المؤلفون: Dimitris Chaniotis, Ioanna Kostavasili, Pavlos Rigas, Nikolaos C. Athanasiadis, Manolis Mavroidis, Irini Skaliora, Wouter P. te Rijdt, Nikolaos Kavantzas, Constantinos H. Davos, J. Peter van Tintelen, Ismini Kloukina

المصدر: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 319(3), H557-H570. AMER PHYSIOLOGICAL SOC

مصطلحات موضوعية: Male, CARDIAC SODIUM-CHANNEL, Potassium Channels, Sympathetic Nervous System, Time Factors, Physiology, Cardiomyopathy, Action Potentials, CARDIOMYOCYTES, Calcium Channels, T-Type, Heart Rate, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, desmosomes, Myocyte, HETEROGENEITY, Sinoatrial Node, Mice, Knockout, HEART-RATE-VARIABILITY, biology, Chemistry, heart rate variability, cytoskeleton, JUNCTIONS, arrhythmogenic cardiomyopathy, Diastolic depolarization, animal models, medicine.anatomical_structure, CONDUCTION SYSTEM, Cardiology, Female, INTERCALATED DISK, Electrical conduction system of the heart, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, Mice, 129 Strain, desmin, ORGANIZATION, Biological Clocks, Physiology (medical), Internal medicine, medicine, Animals, Humans, electron micmscopy, CARDIOMYOPATHY, Desmoplakin, Sinoatrial node, Arrhythmias, Cardiac, medicine.disease, Autonomic nervous system, CELLS, biology.protein, intercalated disks, Desmin

الوصف: Our objective was to investigate the effect of desmin depletion on the structure and function of the sinoatrial pacemaker complex (SANcl) and its implication in arrhythmogenesis. Analysis of mice and humans (SANcl) indicated that the sinoatrial node exhibits high amounts of desmin, desmoplakin, N-cadherin, and β-catenin in structures we call "lateral intercalated disks" connecting myocytes side by side. Examination of the SANcl from an arrhythmogenic cardiomyopathy model, desmin-deficient (Des-/-) mouse, by immunofluorescence, ultrastructural, and Western blot analysis showed that the number of these lateral intercalated disks was diminished. Also, electrophysiological recordings of the isolated compact sinoatrial node revealed increased pacemaker systolic potential and higher diastolic depolarization rate compared with wild-type mice. Prolonged interatrial conduction expressed as a longer P wave duration was also observed in Des-/- mice. Upregulation of mRNA levels of both T-type Ca2+ current channels, Cav3.1 and Cav3.2, in the Des-/- myocardium (1.8- and 2.3-fold, respectively) and a 1.9-fold reduction of funny hyperpolarization-activated cyclic nucleotide-gated K+ channel 1 could underlie these functional differences. To investigate arrhythmogenicity, electrocardiographic analysis of Des-deficient mice revealed a major increase in supraventricular and ventricular ectopic beats compared with wild-type mice. Heart rate variability analysis indicated a sympathetic predominance in Des-/- mice, which may further contribute to arrhythmogenicity. In conclusion, our results indicate that desmin elimination leads to structural and functional abnormalities of the SANcl. These alterations may be enhanced by the sympathetic component of the cardiac autonomic nervous system, which is predominant in the desmin-deficient heart, thus leading to increased arrhythmogenesis.NEW & NOTEWORTHY The sinoatrial node exhibits high amounts of desmin and desmoplakin in structures we call "lateral intercalated disks," connecting side-by-side adjacent cardiomyocytes. These structures are diminished in desmin-deficient mouse models. Misregulation of T-type Ca2+ current and hyperpolarization-activated cyclic nucleotide-gated K+ channel 1 was proved along with prolonged interatrial conduction and cardiac autonomic nervous system dysfunction.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::379ed4c37eaf828eb50b9581401b2439Test
https://doi.org/10.1152/ajpheart.00594.2019Test

