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Article ; Online: Sarcoplasmic reticulum-mitochondria communication; implications for cardiac arrhythmia.

Hamilton, Shanna / Terentyeva, Radmila / Clements, Richard T / Belevych, Andriy E / Terentyev, Dmitry

Journal of molecular and cellular cardiology

2021 Volume 156, Page(s) 105–113

Abstract: Sudden cardiac death due to ventricular tachyarrhythmias remains the major cause of mortality in the world. Heart failure, diabetic cardiomyopathy, old age-related cardiac dysfunction and inherited disorders are associated with enhanced propensity to ... ...

Abstract	Sudden cardiac death due to ventricular tachyarrhythmias remains the major cause of mortality in the world. Heart failure, diabetic cardiomyopathy, old age-related cardiac dysfunction and inherited disorders are associated with enhanced propensity to malignant cardiac arrhythmias. Both defective mitochondrial function and abnormal intracellular Ca
MeSH term(s)	Animals ; Arrhythmias, Cardiac/drug therapy ; Arrhythmias, Cardiac/etiology ; Arrhythmias, Cardiac/metabolism ; Arrhythmias, Cardiac/physiopathology ; Biomarkers ; Calcium/metabolism ; Calcium Signaling ; Disease Susceptibility ; Energy Metabolism ; Homeostasis ; Humans ; Mitochondria, Heart/drug effects ; Mitochondria, Heart/metabolism ; Molecular Targeted Therapy ; Oxidation-Reduction ; Sarcoplasmic Reticulum/drug effects ; Sarcoplasmic Reticulum/metabolism ; Signal Transduction/drug effects
Chemical Substances	Biomarkers ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2021-04-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2021.04.002
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Article ; Online: Maternal exercise preserves offspring cardiovascular health via oxidative regulation of the ryanodine receptor.

Pinckard, Kelsey M / Félix-Soriano, Elisa / Hamilton, Shanna / Terentyeva, Radmila / Baer, Lisa A / Wright, Katherine R / Nassal, Drew / Esteves, Joao Victor / Abay, Eaman / Shettigar, Vikram K / Ziolo, Mark T / Hund, Thomas J / Wold, Loren E / Terentyev, Dmitry / Stanford, Kristin I

Molecular metabolism

2024 Volume 82, Page(s) 101914

Abstract: Objective: The intrauterine environment during pregnancy is a critical factor in the development of obesity, diabetes, and cardiovascular disease in offspring. Maternal exercise prevents the detrimental effects of a maternal high fat diet on the ... ...

Abstract	Objective: The intrauterine environment during pregnancy is a critical factor in the development of obesity, diabetes, and cardiovascular disease in offspring. Maternal exercise prevents the detrimental effects of a maternal high fat diet on the metabolic health in adult offspring, but the effects of maternal exercise on offspring cardiovascular health have not been thoroughly investigated. Methods: To determine the effects of maternal exercise on offspring cardiovascular health, female mice were fed a chow (C; 21% kcal from fat) or high-fat (H; 60% kcal from fat) diet and further subdivided into sedentary (CS, HS) or wheel exercised (CW, HW) prior to pregnancy and throughout gestation. Offspring were maintained in a sedentary state and chow-fed throughout 52 weeks of age and subjected to serial echocardiography and cardiomyocyte isolation for functional and mechanistic studies. Results: High-fat fed sedentary dams (HS) produced female offspring with reduced ejection fraction (EF) compared to offspring from chow-fed dams (CS), but EF was preserved in offspring from high-fat fed exercised dams (HW) throughout 52 weeks of age. Cardiomyocytes from HW female offspring had increased kinetics, calcium cycling, and respiration compared to CS and HS offspring. HS offspring had increased oxidation of the RyR2 in cardiomyocytes coupled with increased baseline sarcomere length, resulting in RyR2 overactivity, which was negated in female HW offspring. Conclusions: These data suggest a role for maternal exercise to protect against the detrimental effects of a maternal high-fat diet on female offspring cardiac health. Maternal exercise improved female offspring cardiomyocyte contraction, calcium cycling, respiration, RyR2 oxidation, and RyR2 activity. These data present an important, translatable role for maternal exercise to preserve cardiac health of female offspring and provide insight on mechanisms to prevent the transmission of cardiovascular diseases to subsequent generations.
MeSH term(s)	Pregnancy ; Mice ; Female ; Animals ; Ryanodine Receptor Calcium Release Channel/metabolism ; Calcium/metabolism ; Obesity/metabolism ; Diet, High-Fat/adverse effects ; Oxidative Stress
Chemical Substances	Ryanodine Receptor Calcium Release Channel ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2024-03-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2708735-9
ISSN	2212-8778 ; 2212-8778
ISSN (online)	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2024.101914
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Article ; Online: NaV1.6 dysregulation within myocardial T-tubules by D96V calmodulin enhances proarrhythmic sodium and calcium mishandling.

