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Article ; Online: Dasatinib targets c-Src kinase in cardiotoxicity

Elmadani, Manar / Raatikainen, Sami / Mattila, Orvokki / Alakoski, Tarja / Piuhola, Jarkko / Åström, Pirjo / Tenhunen, Olli / Magga, Johanna / Kerkelä, Risto

Toxicology Reports. 2023, v. 10 p.521-528

2023

Abstract: Dasatinib is a multitargeted kinase inhibitor used for treatment of chronic myeloid leukemia and acute lymphoblastic leukemia. Unfortunately, treatment of cancer patients with some kinase inhibitors has been associated with cardiotoxicity. Cancer ... ...

Abstract	Dasatinib is a multitargeted kinase inhibitor used for treatment of chronic myeloid leukemia and acute lymphoblastic leukemia. Unfortunately, treatment of cancer patients with some kinase inhibitors has been associated with cardiotoxicity. Cancer treatment with dasatinib has been reported to be associated with cardiotoxic side effects such as left ventricular dysfunction, heart failure, pericardial effusion and pulmonary hypertension. Here we aimed to investigate the molecular mechanisms underlying the cardiotoxicity of dasatinib. We found that among the resident cardiac cell types, cardiomyocytes were most sensitive to dasatinib-induced cell death. Exposure of cardiomyocytes to dasatinib attenuated the activity of extracellular signal-regulated kinase (ERK), which is a downstream target of dasatinib target kinase c-Src. Similar to dasatinib, c-Src depletion in cardiomyocytes compromised cardiomyocyte viability. Overexpression of dasatinib-resistant mutant of c-Src rescued the toxicity of dasatinib on cardiomyocytes, whereas forced expression of wild type c-Src did not have protective effect. Collectively, our results show that c-Src is a key target of dasatinib mediating the toxicity of dasatinib to cardiomyocytes. These findings may influence future drug design and suggest closer monitoring of patients treated with agents targeting c-Src for possible adverse cardiac effects.
Keywords	cancer therapy ; cardiomyocytes ; cardiotoxicity ; cell death ; drug design ; heart failure ; hypertension ; lymphocytic leukemia ; mitogen-activated protein kinase ; mutants ; myeloid leukemia ; pericardial effusion ; protective effect ; toxicity ; toxicology ; viability ; Tyrosine kinase inhibitor ; Proto-oncogene tyrosine-protein kinase Src
Language	English
Size	p. 521-528.
Publishing place	Elsevier B.V.
Document type	Article ; Online
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ZDB-ID	2805786-7
ISSN	2214-7500
ISSN	2214-7500
DOI	10.1016/j.toxrep.2023.04.013
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Dasatinib targets c-Src kinase in cardiotoxicity.

Elmadani, Manar / Raatikainen, Sami / Mattila, Orvokki / Alakoski, Tarja / Piuhola, Jarkko / Åström, Pirjo / Tenhunen, Olli / Magga, Johanna / Kerkelä, Risto

Toxicology reports

2023 Volume 10, Page(s) 521–528

Abstract	Dasatinib is a multitargeted kinase inhibitor used for treatment of chronic myeloid leukemia and acute lymphoblastic leukemia. Unfortunately, treatment of cancer patients with some kinase inhibitors has been associated with cardiotoxicity. Cancer treatment with dasatinib has been reported to be associated with cardiotoxic side effects such as left ventricular dysfunction, heart failure, pericardial effusion and pulmonary hypertension. Here we aimed to investigate the molecular mechanisms underlying the cardiotoxicity of dasatinib. We found that among the resident cardiac cell types, cardiomyocytes were most sensitive to dasatinib-induced cell death. Exposure of cardiomyocytes to dasatinib attenuated the activity of extracellular signal-regulated kinase (ERK), which is a downstream target of dasatinib target kinase c-Src. Similar to dasatinib, c-Src depletion in cardiomyocytes compromised cardiomyocyte viability. Overexpression of dasatinib-resistant mutant of c-Src rescued the toxicity of dasatinib on cardiomyocytes, whereas forced expression of wild type c-Src did not have protective effect. Collectively, our results show that c-Src is a key target of dasatinib mediating the toxicity of dasatinib to cardiomyocytes. These findings may influence future drug design and suggest closer monitoring of patients treated with agents targeting c-Src for possible adverse cardiac effects.
Language	English
Publishing date	2023-04-25
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	2805786-7
ISSN	2214-7500 ; 2214-7500
ISSN (online)	2214-7500
ISSN	2214-7500
DOI	10.1016/j.toxrep.2023.04.013
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Article ; Online: Apelin regulates skeletal muscle adaptation to exercise in a high-intensity interval training model.

