Suppression of Activated FOXO Transcription Factors in the Heart Prolongs Survival in a Mouse Model of Laminopathies

Auguste, Gaëlle; Gurha, Priyatansh; Lombardi, Raffaella; Coarfa, Cristian; Willerson, James T.; Marian, Ali J.

doi:10.1161/circresaha.117.312052

Cited by 60 publications

(92 citation statements)

References 65 publications

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“…We observed a similar disease progression from 1 week to 1 month. But unlike the former study, which showed a significant decrease in mouse weight in 2-week-old Lmna −/− mice 15 , we did not identify a significant difference in growth between wild type (WT) and Lmna −/− mice at 1 week and 2 weeks of age ( Fig. 1a).…”

Section: Resultscontrasting

confidence: 99%

“…Meanwhile, Lmna −/− mice showed down-regulation in key genes in DNA damage response/repair pathways as well as up-regulation in genes involved in the oxidative stress response, acute phase response, cell survival/growth, cardiac hypertrophy, glycolysis, and triglyceride hydrolysis. We identified the up-regulation of FOXO3 (listed in Table 1 apoptosis pathway), which was also found in a previous study in 2-week Lmna −/− mice by Marian et al 15 . However, instead of activation of the pathway in 2-week Lmna D300N mice shown by Marian et al 16 , we identified overall down-regulation of DNA damage response pathway (z score = −1.265).…”

Section: Resultssupporting

confidence: 86%

“…in regulating the expression of certain genes 5,6 . Much effort has been undertaken to identify signaling molecules implicated in Lmna mutations, and especially in LMNA cardiomyopathy, in order to gain insights on how lamins regulate a wide spectrum of cellular processing leading to cardiomyopathy and heart failure [7][8][9][10][11][12][13][14][15][16] . Previously, microarray analysis in a mouse model harboring the Lmna mutation (Lmna H222P/H222P ) for Emery-Dreifuss muscular dystrophy and cardiomyopathy showed that there was over-activation of mitogen-activated protein kinase 3/1 (ERK1/2) and mechanistic targeting of rapamycin kinase (mTOR) pathways [7][8][9]17,18 .…”

mentioning

confidence: 99%

“…Therapeutic inhibition of these pathways has shown delayed left ventricular dilation and improved cardiac function in the animal model of LMNA cardiomyopathy 8,[10][11][12][13][14]18 . Recent RNA sequencing studies found the activation of FOXO transcription factors (in 2-week-old Lmna −/− mice) and E2F/DNA damage response/TP53 pathway (in 2-week Lmna D300N mice) contribute to the pathogenesis of LMNA cardiomyopathy 15,16 .…”

mentioning

confidence: 99%

“…In our present study, we utilized RNA sequence analysis to investigate gene expression profiling throughout the lifespan of Lmna −/− mice with cardiomyopathy to investigate novel Lmna-mediated alterations of signaling pathways leading to dilated cardiomyopathy. While previous studies focused on specific pathways 8,[10][11][12][13][14][15][16]18 in the pathogenesis of LMNA cardiomyopathy (caused by specific Lmna mutations or knockout), our study aimed to provide a systematic overview of the signaling pathways and pathophysiological changes that might synergistically contribute to the development of Lmna −/− induced LMNA cardiomyopathy. To the best of our knowledge, this is the first systematic mechanism study covering the entire disease process of LMNA cardiomyopathy in the Lmna −/− mouse model.…”

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confidence: 99%

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RNA Sequence Analyses throughout the Course of Mouse Cardiac Laminopathy Identify Differentially Expressed Genes for Cell Cycle Control and Mitochondrial Function

Shao

Koh

et al. 2020

Sci Rep

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Lamin A/c (LMNA) gene mutations are a known cause of familial dilated cardiomyopathy, but the precise mechanisms triggering disease progression remain unknown. We hypothesize that analysis of differentially expressed genes (DEGs) throughout the course of Lmna knockout (Lmna −/−)-induced cardiomyopathy may reveal novel Lmna-mediated alterations of signaling pathways leading to dilated cardiomyopathy. Although Lmna was the only DEG down-regulated at 1 week of age, we identified 730 and 1004 DEGs in Lmna −/− mice at 2 weeks and 1 month of age, respectively. At 2 weeks, Lmna −/− mice demonstrated both down-and up-regulation of the key genes involving cell cycle control, mitochondrial dysfunction, and oxidative phosphorylation, as well as down-regulated genes governing DNA damage repair and up-regulated genes involved in oxidative stress response, cell survival, and cardiac hypertrophy. At 1 month, the down-regulated genes included those involved in oxidative phosphorylation, mitochondrial dysfunction, nutrient metabolism, cardiac β-adrenergic signaling, action potential generation, and cell survival. We also found 96 overlapping DEGs at both ages involved in oxidative phosphorylation, mitochondrial function, and calcium signaling. Impaired oxidative phosphorylation was observed at early disease stage, even before the appearance of disease phenotypes, and worsened with disease progression, suggesting its importance in the pathogenesis and progression of LMNA cardiomyopathy. Reduction of oxidative stress might therefore prevent or delay the development from Lmna mutation to LMNA cardiomyopathy. Lamin A/C (LMNA) gene mutations account for approximately 6-8% of known genetic dilated cardiomyopathies, and occur with frequent cardiac conduction system disease 1. Lamins are type V intermediate filament proteins and major components of the nuclear lamina. They line the inner surface of the inner nuclear membrane, where they interact with chromatin associated proteins, nuclear envelope proteins (including nuclear pore complexes), and transcription factors, thereby regulating important cellular events such as chromatin organization, DNA repair/replication, transcription and cell division 2-5. There are two types of lamins. Lamins A and C are A-type lamins coded by the Lmna gene, while B-type lamins (B1 and B2) are coded by two different genes (Lmnb1 and Lmnb2, respectively). Unlike B-type lamins, lamins A and C are also found in nucleoplasm and may play a role

