Role of PI3K/Akt signaling pathway in cardiac fibrosis

Qin, Wu-Ming; Cao, Linghui; Massey, Isaac Yaw

doi:10.1007/s11010-021-04219-w

Cited by 149 publications

(98 citation statements)

References 166 publications

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“…mirTarBase v8.0), the top three miRNA regulators of this gene network were hsa-mir-335-5p , hsa-mir-124-3p , and hsa-mir-26b-5p . Together with the hsa-mir-29b-3p and hsa-mir-29a-3p identified by gProfiler2, we mapped out these miRNAs on the gene-miRNA regulatory networks for the selected KEGG pathways relevant to the DMD-CO phenotypes: (1) Hypertrophy cardiomyopathy, (2) Dilated cardiomyopathy, (3) Arrhythmogenic right ventricular cardiomyopathy (ARVC), (4) PPAR signalling pathway (for adipogenesis), and (5) PI3K-Akt signalling pathway (for cardiac fibrosis (Qin et al, 2021)). The results showed that hypertrophy and dilated cardiomyopathy networks shared the same gene set (50 nodes, 49 edges), miRNA interactions ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Based on the duality effects of these miRNAs, the potential of these miRNAs as therapeutic targets for DMD-related cardiomyopathy need to be assessed carefully. Furthermore, the identified PI3K/Akt signaling pathway enriched in DMD-CO is interesting, as accumulating evidences showed that it plays a role in regulating the occurrence, progression and pathological cardiac fibrosis (Qin et al, 2021) and hypetrophy (Aoyagi and Matsui, 2011).…”

Section: Discussionmentioning

confidence: 99%

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Long-Term Culture of Patient-Derived Cardiac Organoids Recapitulated Duchenne Muscular Dystrophy Cardiomyopathy and Disease Progression

Marini

Marino

Aliberti

et al. 2022

Preprint

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Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disease which to-date incurable. The major cause of death is dilated cardiomyopathy, however the pathogenesis is unclear as existing cellular and animal models do not fully recapitulate the human disease phenotypes. In this study, we generated cardiac organoids from patient-derived pluripotent stem cells (DMD-CO) and isogenic-corrected controls (DMD-Iso-CO) and studied if DMD-related cardiomyopathy and disease progression occur in the organoids upon long-term culture (up to 93 days). Histological analysis showed that DMD-CO lacks initial proliferative capacity, displayed a progressive loss of α-sarcoglycan localization and high stress in endoplasmic reticulum. Additionally, the cardiomyocyte deteriorated over time, and fibrosis and adipogenesis were observed in DMD-CO. RNA sequencing analysis confirmed a distinct transcriptomic profile in DMD-CO which were associated with functional enrichment in hypertrophy/dilated cardiomyopathy, arrhythmia, adipogenesis and fibrosis pathways. Moreover, five miRNAs were identified to be crucial in this dysregulated gene network. In conclusion, we generated patient-derived cardiac organoid model that displayed DMD-related cardiomyopathy and disease progression phenotypes in long-term culture. We envision the feasibility to develop a more complex, realistic and reliable in vitro 3D human cardiac-mimics to study DMD-related cardiomyopathies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long-Term Culture of Patient-Derived Cardiac Organoids Recapitulated Duchenne Muscular Dystrophy Cardiomyopathy and Disease Progression

Marini

Marino

Aliberti

et al. 2022

Preprint

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“…Fibrosis is a common process characterized by excessive ECM accumulation, whereas dynamic remodeling of the ECM around invasive cancer cells is implicated in tumor progression [ 57 ]. Accumulating evidence suggests that the PI3K/Akt signaling pathway plays a positive role in the pathological formation of fibrosis [ 58 ] and various human cancers [ 57 , 59 ]. In contrast, AMPK alleviates fibrogenesis and ECM production in various organs and tissues [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

AMP-activated protein kinase-dependent nuclear localization of glyceraldehyde 3-phosphate dehydrogenase in senescent human diploid fibroblasts