Kilpiö, Teemu / Skarp, Sini / Perjés, Ábel / Swan, Julia / Kaikkonen, Leena / Saarimäki, Samu / Szokodi, István / Penninger, Josef M / Szabó, Zoltán / Magga, Johanna / Kerkelä, Risto

American journal of physiology. Cell physiology

2024 Volume 326, Issue 5, Page(s) C1437–C1450

Abstract: Plasma apelin levels are reduced in aging and muscle wasting conditions. We aimed to investigate the significance of apelin signaling in cardiac and skeletal muscle responses to physiological stress. Apelin knockout (KO) and wild-type (WT) mice were ... ...

Abstract	Plasma apelin levels are reduced in aging and muscle wasting conditions. We aimed to investigate the significance of apelin signaling in cardiac and skeletal muscle responses to physiological stress. Apelin knockout (KO) and wild-type (WT) mice were subjected to high-intensity interval training (HIIT) by treadmill running. The effects of apelin on energy metabolism were studied in primary mouse skeletal muscle myotubes and cardiomyocytes. Apelin increased mitochondrial ATP production and mitochondrial coupling efficiency in myotubes and promoted the expression of mitochondrial genes both in primary myotubes and cardiomyocytes. HIIT induced mild concentric cardiac hypertrophy in WT mice, whereas eccentric growth was observed in the left ventricles of apelin KO mice. HIIT did not affect myofiber size in skeletal muscles of WT mice but decreased the myofiber size in apelin KO mice. The decrease in myofiber size resulted from a fiber type switch toward smaller slow-twitch type I fibers. The increased proportion of slow-twitch type I fibers in apelin KO mice was associated with upregulation of myosin heavy chain slow isoform expression, accompanied with upregulated expression of genes related to fatty acid transport and downregulated expression of genes related to glucose metabolism. Mechanistically, skeletal muscles of apelin KO mice showed defective induction of insulin-like growth factor-1 signaling in response to HIIT. In conclusion, apelin is required for proper skeletal and cardiac muscle adaptation to high-intensity exercise. Promoting apelinergic signaling may have benefits in aging- or disease-related muscle wasting conditions.
MeSH term(s)	Animals ; Apelin/metabolism ; Apelin/genetics ; Mice, Knockout ; Adaptation, Physiological ; Mice ; Physical Conditioning, Animal/physiology ; Muscle, Skeletal/metabolism ; High-Intensity Interval Training/methods ; Male ; Myocytes, Cardiac/metabolism ; Energy Metabolism ; Mice, Inbred C57BL ; Muscle Fibers, Skeletal/metabolism ; Muscle Fibers, Slow-Twitch/metabolism ; Cardiomegaly/metabolism ; Cardiomegaly/genetics ; Cardiomegaly/physiopathology ; Cardiomegaly/pathology
Chemical Substances	Apelin ; Apln protein, mouse
Language	English
Publishing date	2024-03-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	392098-7
ISSN	1522-1563 ; 0363-6143
ISSN (online)	1522-1563
ISSN	0363-6143
DOI	10.1152/ajpcell.00427.2023
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Article ; Online: Endothelin-1 is associated with mortality that can be attenuated with high intensity statin therapy in patients with stable coronary artery disease.

Lin, Ruizhu / Junttila, Juhani / Piuhola, Jarkko / Lepojärvi, E Samuli / Magga, Johanna / Kiviniemi, Antti M / Perkiömäki, Juha / Huikuri, Heikki / Ukkola, Olavi / Tulppo, Mikko / Kerkelä, Risto

Communications medicine

2023 Volume 3, Issue 1, Page(s) 87

Abstract: Background: All coronary artery disease (CAD) patients do not benefit equally of secondary prevention. Individualized intensity of drug therapy is currently implemented in guidelines for CAD and diabetes. Novel biomarkers are needed to identify patient ... ...