المؤلفون: Jian Xu, Yuannyu Zhang, Zhao V. Wang, Guanqiao Ding, Yuan Wang, Herman I. May, Thomas G. Gillette, Hang Wang

المصدر: American Journal of Physiology-Heart and Circulatory Physiology. 313:H1119-H1129

مصطلحات موضوعية: Male, 0301 basic medicine, medicine.medical_specialty, Time Factors, Physiology, Muscle Proteins, Aorta, Thoracic, Cardiomegaly, Biology, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, Physiology (medical), Internal medicine, medicine, Animals, Myocyte, Arterial Pressure, Myocytes, Cardiac, Cells, Cultured, Cell Proliferation, Pressure overload, Dynamics (mechanics), Cardiac myocyte, Constriction, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Animals, Newborn, Gene Expression Regulation, chemistry, Puromycin, Protein Biosynthesis, cardiovascular system, Cardiology, Cardiology and Cardiovascular Medicine, Research Article

الوصف: Hypertension is one of the most important risk factors of heart failure. In response to high blood pressure, the left ventricle manifests hypertrophic growth to ameliorate wall stress, which may progress into decompensation and trigger pathological cardiac remodeling. Despite the clinical importance, the temporal dynamics of pathological cardiac growth remain elusive. Here, we took advantage of the puromycin labeling approach to measure the relative rates of protein synthesis as a way to delineate the temporal regulation of cardiac hypertrophic growth. We first identified the optimal treatment conditions for puromycin in neonatal rat ventricular myocyte culture. We went on to demonstrate that myocyte growth reached its peak rate after 8–10 h of growth stimulation. At the in vivo level, with the use of an acute surgical model of pressure-overload stress, we observed the maximal growth rate to occur at day 7 after surgery. Moreover, RNA sequencing analysis supports that the most profound transcriptomic changes occur during the early phase of hypertrophic growth. Our results therefore suggest that cardiac myocytes mount an immediate growth response in reply to pressure overload followed by a gradual return to basal levels of protein synthesis, highlighting the temporal dynamics of pathological cardiac hypertrophic growth. NEW & NOTEWORTHY We determined the optimal conditions of puromycin incorporation in cardiac myocyte culture. We took advantage of this approach to identify the growth dynamics of cardiac myocytes in vitro. We went further to discover the protein synthesis rate in vivo, which provides novel insights about cardiac temporal growth dynamics in response to pressure overload.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e2c0d69a7436dbf1cd8f68f2130778efTest
https://doi.org/10.1152/ajpheart.00284.2017Test

المؤلفون: Patsy R. Thrasher, Krishna Singh, Suman Dalal, Jonathan M. Peterson, Christopher R. Daniels, Mahipal Singh, Stephanie L. C. Scofield, Kristina A. Lim

المصدر: American Journal of Physiology-Heart and Circulatory Physiology. 316:H617-H628

مصطلحات موضوعية: Male, Physiology, Ischemia, Myocardial Reperfusion Injury, Inflammation, Stimulation, Pharmacology, Mice, Ubiquitin, Physiology (medical), medicine, Extracellular, Animals, Myocyte, Receptor, Ventricular Remodeling, biology, business.industry, Body Weight, Heart, Stroke Volume, Editorial Focus, Organ Size, medicine.disease, Mice, Inbred C57BL, Matrix Metalloproteinase 9, Neutrophil Infiltration, biology.protein, Cytokines, Matrix Metalloproteinase 2, Chemokines, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Reperfusion injury

