- •Preface
- •Contents
- •1 Extracellular and Intracellular Signaling – a New Approach to Diseases and Treatments
- •1.1 Introduction
- •1.1.1 Linear Model of Drug Receptor Interactions
- •1.1.2 Matrix Model of Drug Receptor Interactions
- •1.2 Experimental Approaches to Disease Treatment
- •1.3 Adipokines and Disease Causation
- •1.4 Questions in Disease Treatment
- •1.5 Toxic Lifestyles and Disease Treatment
- •References
- •2.1 Introduction
- •2.2 Heterogeneity of Adipose Tissue Composition in Relation to Adipokine and Cytokine Secretion
- •2.3 Feedback between FA and the Adipocyte
- •2.6 Metabolic Programming of Autocrine Signaling in Adipose Tissue
- •2.8 Cell Heterogeneity in the Pancreatic Islet
- •2.16 Concluding Remarks
- •Acknowledgements
- •References
- •3 One Receptor for Multiple Pathways: Focus on Leptin Signaling
- •3.1 Leptin
- •3.2 Leptin Receptors
- •3.3 Leptin Receptor Signaling
- •3.3.4 AMPK
- •3.3.5 SOCS3
- •3.4 Leptin Receptor Interactions
- •3.4.1 Apolipoprotein D
- •3.4.2 Sorting Nexin Molecules
- •3.4.3 Diacylglycerol Kinase Zeta
- •3.4.4 Apolipoprotein J
- •References
- •4.1 Introduction
- •4.2 Leptin: A Brief Introduction
- •4.3 Expression of Leptin Receptors in Cardiovascular Tissues
- •4.6 Post Receptor Leptin Signaling
- •4.6.2 Mitogen Activated Protein Kinase Stimulation
- •4.7 Adiponectin
- •4.7.1 Adiponectin and Cardiovascular Disease
- •4.7.2 Adiponectin and Experimental Cardiac Hypertrophy
- •4.8 Resistin
- •4.8.1 Cardiac Actions of Resistin
- •4.8.1.1 Experimental Studies on the Cardiac Actions of Resistin
- •4.9 Apelin
- •4.9.1 Apelin and Heart Disease
- •4.10 Visfatin
- •4.11 Other Novel Adipokines
- •4.12 Summary, Conclusions and Future Directions
- •Acknowledgements
- •References
- •5 Regulation of Muscle Proteostasis via Extramuscular Signals
- •5.1 Basic Protein Synthesis
- •5.2.1 Hormones
- •5.2.1.1 Mechanisms of Action: Glucocorticoids
- •5.2.1.2 Mechanisms of Action: TH (T3)
- •5.2.1.3 Mechanisms of Action: Testosterone
- •5.2.1.4 Mechanisms of Action: Epinephrine
- •5.2.2 Local Factors (Autocrine/Paracrine)
- •5.2.2.1 Mechanisms of Action: Insulin/IGF Spliceoforms
- •5.2.2.2 Mechanisms of Action: Fibroblast Growth Factor (FGF)
- •5.2.2.3 Mechanisms of Action: Myostatin
- •5.2.2.4 Mechanisms of Action: Cytokines
- •5.2.2.5 Mechanisms of Action: Neurotrophins
- •5.2.2.7 Mechanisms of Action: Extracellular Matrix
- •5.2.2.8 Mechanisms of Action: Amino Acids (AA)
- •5.3 Regulation of Muscle Proteostasis in Humans
- •5.3.1 Nutrients as Regulators of Muscle Proteostasis in Man
- •5.3.2 Muscular Activity (i.e. Exercise) as a Regulator of Muscle Proteostasis
- •5.4 Conditions Associated with Alterations in Muscle Proteostasis in Humans
- •5.4.2 Disuse Atrophy
- •5.4.3 Sepsis
- •5.4.4 Burns
- •5.4.5 Cancer Cachexia
- •References
- •6 Contact Normalization: Mechanisms and Pathways to Biomarkers and Chemotherapeutic Targets
- •6.1 Introduction
- •6.2 Contact Normalization
- •6.3 Cadherins
- •6.4 Gap Junctions
- •6.5 Contact Normalization and Tumor Suppressors
- •6.6 Contact Normalization and Tumor Promoters
- •6.7 Conclusions
- •References
- •7.1 Introduction
- •7.2 Background on Migraine Headache
- •7.3 Migraine and Neuropathic Pain
- •7.4 Role of Astrocytes in Pain
- •7.5 Adipokines and Related Extracellular Signalling
- •7.6 The Future of Signaling Research to Migraine
- •Acknowledgements
- •References
- •8.1 Alzheimer’s Disease
- •8.1.2 Target for AD Therapy
- •8.2 AD and Metabolic Dysfunction
- •8.2.1 Impaired Glucose Metabolism
- •8.2.2 Lipid Disorders
- •8.2.3 Obesity
- •8.3 Adipokines
- •8.3.1 Leptin
- •8.3.2 Adiponectin
- •8.3.3 Resistin
- •8.3.4 Visfatin
- •8.3.5 Plasminogen Activator Inhibitor
- •8.3.6 Interleukin-6
- •8.4 Conclusions
- •References
- •9.1 Introduction
- •9.1.1 Structure and Function of Astrocytes
- •9.1.1.1 Morphology
- •9.1.1.2 Astrocyte Functions
- •9.1.2 Responses of Astrocytes to Injury
- •9.1.2.1 Reactive Astrocytosis
- •9.1.2.2 Cell Swelling
- •9.1.2.3 Alzheimer Type II Astrocytosis
- •9.2 Intracellular Signaling System in Reactive Astrocytes