Tarasov, Mikhail / Struckman, Heather L / Olgar, Yusuf / Miller, Alec / Demirtas, Mustafa / Bogdanov, Vladimir / Terentyeva, Radmila / Soltisz, Andrew M / Meng, Xiaolei / Min, Dennison / Sakuta, Galina / Dunlap, Izabella / Duran, Antonia D / Foster, Mark P / Davis, Jonathan P / Terentyev, Dmitry / Györke, Sándor / Veeraraghavan, Rengasayee / Radwański, Przemysław B

The Journal of clinical investigation

2023 Volume 133, Issue 7

Abstract: Calmodulin (CaM) plays critical roles in cardiomyocytes, regulating Na+ (NaV) and L-type Ca2+ channels (LTCCs). LTCC dysregulation by mutant CaMs has been implicated in action potential duration (APD) prolongation and arrhythmogenic long QT (LQT) ... ...

Abstract	Calmodulin (CaM) plays critical roles in cardiomyocytes, regulating Na+ (NaV) and L-type Ca2+ channels (LTCCs). LTCC dysregulation by mutant CaMs has been implicated in action potential duration (APD) prolongation and arrhythmogenic long QT (LQT) syndrome. Intriguingly, D96V-CaM prolongs APD more than other LQT-associated CaMs despite inducing comparable levels of LTCC dysfunction, suggesting dysregulation of other depolarizing channels. Here, we provide evidence implicating NaV dysregulation within transverse (T) tubules in D96V-CaM-associated arrhythmias. D96V-CaM induced a proarrhythmic late Na+ current (INa) by impairing inactivation of NaV1.6, but not the predominant cardiac NaV isoform NaV1.5. We investigated arrhythmia mechanisms using mice with cardiac-specific expression of D96V-CaM (cD96V). Super-resolution microscopy revealed close proximity of NaV1.6 and RyR2 within T-tubules. NaV1.6 density within these regions increased in cD96V relative to WT mice. Consistent with NaV1.6 dysregulation by D96V-CaM in these regions, we observed increased late NaV activity in T-tubules. The resulting late INa promoted aberrant Ca2+ release and prolonged APD in myocytes, leading to LQT and ventricular tachycardia in vivo. Cardiac-specific NaV1.6 KO protected cD96V mice from increased T-tubular late NaV activity and its arrhythmogenic consequences. In summary, we demonstrate that D96V-CaM promoted arrhythmias by dysregulating LTCCs and NaV1.6 within T-tubules and thereby facilitating aberrant Ca2+ release.
MeSH term(s)	Mice ; Animals ; Calmodulin/genetics ; Calmodulin/metabolism ; Calcium/metabolism ; Sodium/metabolism ; Arrhythmias, Cardiac/genetics ; Arrhythmias, Cardiac/metabolism ; Long QT Syndrome/genetics ; Myocytes, Cardiac/metabolism ; NAV1.5 Voltage-Gated Sodium Channel/genetics
Chemical Substances	Calmodulin ; Calcium (SY7Q814VUP) ; Sodium (9NEZ333N27) ; NAV1.5 Voltage-Gated Sodium Channel
Language	English
Publishing date	2023-04-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI152071
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Article ; Online: STIM1 ablation impairs exercise-induced physiological cardiac hypertrophy and dysregulates autophagy in mouse hearts.