Sohn

Kwak

Rhim³

et al. 2022

Aging

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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme that participates in various cellular events, such as DNA repair and apoptosis. The functional diversity of GAPDH depends on its intracellular localization. Because AMP-activated protein kinase (AMPK) regulates the nuclear translocation of GAPDH in young cells and AMPK activity significantly increases during aging, we investigated whether altered AMPK activity is involved in the nuclear localization of GAPDH in senescent cells. Age-dependent nuclear translocation of GAPDH was confirmed by confocal laser scanning microscopy in human diploid fibroblasts (HDFs) and by immunohistochemical analysis in aged rat skin cells. Senescence-induced nuclear localization was reversed by lysophosphatidic acid but not by platelet-derived growth factor. The extracellular matrix from young cells also induced the nuclear export of GAPDH in senescent HDFs. An activator of AMPK, 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), increased the level of nuclear GAPDH, whereas an inhibitor of AMPK, Compound C, decreased the level of nuclear GAPDH in senescent HDFs. Transfection with AMPKα siRNA prevented nuclear translocation of GAPDH in senescent HDFs. The stimulatory effect of AICAR and serum depletion on GAPDH nuclear translocation was reduced in AMPKα1/α2-knockout mouse embryonic fibroblasts. Overall, increased AMPK activity may play a role in the senescence-associated nuclear translocation of GAPDH.

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“…A growing body of evidence delineates that the PI3K/AKT signaling pathway plays a key role in a multitude of processes related to the incidence, advancement, and pathological generation of cardiac fibrogenesis via the regulation of cell survival, apoptosis and cardiac contractility, albeit activating the target genes [ 100 , 116 , 117 , 118 ]. Essentially, the triggering of PI3K by receptor tyrosine kinases determines phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to bring about phosphatidylinositol-3,4,5-triphosphate (PIP3) and activates the signaling pathway [ 119 ].…”

Section: Network Of Interactions Between Signaling Pathwaysmentioning

confidence: 99%

“…The activity of PI3K is counteracted by the tumor suppressor protein Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), which detaches the phosphate group from the 3′ end of the inositol ring of PIP3, thereby negatively regulating the pathway [ 119 , 120 ]. AKT kinase represents activated downstream of PIP3 and synchronizes miscellaneous downstream effectors, including the mammalian target of rapamycin (mTOR), GSK3B, and Forkhead box proteins O1/3 (FOXO1/3) [ 118 , 121 ]. Suppression of mTOR with rapamycin avoids cardiac hypertrophy, advocating that mTOR plays a pivotal role in cardioprotection [ 122 ].…”

Section: Network Of Interactions Between Signaling Pathwaysmentioning

confidence: 99%

Dynamic Involvement of Telocytes in Modulating Multiple Signaling Pathways in Cardiac Cytoarchitecture

Cucu

Nicolescu

Busnatu

et al. 2022

IJMS

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Cardiac interstitium is a complex and dynamic environment, vital for normal cardiac structure and function. Telocytes are active cellular players in regulating main events that feature myocardial homeostasis and orchestrating its involvement in heart pathology. Despite the great amount of data suggesting (microscopically, proteomically, genetically, etc.) the implications of telocytes in the different physiological and reparatory/regenerative processes of the heart, understanding their involvement in realizing the heart’s mature cytoarchitecture is still at its dawn. Our scrutiny of the recent literature gave clearer insights into the implications of telocytes in the WNT signaling pathway, but also TGFB and PI3K/AKT pathways that, inter alia, conduct cardiomyocytes differentiation, maturation and final integration into heart adult architecture. These data also strengthen evidence for telocytes as promising candidates for cellular therapies in various heart pathologies.

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Role of PI3K/Akt signaling pathway in cardiac fibrosis

Cited by 149 publications

References 166 publications

Long-Term Culture of Patient-Derived Cardiac Organoids Recapitulated Duchenne Muscular Dystrophy Cardiomyopathy and Disease Progression

Long-Term Culture of Patient-Derived Cardiac Organoids Recapitulated Duchenne Muscular Dystrophy Cardiomyopathy and Disease Progression

AMP-activated protein kinase-dependent nuclear localization of glyceraldehyde 3-phosphate dehydrogenase in senescent human diploid fibroblasts

Dynamic Involvement of Telocytes in Modulating Multiple Signaling Pathways in Cardiac Cytoarchitecture

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