الوصف: β-Adrenergic receptor (β-AR) stimulation increases extracellular levels of ubiquitin (UB) in myocytes, and exogenous UB decreases β-AR-stimulated myocyte apoptosis and myocardial fibrosis. Here, we hypothesized that exogenous UB modulates the inflammatory response, thereby playing a protective role in cardiac remodeling after ischemia-reperfusion (I/R) injury. C57BL/6 mice infused with vehicle or UB (1 μg·g−1·h−1) were subjected to myocardial I/R injury. Functional and biochemical parameters of the heart were examined 3 days post-I/R. Heart weight-to-body weight ratios were similarly increased in I/R and UB + I/R groups. The area at risk and infarct size were significantly lower in UB + I/R versus I/R groups. Measurement of heart function using echocardiography revealed that I/R decreases percent fractional shortening and percent ejection fraction. However, the decrease in fractional shortening and ejection fraction was significantly lower in the UB + I/R group. The UB + I/R group displayed a significant decrease in inflammatory infiltrates, neutrophils, and macrophages versus the I/R group. Neutrophil activity was significantly lower in the UB + I/R group. Analysis of the concentration of a panel of 23 cytokines/chemokines in the serum using a Bio-Plex assay revealed a significantly lower concentration of IL-12 subunit p40 in the UB + I/R versus I/R group. The concentration of monocyte chemotactic protein-1 was lower, whereas the concentration of macrophage inflammatory protein-1α was significantly higher, in the UB+I/R group versus the sham group. Expression of matrix metalloproteinase (MMP)-2 and activity of MMP-9 were higher in the UB + I/R group versus the I/R group. Levels of ubiquitinated proteins and tissue inhibitor of metalloproteinase 2 expression were increased to a similar extent in both I/R groups. Thus, exogenous UB plays a protective role in myocardial remodeling post-I/R with effects on cardiac function, area at risk/infarct size, the inflammatory response, levels of serum cytokines/chemokines, and MMP expression and activity.NEW & NOTEWORTHY Stimulation of β-adrenergic receptors increases extracellular levels of ubiquitin (UB) in myocytes, and exogenous UB decreases β-adrenergic receptor-stimulated myocyte apoptosis and myocardial fibrosis. Here, we provide evidence that exogenous UB decreases the inflammatory response and preserves heart function 3 days after myocardial ischemia-reperfusion injury. Further identification of the molecular events involved in the anti-inflammatory role of exogenous UB may provide therapeutic targets for patients with ischemic heart disease.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::af8249b9e6eaa9c7680761e7c0b6224aTest
https://doi.org/10.1152/ajpheart.00654.2018Test

المؤلفون: Keerat Kaur, Piero Anversa, Polina Goichberg, Leonard M. Eisenberg, Khaled Qanud, John G. Edwards, Giulia Borghetti, Annarosa Leri, Alejandro Andrade-Vicenty, Carol A. Eisenberg, Marcello Rota, Mriganka Nerkar, Andrea Sorrentino, Sergio Signore, Thomas H. Hintze, Dong Sun, Jason T. Jacobson

المصدر: American Journal of Physiology-Heart and Circulatory Physiology. 314:H68-H81

مصطلحات موضوعية: Male, 0301 basic medicine, medicine.medical_specialty, Physiology, Notch signaling pathway, Mice, Transgenic, Biology, Membrane Potentials, 03 medical and health sciences, Physiology (medical), Internal medicine, medicine, Animals, Myocyte, Myocytes, Cardiac, Receptor, Notch1, Cells, Cultured, Sodium, Kv Channel-Interacting Proteins, Cell biology, Mice, Inbred C57BL, Kinetics, Electrophysiology, 030104 developmental biology, Endocrinology, Potassium Channels, Voltage-Gated, Potassium, Female, Cardiology and Cardiovascular Medicine, Transduction (physiology), Signal Transduction, Research Article