- •9.2.1 Oxidative/Nitrosative Stress (ONS)
- •9.2.2 Protein Kinase C (PKC)
- •9.2.5 Signal Transducer and Activator of Transcription 3 (STAT3)
- •9.3 Signaling Systems in Astrocyte Swelling
- •9.3.1 Oxidative/Nitrosative Stress (ONS)
- •9.3.2 Cytokines
- •9.3.3 Protein Kinase C (PKC)
- •9.3.5 Protein Kinase G (PKG)
- •9.3.7 Signal Transducer and Activator of Transcription 3 (STAT3)
- •9.3.10 Ion Channels/Transporters/Exchangers
- •9.4 Conclusions and Perspectives
- •Acknowledgements
- •References
- •10.1 Adipokines, Toxic Lipids and the Aging Brain
- •10.1.1 Toxic Lifestyles, Adipokines and Toxic Lipids
- •10.1.2 Ceramide Toxicity in the Brain
- •10.3 Oxygen Radicals, Hydrogen Peroxide and Cell Death
- •10.4 Gene Transcription and DNA Damage
- •10.5 Conclusions
- •References
- •11.1 Introduction
- •11.2 Cellular Signaling
- •11.2.1 Types of Signaling
- •11.2.2 Membrane Proteins in Signaling
- •11.3 G Protein-Coupled Receptors
- •11.3.1 Structure of GPCRs
- •11.3.1.1 Structure Determination
- •11.3.1.2 Structural Diversity of Current GPCR Structures
- •11.3.1.3 Prediction of GPCR Structure and Ligand Binding
- •11.3.2 GPCR Activation: Conformation Driven Functional Selectivity
- •11.3.2.2 Ligand or Mutation Stabilized Ensemble of GPCR Conformations
- •11.3.2.4 GPCR Dimers and Interaction with Other Proteins
- •11.3.3 Functional Control of GPCRs by Ligands
- •11.3.3.1 Biased Agonism
- •11.3.3.2 Allosteric Ligands and Signal Modulation
- •11.3.4 Challenges in GPCR Targeted Drug Design
- •11.4 Summary and Looking Ahead
- •Acknowledgements
- •References
- •12.1 Introduction
- •12.5.1 Anthocyanins
- •12.5.2 Gallates
- •12.5.3 Quercetin
- •12.5.5 Piperine
- •12.5.6 Gingerol
- •12.5.7 Curcumin
- •12.5.8 Guggulsterone
- •12.6.1 Phytanic Acid
- •12.6.2 Dehydroabietic Acid
- •12.6.3 Geraniol
- •12.7 Agonists of LXR that Reciprocally Inhibit NF-jB
- •12.7.1 Stigmasterol
- •12.7.3 Ergosterol
- •12.8 Conclusion
- •References
- •13.1 Introduction
- •13.2 Selective Dopaminergic Neuronal Death
- •13.3 Signaling Pathways Involved in Selective Dopaminergic Neuronal Death
- •13.3.1 Initiators and Signaling Molecules
- •13.3.1.1 Response to Oxidative and Nitrosative Stress
- •13.3.1.2 Response to Altered Proteostasis
- •13.3.1.3 Response to Glutamate
- •13.3.1.4 Other Initiators
- •13.3.2 Signal Transducers, Intracellular Messengers and Upstream Elements
- •13.3.2.2 Small GTPases
- •13.3.3 Intracellular Signaling Cascades
- •13.3.3.1 Mitogen Activated Protein Kinases (MAPK) Pathway
- •13.3.3.2 PI3K/Akt Pathway
- •13.3.3.4 Unfolded Protein Response (UPR)
- •13.3.4 Potentially Involved Intracellular Signaling Components
- •13.3.4.3 PINK1
- •13.3.5.2 Dopamine Metabolism
- •13.3.5.3 Cell Cycle
- •13.3.5.4 Autophagy
- •13.3.5.5 Apoptosis
- •13.4 Conclusions
- •References
- •Subject Index
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hypertrophy.16 Leptin has also been shown to induce hyperplasia in the immortalized atrial HL-1 cell line via an ERK-dependent pathway.19 The results from studies using the HL-1 cell line are di cult to compare to primary culture of ventricular myocytes since the two models would likely respond to stimuli di erently in view of the fact that the primary response of HL-1 cells is hyperplasia, not hypertrophy. Recent evidence suggests that p38 activation (as well as activation of AMPK) mediates the anti-apoptotic e ect of leptin in cultured myocytes,42 although it should be added that STAT-3 activity has also been implicated in this phenomenon.43 Moreover, leptin-induced cardiac fatty acid oxidation has recently been demonstrated to occur by a multiplicity of cell signaling transducers including STAT-3, NO and p38 MAPK activation.44
4.6.3Pivotal Role for the RhoA/ROCK System in Mediating the Hypertrophic E ects of Leptin
