applied Pressure 300
10.2.2 Calibration of Force Exerted Via the Nanopipette 300
10.3 Example Application 300
10.3.1 Probing (Activating) Mechanosensitive Receptors 301
10.3.2 Mechanical Properties of Cells 301
10.4 Concluding Remarks 302
References 302
Part III Mechano-Electric Feedback in the Whole Heart and a Computer Simulation Study 304
11 The Contribution of MEF to Electrical Heterogeneity and Arrhythmogenesis 305
11.1 Introduction 305
11.2 Electrical Heterogeneity and Arrhythmias 307
11.2.1 Atrial Arrhythmias 307
11.2.2 Ventricular Arrhythmias 307
11.2.3 Summary 308
11.3 A Brief Look at MEF 309
11.3.1 MEF at the Cellular and Whole Heart Level 309
11.3.2 Mechanisms Responsible for MEF 311
11.3.2.1 The Potassium Selective Stretch-Sensitive Channels: 312
11.3.2.2 Non-selective Cation Channels (SACs) 312
11.3.2.3 Other Mechanisms Contributing to MEF 313
11.4 The Role of MEF in Normal Heart and Cardiac Diseases 314
11.4.1 The Heterogeneity of MEF in the Heart 316
11.4.1.1 Atria 316
11.4.1.2 Ventricles 317
11.4.1.3 Distribution of Stretch Sensitive Channels in Ventricle 318
11.5 The Contribution of MEF to Arrhythmogenesis 319
11.5.1 Atrial Arrhythmias 320
11.5.2 Ventricular Arrhythmias 320
11.6 Conclusion 322
References 323
12 Mechanical Modulation of a Reentrant Arrhythmia: The Atrial Flutter Case 331
12.1 The Beat-to-Beat Variability of Atrial Flutter Cycle Length 331
12.2 The Relation Between Atrial Size and Atrial Flutter Rate 333
12.3 The Mechanical Origin of Atrial Flutter Cycle Length Variability 335
12.3.1 Ventricular Contraction and Respiration: The Sources of AFL Cycle Length Variability 335
12.3.2 The Response to Pharmacological Denervation 338
12.3.3 Correlation with Pressure/Volume Changes 339
12.3.4 The MEF Paradigm for Atrial Flutter Cycle Length Variability 341
12.4 A Mathematical Model for MEF Effects on Atrial Flutter Cycle Length Variability 344
12.4.1 Model Formulation 345
12.4.2 Model Predictions 347
12.5 Conclusions and Perspectives 350
References 350
13 Early Hypertrophic Signals After Myocardial Stretch. Role of Reactive Oxygen Species and the Sodium/Hydrogen Exchanger 356
13.1 Introduction 356
13.2 NHE-1 and Myocardial Stretch 357
13.3 Evidences for the ANG II-Induced Release of ET-1 Autocrine Mechanism 367
13.4 The Slow Force Response as the Mechanical Counterpart of the Autocrine Mechanism Triggered by Stretch: the Anreps Phenomenon 369
13.5 Role of ROS After Stretch, ANG II and ET-1 372
13.6 The Mechanical and Hypertrophic Effect of NHE-1 Activation 383
References 392
14 Stretch-Induced Inotropy in Atrial and Ventricular Myocardium 401
14.1 Introduction 401
14.1.1 The SFR in Human Ventricular Myocardium 403
14.1.2 The SFR in Human Atrial Myocardium 404
14.2 Involved Proteins 405
14.2.1 No Contribution of Stretch Activated Channels 405
14.3 Role of Myosin Light Chain Phosphorylation by MLCK 406
14.4 Differential Regulation in Atrial Vs. Ventricular Myocardium: [Na + ] i 407
14.5 Various Pathways and Mechanisms Contribute to the SFR 408
14.6 Physiological Role of the SFR 411
References 411
15 Effects of Wall Stress on the Dynamics of Ventricular Fibrillation: A Computer Simulation Study of Mechanoelectric Feedback 414
15.1 About Ventricular Fibrillation 414
15.1.1 What is Ventricular Fibrillation? 415
15.1.2 How Does Ventricular Fibrillation Occur and How is it Sustained? 415
15.1.2.1 Spiral Wave 415
15.1.2.2 Action Potential Duration (APD) Restitution Curve 416
15.1.3 Defibrillation 417
15.2 Effects of Mechanical Change on VF 417