الوصف: Notch receptor signaling is active during cardiac development and silenced in myocytes after birth. Conversely, outward K+Kv currents progressively appear in postnatal myocytes leading to shortening of the action potential (AP) and acquisition of the mature electrical phenotype. In the present study, we tested the possibility that Notch signaling modulates the electrical behavior of cardiomyocytes by interfering with Kv currents. For this purpose, the effects of Notch receptor activity on electrophysiological properties of myocytes were evaluated using transgenic mice with inducible expression of the Notch1 intracellular domain (NICD), the functional fragment of the activated Notch receptor, and in neonatal myocytes after inhibition of the Notch transduction pathway. By patch clamp, NICD-overexpressing cells presented prolonged AP duration and reduced upstroke amplitude, properties that were coupled with reduced rapidly activating Kv and fast Na+currents, compared with cells obtained from wild-type mice. In cultured neonatal myocytes, inhibition of the proteolitic release of NICD with a γ-secretase antagonist increased transcript levels of the Kv channel-interacting proteins 2 (KChIP2) and enhanced the density of Kv currents. Collectively, these results indicate that Notch signaling represents an important regulator of the electrophysiological behavior of developing and adult myocytes by repressing, at least in part, repolarizing Kv currents.NEW & NOTEWORTHY We investigated the effects of Notch receptor signaling on the electrical properties of cardiomyocytes. Our results indicate that the Notch transduction pathway interferes with outward K+Kv currents, critical determinants of the electrical repolarization of myocytes.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c126235a3ae41f765dae520884bff105Test
https://doi.org/10.1152/ajpheart.00587.2016Test

المؤلفون: Daniel E. Michele, Anoop Gopal, Marc Witcher, Matthew D. Campbell

المصدر: American Journal of Physiology-Heart and Circulatory Physiology. 310:H1140-H1150

مصطلحات موضوعية: Cardiomyopathy, Dilated, musculoskeletal diseases, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Cell Membrane Permeability, Glycosylation, Physiology, Mutant, 030105 genetics & heredity, Biology, Transfection, medicine.disease_cause, Mechanotransduction, Cellular, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, Sarcoglycans, Physiology (medical), Internal medicine, medicine, Animals, Humans, Myocyte, Genetic Predisposition to Disease, Myocytes, Cardiac, Cells, Cultured, Genes, Dominant, Mutation, Cell Membrane, Cardiac myocyte, Dilated cardiomyopathy, musculoskeletal system, medicine.disease, Myocardial Contraction, Cell biology, Protein Transport, Sarcoglycan, Phenotype, Endocrinology, chemistry, Call for Papers, Stress, Mechanical, Cardiology and Cardiovascular Medicine, Protein Processing, Post-Translational, Limb-girdle muscular dystrophy

الوصف: Delta-sarcoglycan is a component of the sarcoglycan subcomplex within the dystrophin-glycoprotein complex located at the plasma membrane of muscle cells. While recessive mutations in δ-sarcoglycan cause limb girdle muscular dystrophy 2F, dominant mutations in δ-sarcoglycan have been linked to inherited dilated cardiomyopathy (DCM). The purpose of this study was to investigate functional cellular defects present in adult cardiac myocytes expressing mutant δ-sarcoglycans harboring the dominant inherited DCM mutations R71T or R97Q. This study demonstrates that DCM mutant δ-sarcoglycans can be stably expressed in adult rat cardiac myocytes and traffic similarly to wild-type δ-sarcoglycan to the plasma membrane, without perturbing assembly of the dystrophin-glycoprotein complex. However, expression of DCM mutant δ-sarcoglycan in adult rat cardiac myocytes is sufficient to alter cardiac myocyte plasma membrane stability in the presence of mechanical strain. Upon cyclical cell stretching, cardiac myocytes expressing mutant δ-sarcoglycan R97Q or R71T have increased cell-impermeant dye uptake and undergo contractures at greater frequencies than myocytes expressing normal δ-sarcoglycan. Additionally, the R71T mutation creates an ectopic N-linked glycosylation site that results in aberrant glycosylation of the extracellular domain of δ-sarcoglycan. Therefore, appropriate glycosylation of δ-sarcoglycan may also be necessary for proper δ-sarcoglycan function and overall dystrophin-glycoprotein complex function. These studies demonstrate that DCM mutations in δ-sarcoglycan can exert a dominant negative effect on dystrophin-glycoprotein complex function leading to myocardial mechanical instability that may underlie the pathogenesis of δ-sarcoglycan-associated DCM.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/dilated-cardiomyopathy-delta-sarcoglycan-mutations-cause-cardiomyocyte-membrane-instabilityTest/ .