Over the past number of years it has become apparent that the Rho/ROCK pathway, a downstream target protein of small GTP-binding protein Rho important for regulation of cell morphology, is likely also an important contributor to hypertrophy, although the mechanism leading to activation of Rho GTPases and subsequently to cardiac hypertrophy has not been well characterized.45,46 RhoA activates several protein kinases, including Rho kinases (ROCK). This leads to the activation of LIM kinase-2 (LIMK2) resulting in phosphorylation (inactivation) of the actin binding protein cofilin, an important factor in the regulation of actin dynamics, which in turn leads to depletion of globular actin (G-actin) pool and enhanced actin polymerization (F-actin). Work from our laboratory has recently shown that leptin is a potent activator of the RhoA/ROCK pathway leading to a decrease in the G/F actin ratio.47 The precise mechanism of how activation of this pathway leads to cardiac hypertrophy is not known with certainty. Interestingly, however, activation of RhoA/ROCK by leptin results in the selective translocation of p38, but not other MAPK isoforms, to the nucleus,48 a finding in agreement with our initial observation that leptininduced hypertrophy can be blocked by p38, but not by ERK inhibition.16 Intact caveolae are also critical for both the activation of the RhoA pathway and the resultant p38 translocation and hypertrophy.48 The role of caveolae in mediating the hypertrophic e ects of leptin was supported by various lines of evidence.48 Firstly, leptin significantly increased the number of caveolae as well as caveolin-3 protein expression in myocytes. Secondly, OBR were found to be colocalized with caveolae. Lastly, disruption of caveolae with the cholesterol-depleting agent methyl-beta-cyclodextrin was found to prevent leptin-induced hypertrophy, which was reversed by exogenous cholesterol repletion.
4.7 Adiponectin
Adiponectin is a 30-kDa protein secreted by adipose tissue that plays a critical role in di erentiation of adipocytes. The peptide belongs to the complement 1 family and can exist as a monomer or high-molecular-weight multimers.49
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Chapter 4 |
Adiponectin can function as a full-length protein of 245 amino acids or a smaller globular fragment of 137 amino acids. The plasma adiponectin concentration in humans may range from 3 to 30 mg per ml and accounts for 0.01% of total plasma protein.50 Adiponectin expression and subsequent release from adipocytes is stimulated by activation of peroxisome proliferators-activated receptor (PPAR)-g, a key transcriptional factor involved in adipocyte di erentiation.51
Two adiponectin receptors, termed as AdipoR1 (adiponectin receptor 1) having 375 amino acids and AdipoR2 (adiponectin receptor 2) with 311 amino acids, have been identified.52 Structural analysis revealed that these receptors are integral membrane proteins containing conserved seven-transmembrane domains with internal N-terminus and external C-terminus.52 Scatchard plot analysis demonstrated that AdipoR1 binds to globular adiponectin whereas AdipoR2 binds to full-length adiponectin.52 AdipoR1 was shown to be expressed ubiquitously, while AdipoR2 expression is more restricted. In the heart, AdipoR1 is expressed in substantially greater abundance compared to AdipoR2.52
4.7.1Adiponectin and Cardiovascular Disease
Adiponectin is the most abundant adipokine secreted by adipose tissue and has been suggested to be involved in various cardiovascular diseases.53 Adiponectin levels are significantly reduced in obese subjects54 and patients with type 2 diabetes.55 The direct role of adiponectin in pathogenesis of cardiac disease still needs to be elucidated; however, it has been observed that increased plasma adiponectin levels are associated with a lower risk of myocardial infarction and coronary artery disease in men.56,57 Adiponectin levels were shown to be reduced significantly in patients with coronary artery disease58,59 as well as in patients with heart failure.60 In addition an inverse correlation was reported between adiponectin levels and other cardiovascular risk factors such as hyperlipidemia,50 hypertension61 and C-reactive protein levels.62 Adiponectin levels may also be a predictor of mortality in patients with chronic heart failure63 and coronary artery disease.64 A recent study showed a particularly