Quantitative tests reveal that microtubules tune the healthy heart but underlie arrhythmias in pathology

Joca, Humberto C.; Coleman, Andrew; Ward, Chris W.; Williams, George S.B.

doi:10.1113/jp277083

Cited by 8 publications

(8 citation statements)

References 44 publications

(118 reference statements)

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“…Growing evidence indicates that the MT cytoskeleton plays an essential role in the development of DMD cardiomyopathy. The dense and disorganized MT network (58) in mdx cardiomyocytes correlates strongly with enhanced ROS production and Ca 2+ mishandling (59)(60)(61)(62). Targeting the MT network protects mdx mice against stress-induced arrhythmias (35).…”

Section: Resultsmentioning

confidence: 99%

“…However, we must point out that Taxol treatment also increases levels of detyrosinated tubulin, which is detrimental when enhanced in DMD and other cardiac disorders (58,59,87). Therefore, further stabilization of dystrophic MTs will not only exacerbate the DMD phenotype through previously defined mechanisms, such as impaired contractility (35), increased ROS production (62), and aberrant Ca 2+ signaling (61), but may also enhance Cx43 mislocalization.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Prevention of connexin-43 remodeling protects against Duchenne muscular dystrophy cardiomyopathy

Himelman¹,

Lillo²,

Nouet³

et al. 2020

Journal of Clinical Investigation

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prevention of connexin-43 remodeling protects against Duchenne muscular dystrophy cardiomyopathy

Himelman¹,

Lillo²,

Nouet³

et al. 2020

Journal of Clinical Investigation

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“…ECC gain is calculated by dividing the integrated RyR2 flux by the integrated LCC flux. See our previous publication for more details 14,17 . For ARDKO simulations, parameters were modified according to Table S9.…”

Section: Methodsmentioning

confidence: 99%

Chronic Sympathetic Hyperactivity Triggers Electrophysiological Remodeling and Disrupts Excitation-Contraction Coupling in Heart

Joca

Santos‐Miranda

Joviano‐Santos

et al. 2020

Sci Rep

Self Cite

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the sympathetic nervous system is essential for maintenance of cardiac function via activation of postjunctional adrenergic receptors. Prolonged adrenergic receptor activation, however, has deleterious long-term effects leading to hypertrophy and the development of heart failure. Here we investigate the effect of chronic adrenergic receptors activation on excitation-contraction coupling (ECC) in ventricular cardiomyocytes from a previously characterized mouse model of chronic sympathetic hyperactivity, which are genetically deficient in the adrenoceptor α2A and α2C genes (ARDKO). When compared to wild-type (WT) cardiomyocytes, ARDKO displayed reduced fractional shortening (~33%) and slower relaxation (~20%). Furthermore, ARDKO cells exhibited several electrophysiological changes such as action potential (AP) prolongation (~50%), reduced L-type calcium channel (LCC) current (~33%), reduced outward potassium (K +) currents (~30%), and increased sodium/calcium exchanger (NCX) activity (~52%). Consistent with reduced contractility and calcium (Ca 2+) currents, the cytosolic Ca 2+ ([Ca 2+ ] i) transient from ARDKO animals was smaller and decayed slower. Importantly, no changes were observed in membrane resting potential, AP amplitude, or the inward K + current. Finally, we modified our existing cardiac ECC computational model to account for changes in the ARDKO heart. Simulations suggest that cellular changes in the ARDKO heart resulted in variable and dyssynchronous Ca 2+-induced ca 2+ release therefore altering [Ca 2+ ] i transient dynamics and reducing force generation. In conclusion, chronic sympathetic hyperactivity impairs ECC by changing the density of several ionic currents (and thus AP repolarization) causing altered Ca 2+ dynamics and contractile activity. this demonstrates the important role of ecc remodeling in the cardiac dysfunction secondary to chronic sympathetic activity. Activation of the sympathetic nervous system (SNS) exerts several effects on the cardiovascular system. These include accelerating heart rate, increasing cardiac contractility, reducing venous capacity, and promoting vasoconstriction of resistance arteries 1. Coordination of sympathetic activity through cardiovascular reflexes enables accurate, short and long term control of blood flow and pressure 2. Furthermore, a physiological increase in sympathetic activity is a determinant for cardiovascular responsiveness to exercise or other stress stimuli (e.g., fight-or-flight response). In the heart, SNS effects are mainly through stimulation of β-adrenergic receptors (β-AR) 3. The decline in the cardiac contractile capacity after an acute myocardial infarction or chronic pressure overload 4 triggers the activation of compensatory mechanisms such as renin-angiotensin-aldosterone system (RAAS), the cytokine system, and the SNS 5. Regarding SNS, continuous or excessive stimulation of β-AR in the

