Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury

Tao, Ge; Kahr, Peter C.; Morikawa, Yuka; Zhang, Min; Rahmani, Mahdis; Heallen, Todd R.; Li, Lele; Sun, Zhao; Olson, Eric N.; Amendt, Brad A.; Martin, James F.

doi:10.1038/nature17959

Cited by 242 publications

(276 citation statements)

References 32 publications

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“…In all cases, disruption of the targeted NRF2 gene did not lead to any apparent structural and functional abnormalities in the neonatal and early postnatal heart under non-stressed physiological conditions [79]. However, NRF2 deficiency resulted in a rapid onset of cardiac dysfunction during experimental pressure overload (due to transverse aortic constriction [80]) or regional ischemic injury (due to cardiac artery occlusion [81,82] in young adult (2-month-old) mice. These results indicated that NRF2 inhibition can increase sensitivity of the young heart to pathological stress and thus exaggerate susceptibility to cardiac dysfunction.…”

Section: Nrf2 Transcription Factormentioning

confidence: 94%

“…These results indicated that NRF2 inhibition can increase sensitivity of the young heart to pathological stress and thus exaggerate susceptibility to cardiac dysfunction. Recently, it was found that NRF2 loss-of-function leads to suppression and distortion of regenerative processes in the apex resection mouse model [82].…”

Section: Nrf2 Transcription Factormentioning

confidence: 99%

“…A fourth isoform, PITX2D described, to date, only in humans acts as a dominant-negative factor [99]. PITX2 regulates the expression of cyclin D2 (CCND2) [100], forkhead box J1 (FOXJ1) TF [101], lymphoid enhancer factor (LEF-1) [102], natriuretic peptide precursor A (NPPA) [103,104], myogenic factor 5 (MYF5) [105], and antioxidant scavenger genes [82]. Other target genes of PITX2 include channel and calcium-handling genes, and genes are expressed in intercalated disks of cardiac myocytes (recently reviewed in [106]).…”

Section: Pitx2 Transcription Factormentioning

confidence: 99%

“…Genes involved in cell junction assembly, ion transport, and proliferation pathways were found to be activated in mouse mutants with conditionally inactivated PITX2 in the postnatal atrial myocardium [108], but it is unclear whether these are direct or indirect PIXT2C target genes in a cardiomyocyte background. Recently, a total of 505 direct PITX2 target genes were identified in the mouse postnatal ventricular myocardium, including genes encoding transport chain components and reactive oxygen species scavengers [82].…”

Section: Pitx2 Transcription Factormentioning

confidence: 99%

“…b Combinatorial TF interactions. Schematic illustrates TBX5::GATA4 [130], TBX5::GATA-6 [131], TBX5::MYOCD [132], GATA-4::GATA-6 [54], SRF::MYOCD [68], SRF::PITX2 [133], PIXT2::GATA-4 [134], and PITX2::NRF2 [82] proteinprotein interactions that lead to cooperative regulation of target gene expression in vitro. c TBX5 [29], GATA-4 [135], SRF [136], MYOCD [137], NRF2 [138], and PITX2 [97] are coexpressed in the adult human left ventricle (LV), suggesting that the interplay of these TFs in vitro (shown in b) also takes place in vivo (data for GATA-6 equivalent to those for GATA-4 are currently lacking).…”

Section: Introductionmentioning

confidence: 99%

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Myocardial transcription factors in diastolic dysfunction: clues for model systems and disease

Михайлов

Torrado

2016

Heart Fail Rev

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There are multiple intrinsic mechanisms for diastolic dysfunction ranging from molecular to structural derangements in ventricular myocardium. The molecular mechanisms regulating the progression from normal diastolic function to severe dysfunction still remain poorly understood. Recent studies suggest a potentially important role of core cardio-enriched transcription factors (TFs) in the control of cardiac diastolic function in health and disease through their ability to regulate the expression of target genes involved in the process of adaptive and maladaptive cardiac remodeling. The current relevant findings on the role of a variety of such TFs (TBX5, GATA-4/6, SRF, MYOCD, NRF2, and PITX2) in cardiac diastolic dysfunction and failure are updated, emphasizing their potential as promising targets for novel treatment strategies. In turn, the new animal models described here will be key tools in determining the underlying molecular mechanisms of disease. Since diastolic dysfunction is regulated by various TFs, which are also involved in cross talk with each other, there is a need for more in-depth research from a biomedical perspective in order to establish efficient therapeutic strategies.