Abstract	Background: All coronary artery disease (CAD) patients do not benefit equally of secondary prevention. Individualized intensity of drug therapy is currently implemented in guidelines for CAD and diabetes. Novel biomarkers are needed to identify patient subgroups potentially benefitting from individual therapy. This study aimed to investigate endothelin-1 (ET-1) as a biomarker for increased risk of adverse events and to evaluate if medication could alleviate the risks in patients with high ET-1. Methods: A prospective observational cohort study ARTEMIS included 1946 patients with angiographically documented CAD. Blood samples and baseline data were collected at enrollment and the patients were followed for 11 years. Multivariable Cox regression was used to assess the association between circulating ET-1 level and all-cause mortality, cardiovascular (CV) death, non-CV death and sudden cardiac death (SCD). Results: Here we show an association of circulating ET-1 level with higher risk for all-cause mortality (HR: 2.06; 95% CI 1.5-2.83), CV death, non-CV death and SCD in patients with CAD. Importantly, high intensity statin therapy reduces the risk for all-cause mortality (adjusted HR: 0.05; 95% CI 0.01-0.38) and CV death (adjusted HR: 0.06; 95% CI 0.01-0.44) in patients with high ET-1, but not in patients with low ET-1. High intensity statin therapy does not associate with reduction of risk for non-CV death or SCD. Conclusions: Our data suggests a prognostic value for high circulating ET-1 in patients with stable CAD. High intensity statin therapy associates with reduction of risk for all-cause mortality and CV death in CAD patients with high ET-1.
Language	English
Publishing date	2023-06-22
Publishing country	England
Document type	Journal Article
ISSN	2730-664X
ISSN (online)	2730-664X
DOI	10.1038/s43856-023-00322-9
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Article ; Online: Novel Screening Method Identifies PI3Kα, mTOR, and IGF1R as Key Kinases Regulating Cardiomyocyte Survival.

Elmadani, Manar / Khan, Suleiman / Tenhunen, Olli / Magga, Johanna / Aittokallio, Tero / Wennerberg, Krister / Kerkelä, Risto

Journal of the American Heart Association

2019 Volume 8, Issue 21, Page(s) e013018

Abstract: Background Small molecule kinase inhibitors (KIs) are a class of agents currently used for treatment of various cancers. Unfortunately, treatment of cancer patients with some of the KIs is associated with cardiotoxicity, and there is an unmet need for ... ...

Abstract	Background Small molecule kinase inhibitors (KIs) are a class of agents currently used for treatment of various cancers. Unfortunately, treatment of cancer patients with some of the KIs is associated with cardiotoxicity, and there is an unmet need for methods to predict their cardiotoxicity. Here, we utilized a novel computational method to identify protein kinases crucial for cardiomyocyte viability. Methods and Results One hundred forty KIs were screened for their toxicity in cultured neonatal cardiomyocytes. The kinase targets of KIs were determined based on integrated data from binding assays. The key kinases mediating the toxicity of KIs to cardiomyocytes were identified by using a novel machine learning method for target deconvolution that combines the information from the toxicity screen and from the kinase profiling assays. The top kinases identified by the model were phosphoinositide 3-kinase catalytic subunit alpha, mammalian target of rapamycin, and insulin-like growth factor 1 receptor. Knockdown of the individual kinases in cardiomyocytes confirmed their role in regulating cardiomyocyte viability. Conclusions Combining the data from analysis of KI toxicity on cardiomyocytes and KI target profiling provides a novel method to predict cardiomyocyte toxicity of KIs.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Animals ; Cardiotoxins/pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Machine Learning ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Kinase Inhibitors/pharmacology ; Rats ; Receptor, IGF Type 1/metabolism ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Cardiotoxins ; IGF1R protein, human ; Protein Kinase Inhibitors ; Adenosine Triphosphate (8L70Q75FXE) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Receptor, IGF Type 1 (EC 2.7.10.1)
Language	English
Publishing date	2019-10-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2653953-6
ISSN	2047-9980 ; 2047-9980
ISSN (online)	2047-9980
ISSN	2047-9980
DOI	10.1161/JAHA.119.013018
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Article ; Online: Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events.