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“…The enhancement of the increase in Ca 2+ sparks and ROS with stretch in ischemia may result from effects on various factors involved in the stretch-induced response (Ward et al, 2014;Joca et al, 2020). Ischemia may increase the mechano-sensitivity or responsiveness of NOX2, and mechano-transduction may be increased due to changes in microtubule properties, cell stiffness, or mechano-sensitive channel function (including transient receptor potential channels), resulting in greater X-ROS production with stretch.…”

Section: Mechanisms Of Enhanced Stretch Effects In Ischemic Conditionsmentioning

confidence: 99%

Ischemia Enhances the Acute Stretch-Induced Increase in Calcium Spark Rate in Ventricular Myocytes

et al. 2020

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In ventricular myocytes, spontaneous release of calcium (Ca 2+) from the sarcoplasmic reticulum via ryanodine receptors ("Ca 2+ sparks") is acutely increased by stretch, due to a stretch-induced increase of reactive oxygen species (ROS). In acute regional ischemia there is stretch of ischemic tissue, along with an increase in Ca 2+ spark rate and ROS production, each of which has been implicated in arrhythmogenesis. Yet, whether there is an impact of ischemia on the stretch-induced increase in Ca 2+ sparks and ROS has not been investigated. We hypothesized that ischemia would enhance the increase of Ca 2+ sparks and ROS that occurs with stretch. Methods: Isolated ventricular myocytes from mice (male, C57BL/6J) were loaded with fluorescent dye to detect Ca 2+ sparks (4.6 µM Fluo-4, 10 min) or ROS (1 µM DCF, 20 min), exposed to normal Tyrode (NT) or simulated ischemia (SI) solution (hyperkalemia [15 mM potassium], acidosis [6.5 pH], and metabolic inhibition [1 mM sodium cyanide, 20 mM 2-deoxyglucose]), and subjected to sustained stretch by the carbon fiber technique (∼10% increase in sarcomere length, 15 s). Ca 2+ spark rate and rate of ROS production were measured by confocal microscopy. Results: Baseline Ca 2+ spark rate was greater in SI (2.54 ± 0.11 sparks•s −1 •100 µm −2 ; n = 103 cells, N = 10 mice) than NT (0.29 ± 0.05 sparks•s −1 •100 µm −2 ; n = 33 cells, N = 9 mice; p < 0.0001). Stretch resulted in an acute increase in Ca 2+ spark rate in both SI (3.03 ± 0.13 sparks•s −1 •100 µm −2 ; p < 0.0001) and NT (0.49 ± 0.07 sparks•s −1 •100 µm −2 ; p < 0.0001), with the increase in SI being greater than NT (+0.49 ± 0.04 vs. +0.20 ± 0.04 sparks•s −1 •100 µm −2 ; p < 0.0001). Baseline rate of ROS production was also greater in SI (1.01 ± 0.01 normalized slope; n = 11, N = 8 mice) than NT (0.98 ± 0.01 normalized slope; n = 12, N = 4 mice; p < 0.05), but there was an acute increase with stretch only in SI (+12.5 ± 2.6%; p < 0.001). Conclusion: Ischemia enhances the stretch-induced increase of Ca 2+ sparks in ventricular myocytes, with an associated enhancement of stretch-induced ROS production. This effect may be important for premature excitation and/or in the development of an arrhythmogenic substrate in acute regional ischemia.

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Quantitative tests reveal that microtubules tune the healthy heart but underlie arrhythmias in pathology

Cited by 8 publications

References 44 publications

Prevention of connexin-43 remodeling protects against Duchenne muscular dystrophy cardiomyopathy

Prevention of connexin-43 remodeling protects against Duchenne muscular dystrophy cardiomyopathy

Chronic Sympathetic Hyperactivity Triggers Electrophysiological Remodeling and Disrupts Excitation-Contraction Coupling in Heart

Ischemia Enhances the Acute Stretch-Induced Increase in Calcium Spark Rate in Ventricular Myocytes

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