Bonilla, Ingrid M / Baine, Stephen / Pokrass, Anastasia / Mariángelo, Juan Ignacio Elio / Kalyanasundaram, Anuradha / Bogdanov, Vladimir / Mezache, Louisa / Sakuta, Galina / Beard, Casey M / Belevych, Andriy / Tikunova, Svetlana / Terentyeva, Radmila / Terentyev, Dmitry / Davis, Jonathan / Veeraraghavan, Rengasayee / Carnes, Cynthia A / Györke, Sandor

Journal of applied physiology (Bethesda, Md. : 1985)

2023 Volume 134, Issue 5, Page(s) 1287–1299

Abstract: Cardiac stromal interaction molecule 1 (STIM1), a key mediator of store-operated ... ...

Abstract	Cardiac stromal interaction molecule 1 (STIM1), a key mediator of store-operated Ca
MeSH term(s)	Mice ; Animals ; Myocytes, Cardiac/metabolism ; Calcium Channels/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Stromal Interaction Molecule 1/metabolism ; Cardiomegaly/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Mice, Knockout ; Calcium/metabolism ; Calcium Signaling ; Mammals/metabolism
Chemical Substances	Calcium Channels ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Stromal Interaction Molecule 1 ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Calcium (SY7Q814VUP) ; Stim1 protein, mouse
Language	English
Publishing date	2023-03-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	219139-8
ISSN	1522-1601 ; 0021-8987 ; 0161-7567 ; 8750-7587
ISSN (online)	1522-1601
ISSN	0021-8987 ; 0161-7567 ; 8750-7587
DOI	10.1152/japplphysiol.00363.2022
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Article ; Online: Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia.

Hamilton, Shanna / Terentyeva, Radmila / Bogdanov, Vladimir / Kim, Tae Yun / Perger, Fruzsina / Yan, Jiajie / Ai, Xun / Carnes, Cynthia A / Belevych, Andriy E / George, Christopher H / Davis, Jonathan P / Gyorke, Sandor / Choi, Bum-Rak / Terentyev, Dmitry

Circulation research

2022 Volume 130, Issue 5, Page(s) 711–724

Abstract: Background: Oxidative stress in cardiac disease promotes proarrhythmic disturbances in Ca: Methods: A rat model of hypertrophy induced by thoracic aortic banding (TAB) was used for ex vivo whole heart optical mapping and for Ca: Results: The SR- ... ...

Abstract	Background: Oxidative stress in cardiac disease promotes proarrhythmic disturbances in Ca Methods: A rat model of hypertrophy induced by thoracic aortic banding (TAB) was used for ex vivo whole heart optical mapping and for Ca Results: The SR-targeted reactive oxygen species biosensor ERroGFP showed increased intra-SR oxidation in TAB VMs that was associated with increased expression of Ero1α (endoplasmic reticulum oxidoreductase 1 alpha). Pharmacological (EN460) or genetic Ero1α inhibition normalized SR redox state, increased Ca Conclusions: A novel axis of intraluminal interaction between RyR2, ERp44, and Ero1α has been identified. Ero1α inhibition exhibits promising therapeutic potential by stabilizing RyR2-ERp44 complex, thereby reducing spontaneous Ca
MeSH term(s)	Animals ; Arrhythmias, Cardiac/metabolism ; Calcium/metabolism ; Calcium Signaling ; Heart Diseases/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Isoproterenol/pharmacology ; Membrane Glycoproteins/metabolism ; Myocytes, Cardiac/metabolism ; Oxidoreductases/metabolism ; Oxidoreductases/pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; Ryanodine Receptor Calcium Release Channel/metabolism ; Sarcoplasmic Reticulum/metabolism
Chemical Substances	Ero1a protein, rat ; Erp44 protein, rat ; Intracellular Signaling Peptides and Proteins ; Membrane Glycoproteins ; Reactive Oxygen Species ; RyR2 protein, rat ; Ryanodine Receptor Calcium Release Channel ; Oxidoreductases (EC 1.-) ; Isoproterenol (L628TT009W) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2022-01-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/CIRCRESAHA.121.320531
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Article ; Online: Impact of I

Bronk, Peter / Kim, Tae Yun / Polina, Iuliia / Hamilton, Shanna / Terentyeva, Radmila / Roder, Karim / Koren, Gideon / Terentyev, Dmitry / Choi, Bum-Rak

Biophysical journal

2020 Volume 119, Issue 3, Page(s) 690–704

Abstract: Cardiac small conductance ... ...