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Section: Nrf2 Transcription Factormentioning

confidence: 94%

Section: Nrf2 Transcription Factormentioning

confidence: 99%

Section: Pitx2 Transcription Factormentioning

confidence: 99%

Section: Pitx2 Transcription Factormentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Myocardial transcription factors in diastolic dysfunction: clues for model systems and disease

Михайлов

Torrado

2016

Heart Fail Rev

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Corneal endothelial cell density and cardiovascular mortality

Scherer¹

2018

Clinical Anatomy

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Based on embryological commonalities between eye and heart development, a global, country-specific meta-analysis of normal, adult corneal endothelial cell density (ECD) was performed and correlated against mortality rates secondary to diseases affecting cardiac neural crest cell (CNCC)-derived cardiovascular structures. A country-specific survey of ECD was performed by searching PubMed for studies reporting ECD datasets from normal adults. All eligible datasets were assigned a country of origin. Country-specific weighted mean ECD were calculated based on dataset n. Country-specific disease mortality rates were obtained from the World Health Organization. The correlations between weighted mean ECD and mortality rates secondary to diseases affecting CNCC-derived cardiovascular structures were calculated. As controls, correlations between ECD and noncardiovascular disease mortality were examined. Pearson correlation coefficients (r) corresponding to P-value < 0.05 were considered significant. Three hundred ninety-two datasets (39,762 eyes) from 267 source-studies were assigned to 42 countries. Significant correlations were found between ECD and mortality due to coronary heart disease (r = -0.39, P = 0.011), hypertension (r = -0.33, P = 0.033), and all-cause cardiac disease (r = -0.36, P = 0.019). No significant correlations were found between ECD and mortality secondary to the control conditions: inflammatory heart disease (mesoderm-derived tissues) (r = -0.12, P = 0.45), diabetes (r = -0.13, P = 0.41), lung disease (r = -0.21, P = 0.18), liver disease (r = -0.13, P = 0.41), renal disease (r = -0.10, P = 0.53), lung cancer (r = 0.02, P = 0.90), pancreatic cancer (r = 0.24, P = 0.13), malnutrition (r = -0.07, P = 0.66), or all-cause mortality (r = 0.04, P = 0.81). Negative correlations exist between ECD and mortality due to coronary artery disease and hypertension. On a population-based level, adult ECD is correlated to mortality from certain cardiovascular diseases. Clin. Anat. 31:927-936, 2018. © 2018 Wiley Periodicals, Inc.

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Proteomic profiling of key transcription factors in the process of neonatal mouse cardiac regeneration capacity loss

Wang

Nie

et al. 2019

Cell Biology International

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The heart lacks complete regeneration capacity. In mice, the cardiac apex can regenerate 1 day after birth, although 7 days after birth the repair occurs with a fibrous scar. However, the key transcription factors (TFs) related to this loss of regeneration capacity remain largely unknown. We aimed to find candidates for key TFs using proteomic profiling and comparison during loss of neonatal mouse cardiac regeneration capacity, with preliminary validation using western blotting (WB) and real-time quantitative polymerase chain reaction (RT-qPCR). A total of 69 common discrepant TFs with similar variation trends in two TF response element experiments were identified, 18 of which were matched to known key signaling pathways of cardiac regeneration after pathway enrichment of downstream genes. Validation using RT-qPCR-selected DACH1, RBL1 (P107), and TBX20, and further validation with WB-selected RBL1 (P107) and TBX20. We therefore identified two candidates for key TFs in the loss of mouse cardiac apex regeneration capacity. TBX20 has been biologically validated, and RBL1 (P107) needs to be validated in the future.Abbreviations: catTFREs, concatenated tandem array of 50 consensus TFREs; FOT, frequency of total; LC-MS, nano-liquid chromatography/tandem mass spectrometry; RT-qPCR, real-time quantitative polymerase chain reaction; TFRE, TF response elements; TFs, transcription factors; WB, western blotting First author under standardized training of residents at West China hospital.

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Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury

Cited by 242 publications

References 32 publications

Myocardial transcription factors in diastolic dysfunction: clues for model systems and disease

Myocardial transcription factors in diastolic dysfunction: clues for model systems and disease

Corneal endothelial cell density and cardiovascular mortality

Proteomic profiling of key transcription factors in the process of neonatal mouse cardiac regeneration capacity loss

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