15.2.1 Increased Defibrillation Thresholds in Dilated Hearts 418
15.2.1.1 Multiple Factors That Could Influence DFT 418
15.2.1.2 Potential Mechanism of DFT Increase by Acute Ventricular Dilatation 419
15.2.2 High Inducibility of VF by Mechanical Loading 420
15.2.3 The Role of MEF in Mechanical Induction of VF 420
15.3 Previous Studies on the Effects of MEF on VF Dynamics 421
15.3.1 Experimental Studies 421
15.3.2 Computer Simulation 424
15.4 Methods of Our Computer Simulation 425
15.4.1 Ionic Transmembrane Current 425
15.4.2 Stretch-Activated Currents 426
15.4.3 A Model of Excitation Propagation 428
15.4.4 The Generation of Contraction Force 429
15.4.5 Constitutive Equation for Cardiac Muscles 429
15.4.6 A Fully Coupled Electromechanical Model 430
15.4.7 Efficient Dynamic Finite Element Method 432
15.5 Examples of Our Computer Simulations 433
15.5.1 The Effects of Stretch on CV 434
15.5.2 The Effects of Stretch on APD 434
15.5.3 The Effects of Stretch on SW Dynamics 434
15.6 Future Research 438
15.7 Appendix: Definitions for Finite Element Analysis 442
References 443
16 Electromechanical Modelling of Cardiac Tissue 447
16.1 Introduction 447
16.2 The Mechano-Electrical Feedback (MEF) in Heart Tissue 449
16.2.1 Mechano-Electrical Feedback and Arrhythmias 450
16.3 Mechanics of Cardiac Tissues 451
16.3.1 Active and Visible Deformations 452
16.3.2 Balance Equations 454
16.3.3 Mechanical Behaviour of the Tissue 455
16.4 Electrophysiology of Cardiac Tissues 458
16.4.1 Diffusion-reaction on a Moving Medium 460
16.4.2 Stretch Activated current 463
16.4.3 Calcium Dynamics 464
16.5 Numerical Simulations, Results and Discussion 464
16.5.1 General Features of the Model 465
16.5.2 Stretch Induced Currents 467
16.5.3 Vortex Lines 469
16.5.4 What's Next? 470
References 472
Part IV Arteries as a Source of Myogenic Contractile Activity: Ionic Mechanisms 476
17 Specific Mechanotransduction Signaling Involved in Myogenic Responses of the Cerebral Arteries 477
17.1 Introduction 477
17.2 Cerebral Arteries as a Source of Myogenic Contractile Activity 478
17.2.1 Distinctive Role of the Large Cerebral Arteries 479
17.2.2 Development of the Circumferential Muscle Layer 479
17.2.3 Ultrastructure and Localization of Activator Ca 2+ 480
17.2.4 Cell-to-Cell Communication Among Medial Smooth Muscle Cells 481
17.3 Ionic Mechanisms for Myogenic Contractile Responses to Mechanical Stretch in the Cerebral Arteries 482
17.3.1 Simultaneous Recording of Stretch-Induced Contraction and Ca 2+ Signals 482
17.3.2 Ion Channels Involved in Stretch-Induced Contraction in Cerebral Arteries 483
17.3.3 Hypotonically Induced Contraction of Cerebral Arteries 485
17.3.4 TRP Channels as Candidates for Mechanosensitive Cation Channels 487
17.4 Multiple Phosphorylation of 20-kDa Myosin Light Chain of Cerebral Artery Smooth Muscles as a Self-inhibitory Mechanism in Stretch-Induced Contraction 488
17.4.1 Triphosphorylation of Myosin Light Chain Induced by Mechanical Stretch 488
17.4.2 Interactive Role of Mechano-Sensitive Kinases: Protein Kinase C, Rho/Rho Kinase, and Protein Tyrosine Kinase 490
17.4.3 Significance of the Self-inhibitory Mechanism in Stretch-Induced Contraction 491
17.5 Relevance of Stretch-Induced Contraction and Vasospasm 493
17.5.1 Cerebral Vasospasm 493
17.5.2 Beyond Vasospastic Episodes 495
17.6 Stretch-Induced Contraction as a Drug Evaluation System 496
17.6.1 Promoters 496
17.6.2 Inhibitors 498
17.7 Conclusion and Perspectives 499
References 500
Index 506