strong relationship between elevated plasma adiponectin levels and mortality in patients with heart failure but an association was also present in patients without cardiovascular disease.65 However, an association between plasma adiponectin levels and cardiovascular morbidity or mortality is not uniform as recent studies were unable to demonstrate any relationship between plasma adiponectin levels and the severity of coronary artery disease.66–69 Such discrepant findings clearly support further research into the clinical relevance of adiponectin in cardiovascular disease. However, from a general perspective adiponectin exerts e ects opposite to those manifested in response to leptin and as such exerts primarily beneficial e ects in mitigating cardiac pathology.
4.7.2Adiponectin and Experimental Cardiac Hypertrophy
Adiponectin knockout (ADN-KO) mice subjected to pressure overload by transverse aortic constriction (TAC) demonstrate elevated concentric
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hypertrophy evidenced by increased left ventricular wall thickness as well as increased mortality after 7 days compared to wild-type animals. The adenoviral transfection of adiponectin (Ad-ADN) to ADN-KO mice 3 days prior to subjecting them to TAC attenuated the development of cardiac hypertrophy. In obese db/db mice, which lack the functional leptin receptor Ad-ADN, treatment abolished the TAC-induced increase in interventricular septum and left ventricular posterior wall thickness. In the presence of Ad-ADN, angiotensin II-induced cardiac hypertrophy was attenuated in both ADN-KO and wildtype mice.69 These findings suggest that adiponectin over-expression can reverse the cardiac dysfunction induced by various pathological factors. For example, a-adrenergic receptor stimulation by norepinephrine increased cell surface area and protein synthesis in cardiomyocytes, which was attenuated in the presence of adiponectin.69 Thus, adiponectin appears to be an endogenous anti-remodeling agent that may be beneficial in limiting heart failure.70
4.7.3Cell Signaling Mechanisms Underlying Cardioprotective and Antihypertrophic E ects of Adiponectin
Adiponectin induces e ects most likely via a multiplicity of cell-signaling mechanisms subsequent to adiponectin receptor (AdipoR1/AdipoR2) activation. For example, ERK1/2 MAPK activation was increased in ADN-KO mice subjected to TAC compared to wild-type. ERK1/2 activation induced by a-adrenergic agonist in cardiomyocytes was attenuated in presence of adiponectin or MEK inhibitor U0126.69 Taken together, these studies suggest that the protective e ect of adiponectin is partly mediated through inhibition of ERK1/2 MAPK.
AMPK modulation may also mediate some of the actions of adiponectin. In ADN-KO hearts AMPK phosphorylation at Thr 172 on a-subunit was suppressed compared to wild-type hearts.69 Moreover, activation of AMPK has been proposed as a mechanism for the beneficial e ects of adiponectin.69 ADNKO mice exhibit enhanced and accelerated myocardial remodeling following pressure overload, which is associated with reduced AMPK levels.71,72 Hearts from ADN-KO mice also developed larger infarct area compared to wild-type after subjecting them to ischemia/reperfusion (IR). In the presence of exogenous adiponectin, both ADN-KO and wild-type hearts had reduced infarct size after IR, an e ect associated with AMPK activation and suppression of TNFa production in myocardium.73 A role for AMPK has also been demonstrated in a study implicating adiponectin as the underlying factor in mediating cardioprotection in mice subjected to a calorie-restricted diet.74
Adiponectin has also been shown to attenuate the increased gp91 protein in cardiac tissue subjected to IR and thus reduced oxidative stress-induced tissue injury.75 Studies on the regulation of NO production from eNOS and iNOS by adiponectin demonstrated that in the hearts of ADN-KO mice subjected to IR eNOS phosphorylation is decreased and iNOS activity is increased compared to wild-type.75 This may suggest that under physiological conditions adiponectin