Targeted Inactivation of Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Gene Prevents Ischemic Preconditioning in Isolated Mouse Heart

Chen, Hong; Liu, Luis L.; Ye, Linda L.; Guckin, Conor Mc; Tamowski, Susan; Scowen, Paul; Tian, Honglin; Murray, Kathleen; Hatton, William J.; Duan, Dayue Darrel

doi:10.1161/01.cir.0000138110.84758.bb

Cited by 37 publications

(39 citation statements)

References 23 publications

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“…The CFTR channel gene, mRNA, and protein are expressed in the human and rat brain and in hypothalamic cell lines (32)(33)(34). Here, we show that the clofibric acid analog gemfibrozil, a nonselective CFTR inhibitor (25,35), reverses the effects of low glucose in ARC and VMN glucose-inhibited neurons and blocks their ability to detect subsequent changes in glucose. These data support the hypothesis that the CFTR channel could mediate glucose sensing in ARC and VMN glucose-inhibited neurons.…”

Section: Discussionmentioning

confidence: 75%

Characterization of Glucosensing Neuron Subpopulations in the Arcuate Nucleus

et al. 2007

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Four types of responses to glucose changes have been described in the arcuate nucleus (ARC): excitation or inhibition by low glucose concentrations <5 mmol/l (glucose-excited and -inhibited neurons) and by high glucose concentrations >5 mmol/l (high glucose-excited and -inhibited neurons). However, the ability of the same ARC neuron to detect low and high glucose concentrations has never been investigated. Moreover, the mechanism involved in mediating glucose sensitivity in glucose-inhibited neurons and the neurotransmitter identity (neuropeptide Y [

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Section: Discussionmentioning

confidence: 75%

Characterization of Glucosensing Neuron Subpopulations in the Arcuate Nucleus

et al. 2007

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“…Indeed, absence of a cardiac effect of the mutant CFTR on the heart is supported by similar graft survival of hearts obtained from donors with cystic fibrosis during a domino heart transplan tation, and hearts obtained from donors without cystic fibrosis 122 . Conversely, heart tissue expresses a unique splicing variant of CFTR 123 , and in vitro cardio myocyte prepar ations from Cftr −/− mice lose the cardio protective effect of preconditioning 124 and have an increased dependence of heart contractility on Ca 2+ /calmodulin dependent kinase type II and Ca 2+ activated Cl − chan nels 125 . Mutations in CFTR, which induce loss of function of the protein, can therefore affect cardiac function and contribute to cardiac manifestations of cystic fibrosis.…”

Section: Derailment Owing To Genetic Mutationsmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

137

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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“…Using gene targeting technique to specifically inactivate ClC-3 gene expression in the mouse provides a unique and powerful approach to directly address the question whether VRCCs play a role in both eIPC and swIPC. In this study, therefore, we applied both in vitro IPC of isolated working heart [31] and in vivo mouse eIPC and swIPC model [2] to a ClC-3 knockout (ClCn3 -/-) murine line [26,32] a Isolated Langendorff and working heart preparations Cardiac hemodynamic parameters were recorded from isolated Langendorff and working heart preparations continuously during the experiment and analyzed off-line by HSE data acquisition system (HSE HAEMODYN, Harvard Apparatus) as described previously [31,33]. Briefly, hearts were removed rapidly from mice anesthetized with pentobarbital sodium (50 mg/ kg, intraperitoneal injection).…”

Section: Introductionmentioning

confidence: 99%

Activation of Volume Regulated Chloride Channels Protects Myocardium from Ischemia/reperfusion Damage in Second-window Ischemic Preconditioning

Bozeat

Xiang

et al. 2011

Cell Physiol Biochem

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Activation of volume regulated chloride channels (VRCCs) has been shown to be cardioprotective in ischemic preconditioning (IPC) of isolated hearts but the underlying molecular mechanisms remain unclear. Recent independent studies support that ClC-3, a ClC voltage-gated chloride channel, may function as a key component of the VRCCs. Thus, ClC-3 knockout (Clcn3^-/-) mice and their age-matched heterozygous (Clcn3^+/-) and wild-type (Clcn3^+/+) littermates were used to test whether activation of VRCCs contributes to cardioprotection in early and/or second-window IPC. Targeted disruption of ClC-3 gene caused a decrease in the body weight but no changes in heart/body weight ratio. Telemetry ECG and echocardiography revealed no differences in ECG and cardiac function under resting conditions among all groups. Under treadmill stress (10 m/min for 10 min), the Clcn3^-/- mice had significant slower heart rate (648±12 bpm) than Clcn3^+/+ littermates (737±19 bpm, n=6, P<0.05). Ex vivo IPC in the isolated working-heart preparations protected cardiac function during reperfusion and significantly decreased apoptosis and infarct size in all groups. In vivo early IPC significantly reduced infarct size in all groups including Clcn3^-/- mice (22.7±3.7% vs control 40.1±4.3%, n=22, P=0.004). Second-window IPC significantly reduced apoptosis and infarction in Clcn3^+/+ (22.9±3.2% vs 45.7±5.4%, n=22, P<0.001) and Clcn3^+/- mice (27.5±4.1% vs 42.2±5.7%, n=15, P<0.05) but not in Clcn3^-/- littermates (39.8±4.9% vs 41.5±8.2%, n=13, P>0.05). Impaired cell volume regulation of the Clcn3^-/- myocytes may contribute to the failure of cardioprotection by second-window IPC. These results strongly support that activation of VRCCs may play an important cardioprotective role in second-window IPC.

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Targeted Inactivation of Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Gene Prevents Ischemic Preconditioning in Isolated Mouse Heart

Cited by 37 publications

References 23 publications

Characterization of Glucosensing Neuron Subpopulations in the Arcuate Nucleus

Characterization of Glucosensing Neuron Subpopulations in the Arcuate Nucleus

Proteostasis in cardiac health and disease

Activation of Volume Regulated Chloride Channels Protects Myocardium from Ischemia/reperfusion Damage in Second-window Ischemic Preconditioning

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