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4eb48c2edf1034e2def2b31358625978Test
https://doi.org/10.1152/ajpheart.00521.2015Test

المؤلفون: Pramod Sahadevan, Jean-Claude Tardif, Dharmendra Dingar, Bahira Hussein, Fatiha Sahmi, Sherin Ali Nawaito, Matthias Gaestel, Marc-Antoine Gillis, Bruce G. Allen, Yanfen Shi

المصدر: American Journal of Physiology-Heart and Circulatory Physiology. 313:H46-H58

مصطلحات موضوعية: Male, 0301 basic medicine, Cardiac function curve, medicine.medical_specialty, Physiology, p38 mitogen-activated protein kinases, Protein Serine-Threonine Kinases, Biology, Muscle hypertrophy, Mice, Ventricular Dysfunction, Left, 03 medical and health sciences, Physiology (medical), Internal medicine, medicine, Animals, Myocyte, Fibroblast, Protein kinase A, Ventricular remodeling, Mice, Knockout, Pressure overload, Ventricular Remodeling, Intracellular Signaling Peptides and Proteins, Stroke Volume, medicine.disease, Myocardial Contraction, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Haplotypes, Hypertrophy, Left Ventricular, Cardiology and Cardiovascular Medicine

الوصف: MAPK-activated protein kinase-5 (MK5) is a protein serine/threonine kinase that is activated by p38 MAPK and the atypical MAPKs ERK3 and ERK4. The physiological function(s) of MK5 remains unknown. Here, we examined the effect of MK5 haplodeficiency on cardiac function and myocardial remodeling. At 12 wk of age, MK5 haplodeficient mice (MK5+/−) were smaller than age-matched wild-type littermates (MK5+/+), with similar diastolic function but reduced systolic function. Transverse aortic constriction (TAC) was used to induce chronic pressure overload in 12-wk-old male MK5+/− and MK5+/+ mice. Two weeks post-TAC, heart weight-to-tibia length ratios were similarly increased in MK5+/− and MK5+/+ hearts, as was the abundance of B-type natriuretic peptide and β-myosin heavy chain mRNA. Left ventricular ejection fraction was reduced in both MK5+/+ and MK5+/− mice, whereas regional peak systolic tissue velocities were reduced and isovolumetric relaxation time was prolonged in MK5+/+ hearts but not in MK5+/− hearts. The TAC-induced increase in collagen type 1-α1 mRNA observed in MK5+/+ hearts was markedly attenuated in MK5+/− hearts. Eight weeks post-TAC, systolic function was equally impaired in MK5+/+ and MK5+/− mice. In contrast, the increase in E wave deceleration rate and progression of hypertrophy observed in TAC MK5+/+ mice were attenuated in TAC MK5+/− mice. MK5 immunoreactivity was detected in adult fibroblasts but not in myocytes. MK5+/+, MK5+/−, and MK5−/− fibroblasts all expressed α-smooth muscle actin in culture. Hence, reduced MK5 expression in cardiac fibroblasts was associated with the attenuation of both hypertrophy and development of a restrictive filling pattern during myocardial remodeling in response to chronic pressure overload. NEW & NOTEWORTHY MAPK-activated protein kinase-5 (MK5)/p38-regulated/activated protein kinase is a protein serine/threonine kinase activated by p38 MAPK and/or the atypical MAPKs ERK3 and ERK4. MK5 immunoreactivity was detected in adult ventricular fibroblasts but not in myocytes. MK5 haplodeficiency attenuated the progression of hypertrophy, reduced collagen type 1 mRNA, and protected diastolic function in response to chronic pressure overload.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3b0051fd695a54c0ff86c8539491cbb1Test
https://doi.org/10.1152/ajpheart.00597.2016Test

المؤلفون: Leanne Groban, Sarfaraz Ahmad, Louis J. Dell'Italia, Carlos M. Ferrario, Michael Bader, Yan Jiao, Jasmina Varagic, Jessica L VonCannon

