Response by Zhou et al to Letter Regarding Article, “Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy”

Zhou, Jibin; Ahmad, Firdos; Lal, Hind; Force, Thomas

doi:10.1161/circresaha.116.309093

Cited by 16 publications

(5 citation statements)

References 10 publications

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“…RNA-seq analysis of the phospholamban (PLN) R9C model of heart failure (HF) showed that like in the SRF HKO model, upregulation of Nmrk2 gene is an early event occurring prior the development of overt DCM and HF [ 7 ] ( Figure 1 H). Nmrk2 was also reported as the top upregulated gene (FC 16.87, p < 0.001) in glycogen synthase kinase 3 (GSK-3)–deficient hearts, which is involved in cardiac cells homeostasis and energy metabolism [ 29 , 30 ].…”

Section: Resultsmentioning

confidence: 99%

NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging

Tannous

Deloux

Karoui

et al. 2021

IJMS

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Dilated cardiomyopathy (DCM) is a disease of multifactorial etiologies, the risk of which is increased by male sex and age. There are few therapeutic options for patients with DCM who would benefit from identification of common targetable pathways. We used bioinformatics to identify the Nmrk2 gene involved in nicotinamide adenine dinucleotde (NAD) coenzyme biosynthesis as activated in different mouse models and in hearts of human patients with DCM while the Nampt gene controlling a parallel pathway is repressed. A short NMRK2 protein isoform is also known as muscle integrin binding protein (MIBP) binding the α7β1 integrin complex. We investigated the cardiac phenotype of Nmrk2-KO mice to establish its role in cardiac remodeling and function. Young Nmrk2-KO mice developed an eccentric type of cardiac hypertrophy in response to pressure overload rather than the concentric hypertrophy observed in controls. Nmrk2-KO mice developed a progressive DCM-like phenotype with aging, associating eccentric remodeling of the left ventricle and a decline in ejection fraction and showed a reduction in myocardial NAD levels at 24 months. In agreement with involvement of NMRK2 in integrin signaling, we observed a defect in laminin deposition in the basal lamina of cardiomyocytes leading to increased fibrosis at middle age. The α7 integrin was repressed at both transcript and protein level at 24 months. Nmrk2 gene is required to preserve cardiac structure and function, and becomes an important component of the NAD biosynthetic pathways during aging. Molecular characterization of compounds modulating this pathway may have therapeutic potential.

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Section: Resultsmentioning

confidence: 99%

NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging

Tannous

Deloux

Karoui

et al. 2021

IJMS

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“…Interest in Nmrk2 has recently increased due to its strong connection to cardiac-related diseases and aging (73). Similar high increases in Nmrk2 expression (FC=16.87) have been reported in glycogen synthase kinase 3 deficient hearts (74) and in mice models of dilated cardiomyopathy (73,75). Interestingly, a shortened splice variant form of NRK2 termed the muscle integrin binding protein (MIBP) binds to the integrin 1 subunit of the heterodimer integrin 71 but lacks nicotinamide riboside kinase activity (73).…”

Section: Nicotinamide Dinucleotide Synthesis Is Activatedmentioning

confidence: 75%

Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue

Sudlow

Shahverdi

et al. 2023

Preprint

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Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. At high cumulative dosage, the negative effect of oxaliplatin on the heart becomes evident and is linked to a growing number of clinical reports. The aim of this study was to determine how chronic oxaliplatin treatment causes the changes in energy-related metabolic activity in the heart that leads to cardiotoxicity and heart damage in mice. C57BL/6 male mice were treated with a human equivalent dosage of intraperitoneal oxaliplatin (0 and 10 mg/kg) once a week for eight weeks. During the treatment, mice were followed for physiological parameters, ECG, histology and RNA sequencing of the heart. We identified that oxaliplatin induces strong changes in the heart and affects the heart's energy-related metabolic profile. Histological post-mortem evaluation identified focal myocardial necrosis infiltrated with a small number of associated neutrophils. Accumulated doses of oxaliplatin led to significant changes in gene expression related to energy related metabolic pathways including fatty acid (FA) oxidation, amino acid metabolism, glycolysis, electron transport chain, and NAD synthesis pathway. At high accumulative doses of oxaliplatin, the heart shifts its metabolism from FAs to glycolysis and increases lactate production. It also leads to strong overexpression of genes in NAD synthesis pathways such as Nmrk2. Changes in gene expression associated with energy metabolic pathways can be used to develop diagnostic methods to detect oxaliplatin-induced cardiotoxicity early on as well as therapy to compensate for the energy deficit in the heart to prevent heart damage.

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“…For example, germline global deletion of GSK-3β causes embryonic lethality [13] while germline global loss of GSK-3α results in viable animals [14] of which the males are sterile and both sexes later develop early aging and age-related complications [15]. Moreover, cardiomyocyte-specific conditional loss of both GSK-3α and GSK-3β isoforms in adult cardiomyocytes leads to mitotic catastrophe and fatal dilated cardiomyopathy [16, 17]. Interestingly, isoform-specific targeting of GSK-3 is found to be protective in a variety of clinical conditions including cancer, neurodegenerative and cardiometabolic disorders [1, 18, 19].…”

Section: Introductionmentioning

confidence: 99%

Natural compound screening predicts novel GSK-3 isoform-specific inhibitors

Ahmad,

Gupta,

Marzook

et al. 2024

Preprint

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Glycogen synthase kinase-3 (GSK-3) plays important roles in the pathogenesis of cardiovascular, metabolic, neurological disorders and cancer. Isoform-specific loss of either GSK-3α or GSK-β often provides cytoprotective effects under such clinical conditions. However, available synthetic small molecule inhibitors are relatively non-specific, and their chronic use may lead to adverse effects. Therefore, screening for natural compound inhibitors to identify the isoform-specific inhibitors may provide improved clinical utility. Here, we screened 70 natural compounds to identify novel natural GSK-3 inhibitors employing comprehensive in silico and biochemical approaches. Molecular docking and pharmacokinetics analysis identified two natural compounds Psoralidin and Rosmarinic acid as potential GSK-3 inhibitors. Specifically, Psoralidin and Rosmarinic acid exhibited the highest binding affinities for GSK-3α and GSK-3β, respectively. Consistent with in silico findings, the kinase assay-driven IC50 revealed superior inhibitory effects of Psoralidin against GSK-3α (IC50=2.26 μM) vs. GSK-3β (IC50=4.23 μM) while Rosmarinic acid was found to be more potent against GSK-3β (IC50=2.24 μM) than GSK-3α (IC50=5.14 μM). Taken together, these studies show that the identified natural compounds may serve as GSK-3 inhibitors with Psoralidin serving as a better inhibitor for GSK-3α and Rosmarinic for GSK-3β isoform, respectively. Further characterization employing in vitro and preclinical models will be required to test the utility of these compounds as GSK-3 inhibitors for cardiometabolic and neurological disorders and cancers.

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Response by Zhou et al to Letter Regarding Article, “Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy”

Cited by 16 publications

References 10 publications

NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging

NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging

Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue

Natural compound screening predicts novel GSK-3 isoform-specific inhibitors

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