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Section: Resultscontrasting

confidence: 99%

Section: Resultssupporting

confidence: 86%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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RNA Sequence Analyses throughout the Course of Mouse Cardiac Laminopathy Identify Differentially Expressed Genes for Cell Cycle Control and Mitochondrial Function

Shao

Koh

et al. 2020

Sci Rep

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Stroke Related Brain–Heart Crosstalk: Pathophysiology, Clinical Implications, and Underlying Mechanisms

Fan,

Cao,

et al. 2024

Advanced Science

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The emergence of acute ischemic stroke (AIS) induced cardiovascular dysfunctions as a bidirectional interaction has gained paramount importance in understanding the intricate relationship between the brain and heart. Post AIS, the ensuing cardiovascular dysfunctions encompass a spectrum of complications, including heart attack, congestive heart failure, systolic or diastolic dysfunction, arrhythmias, electrocardiographic anomalies, hemodynamic instability, cardiac arrest, among others, all of which are correlated with adverse outcomes and mortality. Mounting evidence underscores the intimate crosstalk between the heart and the brain, facilitated by intricate physiological and neurohumoral complex networks. The primary pathophysiological mechanisms contributing to these severe cardiac complications involve the hypothalamic‐pituitary‐adrenal (HPA) axis, sympathetic and parasympathetic hyperactivity, immune and inflammatory responses, and gut dysbiosis, collectively shaping the stroke‐related brain–heart axis. Ongoing research endeavors are concentrated on devising strategies to prevent AIS‐induced cardiovascular dysfunctions. Notably, labetalol, nicardipine, and nitroprusside are recommended for hypertension control, while β‐blockers are employed to avert chronic remodeling and address arrhythmias. However, despite these therapeutic interventions, therapeutic targets remain elusive, necessitating further investigations into this complex challenge. This review aims to delineate the state‐of‐the‐art pathophysiological mechanisms in AIS through preclinical and clinical research, unraveling their intricate interplay within the brain–heart axis, and offering pragmatic suggestions for managing AIS‐induced cardiovascular dysfunctions.

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Resveratrol improves left ventricular remodeling in chronic kidney disease via Sirt1‐mediated regulation of FoxO1 activity and MnSOD expression

Song

Zhang

et al. 2019

BioFactors

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Left ventricular remodeling commonly complicates end-stage renal disease following chronic kidney disease (CKD). This study investigated the therapeutic efficacy of resveratrol (RSV), a polyphenolic compound, on left ventricular remodeling in subtotal nephrectomy rats and sought to uncover the underlying molecular mechanisms. Subtotal nephrectomy caused renal dysfunction, such as gradual increases in serum creatinine and blood urea nitrogen, glomerular sclerosis, and tubulointerstitial fibrosis. In addition, subtotal nephrectomy also resulted in significant increases in myocyte cross-sectional area, interstitial and perivascular fibrosis, and left ventricular dilatation. All these detrimental effects were alleviated in the presence of RSV. Mechanistically, RSV treatment led to the upregulation of manganese-containing superoxide dismutase (MnSOD) in the heart. Coimmunoprecipitation studies showed that silent information regulator 1 (Sirt1) bound forkhead box protein O1 (FoxO1) and thus reduced acetylated FoxO1. RSV strengthened this interaction between Sirt1 and FoxO1. Loss of one allele of Sirt1 aggravated renal damage, myocyte hypertrophy, and interstitial fibrosis in nephrectomized mice. Taken together, our data show that Sirt1 is an important mediator for the protective roles of RSV on renal and heart damage in CKD rodent model, and FoxO1 and MnSOD are likely downstream targets of Sirt1. Therefore, Sirt1 might be a potential therapeutic target for the treatment of left ventricular remodeling caused by CKD.

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Suppression of Activated FOXO Transcription Factors in the Heart Prolongs Survival in a Mouse Model of Laminopathies

Cited by 60 publications

References 65 publications

RNA Sequence Analyses throughout the Course of Mouse Cardiac Laminopathy Identify Differentially Expressed Genes for Cell Cycle Control and Mitochondrial Function

RNA Sequence Analyses throughout the Course of Mouse Cardiac Laminopathy Identify Differentially Expressed Genes for Cell Cycle Control and Mitochondrial Function

Stroke Related Brain–Heart Crosstalk: Pathophysiology, Clinical Implications, and Underlying Mechanisms

Resveratrol improves left ventricular remodeling in chronic kidney disease via Sirt1‐mediated regulation of FoxO1 activity and MnSOD expression

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