المصدر: American Journal of Physiology-Heart and Circulatory Physiology. 310:H995-H1002

مصطلحات موضوعية: Male, 0301 basic medicine, medicine.medical_specialty, Time Factors, Genotype, Physiology, Angiotensinogen, Cardiomegaly, 030204 cardiovascular system & hematology, Biology, Immunofluorescence, Ventricular Function, Left, Rats, Sprague-Dawley, Renin-Angiotensin System, 03 medical and health sciences, Integrative Cardiovascular Physiology and Pathophysiology, 0302 clinical medicine, Heart Rate, Physiology (medical), Internal medicine, Heart rate, Renin–angiotensin system, medicine, Animals, Humans, Myocyte, Arterial Pressure, Ultrasonography, chemistry.chemical_classification, medicine.diagnostic_test, Hydrolysis, Myocardium, Homozygote, Chymase, Angiotensin II, Peptide Fragments, Disease Models, Animal, Phenotype, 030104 developmental biology, Blood pressure, Enzyme, Endocrinology, chemistry, Hypertension, cardiovascular system, Rats, Transgenic, Cardiology and Cardiovascular Medicine, hormones, hormone substitutes, and hormone antagonists

الوصف: Angiotensin-(1–12) [ANG-(1–12)] is processed into ANG II by chymase in rodent and human heart tissue. Differences in the amino acid sequence of rat and human ANG-(1–12) render the human angiotensinogen (hAGT) protein refractory to cleavage by renin. We used transgenic rats harboring the hAGT gene [TGR(hAGT)L1623] to assess the non-renin-dependent effects of increased hAGT expression on heart function and arterial pressure. Compared with Sprague-Dawley (SD) control rats ( n = 11), male homozygous TGR(hAGT)L1623 ( n = 9) demonstrated sustained daytime and nighttime hypertension associated with no changes in heart rate but increased heart rate lability. Increased heart weight/tibial length ratio and echocardiographic indexes of cardiac hypertrophy were associated with modest reduction of systolic function in hAGT rats. Robust human ANG-(1–12) immunofluorescence within myocytes of TGR(hAGT)L1623 rats was associated with a fourfold increase in cardiac ANG II content. Chymase enzymatic activity, using the rat or human ANG-(1–12) as a substrate, was not different in the cardiac tissue of SD and hAGT rats. Since both cardiac angiotensin-converting enzyme (ACE) and ACE2 activities were not different among the two strains, the changes in cardiac structure and function, blood pressure, and left ventricular ANG II content might be a product of an increased cardiac expression of ANG II generated through a non-renin-dependent mechanism. The data also underscore the existence in the rat of alternate enzymes capable of acting on hAGT protein. Homozygous transgenic rats expressing the hAGT gene represent a novel tool to investigate the contribution of human relevant renin-independent cardiac ANG II formation and function.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::36748134eb47b14ca726dbc3630490e7Test
https://doi.org/10.1152/ajpheart.00833.2015Test

المؤلفون: David A. D'Alessandro, Marco Luciani, Thomas H. Hintze, Giulia Borghetti, Ewa Wybieralska, Edward G. Barrett, Khaled Qanud, Maria Cimini, Christopher Royer, Polina Goichberg, Alex Matsuda, Elizabeth Kertowidjojo, Eric Zhang, Yu Zhou, Andrea Sorrentino, Ramaswamy Kannappan, Piero Anversa, Antonio Cannatà, Andrew Webster, Annarosa Leri, Marianna Meo, Oriyanhan Wunimenghe, Marcello Rota, Sergio Signore, Robert E. Michler

المساهمون: Sorrentino A, Signore S, Qanud K, Borghetti G, Meo M, Cannata A, Zhou Y, Wybieralska E, Luciani M, Kannappan R, Zhang E, Matsuda A, Webster A, Cimini M, Kertowidjojo E, D'Alessandro DA, Wunimenghe O, Michler RE, Royer C, Goichberg P, Leri A, Barrett EG, Anversa P, Hintze TH, Rota M