Kerkelä, Risto / Ulvila, Johanna / Magga, Johanna

Journal of the American Heart Association

2015 Volume 4, Issue 10, Page(s) e002423

MeSH term(s)	Animals ; Diabetes Mellitus/metabolism ; Energy Metabolism/drug effects ; Gene Expression Regulation ; Heart Diseases/drug therapy ; Heart Diseases/genetics ; Heart Diseases/metabolism ; Heart Diseases/pathology ; Heart Diseases/physiopathology ; Humans ; Metabolic Syndrome/metabolism ; Myocardium/metabolism ; Myocardium/pathology ; Natriuretic Peptides/genetics ; Natriuretic Peptides/metabolism ; Natriuretic Peptides/therapeutic use ; Receptors, Atrial Natriuretic Factor/metabolism ; Signal Transduction/drug effects
Chemical Substances	Natriuretic Peptides ; Receptors, Atrial Natriuretic Factor (EC 4.6.1.2)
Language	English
Publishing date	2015-10-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2653953-6
ISSN	2047-9980 ; 2047-9980
ISSN (online)	2047-9980
ISSN	2047-9980
DOI	10.1161/JAHA.115.002423
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Article ; Online: Wnt11 in regulation of physiological and pathological cardiac growth.

Halmetoja, Eveliina / Nagy, Irina / Szabo, Zoltan / Alakoski, Tarja / Yrjölä, Raisa / Vainio, Laura / Viitavaara, Eliina / Lin, Ruizhu / Rahtu-Korpela, Lea / Vainio, Seppo / Kerkelä, Risto / Magga, Johanna

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2022 Volume 36, Issue 10, Page(s) e22544

Abstract: Wnt11 regulates early cardiac development and left ventricular compaction in the heart, but it is not known how Wnt11 regulates postnatal cardiac maturation and response to cardiac stress in the adult heart. We studied cell proliferation/maturation in ... ...

Abstract	Wnt11 regulates early cardiac development and left ventricular compaction in the heart, but it is not known how Wnt11 regulates postnatal cardiac maturation and response to cardiac stress in the adult heart. We studied cell proliferation/maturation in postnatal and adolescent Wnt11 deficient (Wnt11-/-) heart and subjected adult mice with partial (Wnt11+/-) and complete Wnt11 (Wnt11-/-) deficiency to cardiac pressure overload. In addition, we subjected primary cardiomyocytes to recombinant Wnt proteins to study their effect on cardiomyocyte growth. Wnt11 deficiency did not affect cardiomyocyte proliferation or maturation in the postnatal or adolescent heart. However, Wnt11 deficiency led to enlarged heart phenotype that was not accompanied by significant hypertrophy of individual cardiomyocytes. Analysis of stressed adult hearts from wild-type mice showed a progressive decrease in Wnt11 expression in response to pressure overload. When studied in experimental cardiac pressure overload, Wnt11 deficiency did not exacerbate cardiac hypertrophy or remodeling and cardiac function remained identical between the genotypes. When subjecting cardiomyocytes to hypertrophic stimulus, the presence of recombinant Wnt11 together with Wnt5a reduced protein synthesis. In conclusion, Wnt11 deficiency does not affect postnatal cardiomyocyte proliferation but leads to cardiac growth. Interestingly, Wnt11 deficiency alone does not substantially modulate hypertrophic response to pressure overload in vivo. Wnt11 may require cooperation with other noncanonical Wnt proteins to regulate hypertrophic response under stress.
MeSH term(s)	Animals ; Cardiomegaly/metabolism ; Cell Proliferation ; Heart/growth & development ; Mice ; Myocardium ; Myocytes, Cardiac/metabolism ; Wnt Proteins/genetics ; Wnt Proteins/metabolism
Chemical Substances	Wnt Proteins ; Wnt11 protein, mouse
Language	English
Publishing date	2022-09-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202101856RRRR
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Article ; Online: Activation of the hypoxia response pathway protects against age-induced cardiac hypertrophy.

Röning, Tapio / Magga, Johanna / Laitakari, Anna / Halmetoja, Riikka / Tapio, Joona / Dimova, Elitsa Y / Szabo, Zoltan / Rahtu-Korpela, Lea / Kemppi, Anna / Walkinshaw, Gail / Myllyharju, Johanna / Kerkelä, Risto / Koivunen, Peppi / Serpi, Raisa

Journal of molecular and cellular cardiology

2021 Volume 164, Page(s) 148–155

Abstract: Aims: We have previously demonstrated protection against obesity, metabolic dysfunction, atherosclerosis and cardiac ischemia in a hypoxia-inducible factor (HIF) prolyl 4-hydroxylase-2 (Hif-p4h-2) deficient mouse line, attributing these protective ... ...