Abstract	Cardiac small conductance Ca
MeSH term(s)	Action Potentials ; Animals ; Apamin ; Heart Ventricles ; Myocytes, Cardiac ; Rats ; Small-Conductance Calcium-Activated Potassium Channels
Chemical Substances	Small-Conductance Calcium-Activated Potassium Channels ; Apamin (24345-16-2)
Language	English
Publishing date	2020-06-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2020.06.022
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Article ; Online: Interleukin-1β, Oxidative Stress, and Abnormal Calcium Handling Mediate Diabetic Arrhythmic Risk.

Liu, Hong / Zhao, Yang / Xie, An / Kim, Tae-Yun / Terentyeva, Radmila / Liu, Man / Shi, Guangbin / Feng, Feng / Choi, Bum-Rak / Terentyev, Dmitry / Hamilton, Shanna / Dudley, Samuel C

JACC. Basic to translational science

2021 Volume 6, Issue 1, Page(s) 42–52

Abstract: Diabetes mellitus (DM) is associated with increased arrhythmia. Type 2 DM (T2DM) mice showed prolonged QT interval and increased ventricular arrhythmic inducibility, accompanied by elevated cardiac interleukin (IL)-1β, increased mitochondrial reactive ... ...

Abstract	Diabetes mellitus (DM) is associated with increased arrhythmia. Type 2 DM (T2DM) mice showed prolonged QT interval and increased ventricular arrhythmic inducibility, accompanied by elevated cardiac interleukin (IL)-1β, increased mitochondrial reactive oxygen species (mitoROS), and oxidation of the sarcoplasmic reticulum (SR) Ca
Language	English
Publishing date	2021-01-20
Publishing country	United States
Document type	Journal Article
ISSN	2452-302X
ISSN (online)	2452-302X
DOI	10.1016/j.jacbts.2020.11.002
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Article ; Online: MCU overexpression evokes disparate dose-dependent effects on mito-ROS and spontaneous Ca

Hamilton, Shanna / Terentyeva, Radmila / Perger, Fruzsina / Hernández Orengo, Benjamín / Martin, Benjamin / Gorr, Matthew W / Belevych, Andriy E / Clements, Richard T / Györke, Sandor / Terentyev, Dmitry

American journal of physiology. Heart and circulatory physiology

2021 Volume 321, Issue 4, Page(s) H615–H632

Abstract: Cardiac dysfunction in heart failure (HF) and diabetic cardiomyopathy (DCM) is associated with aberrant intracellular ... ...

Abstract	Cardiac dysfunction in heart failure (HF) and diabetic cardiomyopathy (DCM) is associated with aberrant intracellular Ca
MeSH term(s)	Adrenergic beta-Agonists/pharmacology ; Animals ; Arrhythmias, Cardiac/genetics ; Arrhythmias, Cardiac/metabolism ; Arrhythmias, Cardiac/pathology ; Arrhythmias, Cardiac/physiopathology ; Biosensing Techniques ; Calcium/metabolism ; Calcium Channels/genetics ; Calcium Channels/metabolism ; Calcium Signaling/drug effects ; Cells, Cultured ; Disease Models, Animal ; Heart Rate ; Hypertrophy, Left Ventricular/genetics ; Hypertrophy, Left Ventricular/metabolism ; Hypertrophy, Left Ventricular/pathology ; Hypertrophy, Left Ventricular/physiopathology ; Male ; Microscopy, Confocal ; Mitochondria, Heart/drug effects ; Mitochondria, Heart/genetics ; Mitochondria, Heart/metabolism ; Mitochondria, Heart/pathology ; Myocardial Contraction ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Up-Regulation ; Ventricular Function, Left ; Ventricular Remodeling ; Rats
Chemical Substances	Adrenergic beta-Agonists ; Calcium Channels ; Reactive Oxygen Species ; mitochondrial calcium uniporter ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2021-08-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603838-4
ISSN	1522-1539 ; 0363-6135
ISSN (online)	1522-1539
ISSN	0363-6135
DOI	10.1152/ajpheart.00126.2021
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Article ; Online: Pyridostigmine improves cardiac function and rhythmicity through RyR2 stabilization and inhibition of STIM1-mediated calcium entry in heart failure.