المصدر: American Journal of Physiology-Heart and Circulatory Physiology. 310:H873-H890

مصطلحات موضوعية: Male, 0301 basic medicine, Inotrope, Aging, medicine.medical_specialty, Physiology, Population, Action Potentials, Hemodynamics, 030204 cardiovascular system & hematology, Biology, 03 medical and health sciences, Dogs, 0302 clinical medicine, Ventricular hypertrophy, contractile reserve, Physiology (medical), Internal medicine, myocardium, medicine, Animals, Ventricular Function, Myocyte, Repolarization, Myocytes, Cardiac, Decompensation, Myopathy, education, education.field_of_study, medicine.disease, 030104 developmental biology, Endocrinology, Cardiology, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, Muscle Mechanics and Ventricular Function

الوصف: Studies of myocardial aging are complex and the mechanisms involved in the deterioration of ventricular performance and decreased functional reserve of the old heart remain to be properly defined. We have studied a colony of beagle dogs from 3 to 14 yr of age kept under a highly regulated environment to define the effects of aging on the myocardium. Ventricular, myocardial, and myocyte function, together with anatomical and structural properties of the organ and cardiomyocytes, were evaluated. Ventricular hypertrophy was not observed with aging and the structural composition of the myocardium was modestly affected. Alterations in the myocyte compartment were identified in aged dogs, and these factors negatively interfere with the contractile reserve typical of the young heart. The duration of the action potential is prolonged in old cardiomyocytes contributing to the slower electrical recovery of the myocardium. Also, the remodeled repolarization of cardiomyocytes with aging provides inotropic support to the senescent muscle but compromises its contractile reserve, rendering the old heart ineffective under conditions of high hemodynamic demand. The defects in the electrical and mechanical properties of cardiomyocytes with aging suggest that this cell population is an important determinant of the cardiac senescent phenotype. Collectively, the delayed electrical repolarization of aging cardiomyocytes may be viewed as a critical variable of the aging myopathy and its propensity to evolve into ventricular decompensation under stressful conditions.

وصف الملف: ELETTRONICO

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::35cefadb970508693c7e55afc07273b5Test
https://doi.org/10.1152/ajpheart.00682.2015Test

المؤلفون: Shuai-ye Liu, Jie Liu, Jianxin Deng, Wenjuan Liu, Gang Wang, Kai-ping Gao, Ze-xun Lin, Yong-hui Wang

المصدر: American Journal of Physiology-Heart and Circulatory Physiology. 309:H1288-H1302

مصطلحات موضوعية: medicine.medical_specialty, Physiology, Heart Ventricles, Genetic Vectors, Action Potentials, Gating, Biology, Transfection, Adenoviridae, Rats, Sprague-Dawley, Physiology (medical), Internal medicine, medicine, Gene Knockdown Techniques, Animals, Myocyte, Myocytes, Cardiac, Cells, Cultured, Regulation of gene expression, Gene knockdown, Cardiac transient outward potassium current, Age Factors, KCNE2, Mice, Inbred C57BL, Kinetics, Endocrinology, Animals, Newborn, Gene Expression Regulation, Potassium Channels, Voltage-Gated, Potassium, cardiovascular system, biology.protein, RNA Interference, Heterologous expression, Cardiology and Cardiovascular Medicine, Ion Channel Gating