Abstract	Aims: We have previously demonstrated protection against obesity, metabolic dysfunction, atherosclerosis and cardiac ischemia in a hypoxia-inducible factor (HIF) prolyl 4-hydroxylase-2 (Hif-p4h-2) deficient mouse line, attributing these protective effects to activation of the hypoxia response pathway in a normoxic environment. We intended here to find out whether the Hif-p4h-2 deficiency affects the cardiac health of these mice upon aging. Methods and results: When the Hif-p4h-2 deficient mice and their wild-type littermates were monitored during normal aging, the Hif-p4h-2 deficient mice had better preserved diastolic function than the wild type at one year of age and less cardiomyocyte hypertrophy at two years. On the mRNA level, downregulation of hypertrophy-associated genes was detected and shown to be associated with upregulation of Notch signaling, and especially of the Notch target gene and transcriptional repressor Hairy and enhancer-of-split-related basic helix-loop-helix (Hey2). Blocking of Notch signaling in cardiomyocytes isolated from Hif-p4h-2 deficient mice with a gamma-secretase inhibitor led to upregulation of the hypertrophy-associated genes. Also, targeting Hey2 in isolated wild-type rat neonatal cardiomyocytes with siRNA led to upregulation of hypertrophic genes and increased leucine incorporation indicative of increased protein synthesis and hypertrophy. Finally, oral treatment of wild-type mice with a small molecule inhibitor of HIF-P4Hs phenocopied the effects of Hif-p4h-2 deficiency with less cardiomyocyte hypertrophy, upregulation of Hey2 and downregulation of the hypertrophy-associated genes. Conclusions: These results indicate that activation of the hypoxia response pathway upregulates Notch signaling and its target Hey2 resulting in transcriptional repression of hypertrophy-associated genes and less cardiomyocyte hypertrophy. This is eventually associated with better preserved cardiac function upon aging. Activation of the hypoxia response pathway thus has therapeutic potential for combating age-induced cardiac hypertrophy.
MeSH term(s)	Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cardiomegaly/genetics ; Cardiomegaly/metabolism ; Hypoxia/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Hypoxia-Inducible Factor-Proline Dioxygenases/genetics ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism ; Mice ; Rats ; Signal Transduction
Chemical Substances	Basic Helix-Loop-Helix Transcription Factors ; Hypoxia-Inducible Factor 1, alpha Subunit ; Hypoxia-Inducible Factor-Proline Dioxygenases (EC 1.14.11.29)
Language	English
Publishing date	2021-12-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2021.12.003
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Article ; Online: Inhibition of cardiomyocyte Sprouty1 protects from cardiac ischemia-reperfusion injury.

Alakoski, Tarja / Ulvila, Johanna / Yrjölä, Raisa / Vainio, Laura / Magga, Johanna / Szabo, Zoltan / Licht, Jonathan D / Kerkelä, Risto

Basic research in cardiology

2019 Volume 114, Issue 2, Page(s) 7

Abstract: Sprouty1 (Spry1) is a negative modulator of receptor tyrosine kinase signaling, but its role in cardiomyocyte survival has not been elucidated. The aim of this study was to investigate the potential role of cardiomyocyte Spry1 in cardiac ischemia- ... ...