Baine, Stephen / Bonilla, Ingrid / Belevych, Andriy / Stepanov, Andrei / Dorn, Lisa E / Terentyeva, Radmila / Terentyev, Dmitry / Accornero, Federica / Carnes, Cynthia A / Gyorke, Sandor

Journal of cellular and molecular medicine

2021 Volume 25, Issue 10, Page(s) 4637–4648

Abstract: Heart failure (HF) is characterized by asymmetrical autonomic balance. Treatments to restore parasympathetic activity in human heart failure trials have shown beneficial effects. However, mechanisms of parasympathetic-mediated improvement in cardiac ... ...

Abstract	Heart failure (HF) is characterized by asymmetrical autonomic balance. Treatments to restore parasympathetic activity in human heart failure trials have shown beneficial effects. However, mechanisms of parasympathetic-mediated improvement in cardiac function remain unclear. The present study examined the effects and underpinning mechanisms of chronic treatment with the cholinesterase inhibitor, pyridostigmine (PYR), in pressure overload HF induced by transverse aortic constriction (TAC) in mice. TAC mice exhibited characteristic adverse structural (left ventricular hypertrophy) and functional remodelling (reduced ejection fraction, altered myocyte calcium (Ca) handling, increased arrhythmogenesis) with enhanced predisposition to arrhythmogenic aberrant sarcoplasmic reticulum (SR) Ca release, cardiac ryanodine receptor (RyR2) hyper-phosphorylation and up-regulated store-operated Ca entry (SOCE). PYR treatment resulted in improved cardiac contractile performance and rhythmic activity relative to untreated TAC mice. Chronic PYR treatment inhibited altered intracellular Ca handling by alleviating aberrant Ca release and diminishing pathologically enhanced SOCE in TAC myocytes. At the molecular level, these PYR-induced changes in Ca handling were associated with reductions of pathologically enhanced phosphorylation of RyR2 serine-2814 and STIM1 expression in HF myocytes. These results suggest that chronic cholinergic augmentation alleviates HF via normalization of both canonical RyR2-mediated SR Ca release and non-canonical hypertrophic Ca signaling via STIM1-dependent SOCE.
MeSH term(s)	Animals ; Arrhythmias, Cardiac/drug therapy ; Arrhythmias, Cardiac/metabolism ; Arrhythmias, Cardiac/pathology ; Calcium/metabolism ; Cholinesterase Inhibitors/pharmacology ; Heart Failure/drug therapy ; Heart Failure/metabolism ; Heart Failure/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Pyridostigmine Bromide/pharmacology ; Ryanodine Receptor Calcium Release Channel/chemistry ; Stromal Interaction Molecule 1/antagonists & inhibitors
Chemical Substances	Cholinesterase Inhibitors ; Ryanodine Receptor Calcium Release Channel ; Stim1 protein, mouse ; Stromal Interaction Molecule 1 ; ryanodine receptor 2. mouse ; Pyridostigmine Bromide (KVI301NA53) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2021-03-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2074559-X
ISSN	1582-4934 ; 1582-4934 ; 1582-1838
ISSN (online)	1582-4934
ISSN	1582-4934 ; 1582-1838
DOI	10.1111/jcmm.16356
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Article ; Online: Sexual dimorphism in bidirectional SR-mitochondria crosstalk in ventricular cardiomyocytes.

Basic research in cardiology

2023 Volume 118, Issue 1, Page(s) 15

Abstract: Calcium transfer into the mitochondrial matrix during sarcoplasmic reticulum (SR) ... ...

Abstract	Calcium transfer into the mitochondrial matrix during sarcoplasmic reticulum (SR) Ca
MeSH term(s)	Rats ; Male ; Female ; Animals ; Humans ; Aged ; Sarcoplasmic Reticulum ; Myocytes, Cardiac/metabolism ; Reactive Oxygen Species/metabolism ; Sex Characteristics ; Mitochondria/metabolism ; Calcium Signaling ; Calcium/metabolism
Chemical Substances	Reactive Oxygen Species ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2023-05-03
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	189755-x
ISSN	1435-1803 ; 0300-8428 ; 0175-9418
ISSN (online)	1435-1803
ISSN	0300-8428 ; 0175-9418
DOI	10.1007/s00395-023-00988-1
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