الوصف: In heterologous expression systems, KCNE2 has been demonstrated to interact with multiple α-subunits of voltage-dependent cation channels and modulate their functions. However, the physiological and pathological roles of KCNE2 in cardiomyocytes are poorly understood. The present study aimed to investigate the effects of bidirectional modulation of KCNE2 expression on action potential (AP) duration (APD) and voltage-dependent K+ channels in cardiomyocytes. Adenoviral gene delivery and RNA interference were used to either increase or decrease KCNE2 expression in cultured neonatal and adult rat or neonatal mouse ventricular myocytes. Knockdown of KCNE2 prolonged APD in both neonatal and adult myocytes, whereas overexpression of KCNE2 shortened APD in neonatal but not adult myocytes. Consistent with the alterations in APD, KCNE2 knockdown decreased transient outward K+ current ( Ito) densities in neonatal and adult myocytes, whereas KCNE2 overexpression increased Ito densities in neonatal but not adult myocytes. Furthermore, KCNE2 knockdown accelerated the rates of Ito activation and inactivation, whereas KCNE2 overexpression slowed Ito gating kinetics in neonatal but not adult myocytes. Delayed rectifier K+ current densities were remarkably affected by manipulation of KCNE2 expression in mouse but not rat cardiomyocytes. Simulation of the AP of a rat ventricular myocyte with a mathematical model showed that alterations in Ito densities and gating properties can result in similar APD alterations in KCNE2 overexpression and knockdown cells. In conclusion, endogenous KCNE2 in cardiomyocytes is important in maintaining cardiac electrical stability mainly by regulating Ito and APD. Perturbation of KCNE2 expression may predispose the heart to ventricular arrhythmia by prolonging APD.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::eb26552778c9f0829adda90175427df8Test
https://doi.org/10.1152/ajpheart.00757.2014Test

المؤلفون: Guohua Gong, Xiaoyun Liu, Huiliang Zhang, Shey-Shing Sheu, Wang Wang

المصدر: American Journal of Physiology-Heart and Circulatory Physiology. 309:H1166-H1177

مصطلحات موضوعية: genetic structures, Physiology, Cellular respiration, Cell Respiration, Mice, Transgenic, Energetics and Metabolism, Biology, Mitochondrial apoptosis-induced channel, Mitochondria, Heart, Electron Transport, Mice, chemistry.chemical_compound, Bacterial Proteins, Superoxides, Physiology (medical), Animals, Myocyte, Myocytes, Cardiac, Cells, Cultured, chemistry.chemical_classification, Reactive oxygen species, Electron Transport Complex I, Microscopy, Confocal, Superoxide, Electron transport chain, Rats, Cell biology, Luminescent Proteins, Proton-Translocating ATPases, chemistry, Biomarker (medicine), sense organs, Reactive Oxygen Species, Cardiology and Cardiovascular Medicine, Biomarkers

الوصف: Mitochondrial respiration through electron transport chain (ETC) activity generates ATP and reactive oxygen species in eukaryotic cells. The modulation of mitochondrial respiration in vivo or under physiological conditions remains elusive largely due to the lack of appropriate approach to monitor ETC activity in a real-time manner. Here, we show that ETC-coupled mitochondrial flash is a novel biomarker for monitoring mitochondrial respiration under pathophysiological conditions in cultured adult cardiac myocyte and perfused beating heart. Through real-time confocal imaging, we follow the frequency of a transient bursting fluorescent signal, named mitochondrial flash, from individual mitochondria within intact cells expressing a mitochondrial matrix-targeted probe, mt-cpYFP (mitochondrial-circularly permuted yellow fluorescent protein). This mt-cpYFP recorded mitochondrial flash has been shown to be composed of a major superoxide signal with a minor alkalization signal within the mitochondrial matrix. Through manipulating physiological substrates for mitochondrial respiration, we find a close coupling between flash frequency and the ETC electron flow, as measured by oxygen consumption rate in cardiac myocyte. Stimulating electron flow under physiological conditions increases flash frequency. On the other hand, partially block or slowdown electron flow by inhibiting the F0F1ATPase, which represents a pathological condition, transiently increases then decreases flash frequency. Limiting electron entrance at complex I by knocking out Ndufs4, an assembling subunit of complex I, suppresses mitochondrial flash activity. These results suggest that mitochondrial electron flow can be monitored by real-time imaging of mitochondrial flash. The mitochondrial flash frequency could be used as a novel biomarker for mitochondrial respiration under physiological and pathological conditions.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fa7e32fc2de5c0f56c66e89488c45243Test
https://doi.org/10.1152/ajpheart.00462.2015Test