Abstract	Sprouty1 (Spry1) is a negative modulator of receptor tyrosine kinase signaling, but its role in cardiomyocyte survival has not been elucidated. The aim of this study was to investigate the potential role of cardiomyocyte Spry1 in cardiac ischemia-reperfusion (I/R) injury. Infarct areas of mouse hearts showed an increase in Spry1 protein expression, which localized to cardiomyocytes. To investigate if cardiomyocyte Spry1 regulates I/R injury, 8-week-old inducible cardiomyocyte Spry1 knockout (Spry1 cKO) mice and control mice were subjected to cardiac I/R injury. Spry1 cKO mice showed reduction in release of cardiac troponin I and reduced infarct size after I/R injury compared to control mice. Similar to Spry1 knockdown in cardiomyocytes in vivo, RNAi-mediated Spry1 silencing in isolated cardiomyocytes improved cardiomyocyte survival following simulated ischemia injury. Mechanistically, Spry1 knockdown induced cardiomyocyte extracellular signal-regulated kinase (ERK) phosphorylation in healthy hearts and isolated cardiomyocytes, and enhanced ERK phosphorylation after I/R injury. Spry1-deficient cardiomyocytes showed better preserved mitochondrial membrane potential following ischemic injury and an increase in levels of phosphorylated ERK and phosphorylated glycogen synthase kinase-3β (GSK-3β) in mitochondria of hypoxic cardiomyocytes. Overexpression of constitutively active GSK-3β abrogated the protective effect of Spry1 knockdown. Moreover, pharmacological inhibition of GSK-3β protected wild-type cardiomyocytes from cell death, but did not further protect Spry1-silenced cardiomyocytes from hypoxia-induced injury. Cardiomyocyte Spry1 knockdown promotes ERK phosphorylation and offers protection from I/R injury. Our findings indicate that Spry1 is an important regulator of cardiomyocyte viability during ischemia-reperfusion injury.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Cell Survival/physiology ; Male ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocardial Reperfusion Injury/metabolism ; Myocytes, Cardiac/metabolism ; Phosphoproteins/metabolism ; Rats
Chemical Substances	Adaptor Proteins, Signal Transducing ; Membrane Proteins ; Phosphoproteins ; Spry1 protein, mouse
Language	English
Publishing date	2019-01-11
Publishing country	Germany
Document type	Journal Article ; 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/s00395-018-0713-y
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Article ; Online: GSK3β Serine 389 Phosphorylation Modulates Cardiomyocyte Hypertrophy and Ischemic Injury.

Vainio, Laura / Taponen, Saija / Kinnunen, Sini M / Halmetoja, Eveliina / Szabo, Zoltan / Alakoski, Tarja / Ulvila, Johanna / Junttila, Juhani / Lakkisto, Päivi / Magga, Johanna / Kerkelä, Risto

International journal of molecular sciences

2021 Volume 22, Issue 24

Abstract: Prior studies show that glycogen synthase kinase 3β (GSK3β) contributes to cardiac ischemic injury and cardiac hypertrophy. GSK3β is constitutionally active and phosphorylation of GSK3β at serine 9 (S9) inactivates the kinase and promotes cellular growth. ...

Abstract	Prior studies show that glycogen synthase kinase 3β (GSK3β) contributes to cardiac ischemic injury and cardiac hypertrophy. GSK3β is constitutionally active and phosphorylation of GSK3β at serine 9 (S9) inactivates the kinase and promotes cellular growth. GSK3β is also phosphorylated at serine 389 (S389), but the significance of this phosphorylation in the heart is not known. We analyzed GSK3β S389 phosphorylation in diseased hearts and utilized overexpression of GSK3β carrying ser→ala mutations at S9 (S9A) and S389 (S389A) to study the biological function of constitutively active GSK3β in primary cardiomyocytes. We found that phosphorylation of GSK3β at S389 was increased in left ventricular samples from patients with dilated cardiomyopathy and ischemic cardiomyopathy, and in hearts of mice subjected to thoracic aortic constriction. Overexpression of either GSK3β S9A or S389A reduced the viability of cardiomyocytes subjected to hypoxia-reoxygenation. Overexpression of double GSK3β mutant (S9A/S389A) further reduced cardiomyocyte viability. Determination of protein synthesis showed that overexpression of GSK3β S389A or GSK3β S9A/S389A increased both basal and agonist-induced cardiomyocyte growth. Mechanistically, GSK3β S389A mutation was associated with activation of mTOR complex 1 signaling. In conclusion, our data suggest that phosphorylation of GSK3β at S389 enhances cardiomyocyte survival and protects from cardiomyocyte hypertrophy.
MeSH term(s)	Animals ; Cardiomegaly/metabolism ; Cardiomegaly/pathology ; Cell Proliferation ; Cell Survival ; Cells, Cultured ; Glycogen Synthase Kinase 3 beta/metabolism ; Humans ; Male ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice ; Mice, Inbred C57BL ; Myocardial Ischemia/metabolism ; Myocardial Ischemia/pathology ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Phosphorylation ; Rats, Sprague-Dawley ; Rats
Chemical Substances	GSK3B protein, human (EC 2.7.11.1) ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; Gsk3b protein, mouse (EC 2.7.11.1) ; Gsk3b protein, rat (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
Language	English
Publishing date	2021-12-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms222413586
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