Limb-bud and Heart (LBH) mediates proliferation, fibroblast-to-myofibroblast transition and EMT-like processes in cardiac fibroblasts

Wu, Anbiao; Zhang, Lihong; Chen, Jingyang; Li, Hekai; Yang, Pingzhen; Chen, Minsheng; Liu, Qicai

doi:10.1007/s11010-021-04111-7

Cited by 10 publications

(27 citation statements)

References 57 publications

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“…However, this VEGFA regulation does not necessarily rely on PPIs; in fact, CRYAB has been reported to be transcriptionally regulated under exogenous TGF-β1 stimulation [57], while LBH has been verified to function as a transcriptional cofactor in NPC, and to be regulated by TGF-β1 signaling as a downstream factor [21]. Additionally, we demonstrated that CRYAB might be transcriptionally regulated by both TGF-β1 and LBH in our previous studies [10,58]. Since there is no external evidence to support that VEGFA is transcriptionally regulated by LBH as we observed, it could be our next research orientation to further explore the potential mechanisms.…”

Section: Discussionsupporting

confidence: 50%

Exosomal LBH inhibits epithelial-mesenchymal transition and angiogenesis in nasopharyngeal carcinoma via downregulating VEGFA signaling

Wu¹,

Luo²,

Xu³

et al. 2022

Int. J. Biol. Sci.

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Section: Discussionsupporting

confidence: 50%

Exosomal LBH inhibits epithelial-mesenchymal transition and angiogenesis in nasopharyngeal carcinoma via downregulating VEGFA signaling

Wu¹,

Luo²,

Xu³

et al. 2022

Int. J. Biol. Sci.

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“…The establishment of conventional LBH- KO C57BL/6 mice was performed by Cyagen, Inc., via the CRISPR/Cas9 technique (contract ID: KOAI200813MG1) to generate F 0 founder animals; then, the wild-type (WT)/KO offspring were bred, identified, and maintained at the Animal Experiment Center of Zhujiang Hospital (Figure S1 ). The MI model was constructed according to our previous research [ 13 ]. All mice were sacrificed to obtain the hearts on days 2 and 3 after surgery.…”

Section: Methodsmentioning

confidence: 99%

“…Limb-bud and heart (LBH) is a highly conserved transcriptional cofactor that has important roles in embryonic development and cardiogenesis [ 12 ]. In our previous study, aberrant LBH expression initiated by TGF- β 1 stimulation was detected in CFs accumulating in the infarcted myocardium, which promoted CF activation via LBH-CRYAB signaling during post-MI infarct healing [ 13 ]. Additionally, the upregulation of hypoxia inducible factor-1 α (HIF-1 α ) was triggered by hypoxic conditions during the inflammatory phase, which was related to LBH-induced CF proliferative acceleration [ 13 ], whereas CF activation is due to the comprehensive effects of different causes in the post-MI cardiac microenvironment [ 14 ], and potential LBH-associated mechanisms regarding the communication between CFs and other cardiac cell types, such as CMs, endothelial cells, inflammatory cells, and immune cells [ 15 ], remain largely unclear.…”

Section: Introductionmentioning

confidence: 99%

“…In our previous study, aberrant LBH expression initiated by TGF- β 1 stimulation was detected in CFs accumulating in the infarcted myocardium, which promoted CF activation via LBH-CRYAB signaling during post-MI infarct healing [ 13 ]. Additionally, the upregulation of hypoxia inducible factor-1 α (HIF-1 α ) was triggered by hypoxic conditions during the inflammatory phase, which was related to LBH-induced CF proliferative acceleration [ 13 ], whereas CF activation is due to the comprehensive effects of different causes in the post-MI cardiac microenvironment [ 14 ], and potential LBH-associated mechanisms regarding the communication between CFs and other cardiac cell types, such as CMs, endothelial cells, inflammatory cells, and immune cells [ 15 ], remain largely unclear. In our preliminary experiment conducted on a mouse MI model, the upregulation of LBH and CRYAB observed in activated CFs during the inflammatory phase synchronized with the expressional changes in CMs in the peri-infarct myocardium, together with overexpressed HIF-1 α .…”

Section: Introductionmentioning

confidence: 99%

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Limb-Bud and Heart (LBH) Upregulation in Cardiomyocytes under Hypoxia Promotes the Activation of Cardiac Fibroblasts via Exosome Secretion

Chen

et al. 2022

Mediators of Inflammation

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The activation of cardiac fibroblasts (CFs) after myocardial infarction (MI) is essential for post-MI infarct healing, during which the regulation of transforming growth factor beta1 (TGF-β1) signaling is predominant. We have demonstrated that TGF-β1-mediated upregulation of LBH contributes to post-MI CF activation via modulating αB-crystallin (CRYAB), after being upregulated by TGF-β1. In this study, the effect of LBH-CRYAB signaling on the cardiac microenvironment via exosome communication and the corresponding mechanisms were investigated. The upregulation of LBH and CRYAB was verified in both cardiomyocytes (CMs) and CFs in hypoxic, post-MI peri-infarct tissues. CM-derived exosomes were isolated and identified, and LBH distribution was elevated in exosomes derived from LBH-upregulated CMs under hypoxia. Treatment with LBH+ exosomes promoted cellular proliferation, differentiation, and epithelial-mesenchymal transition-like processes in CFs. Additionally, in primary LBHKO CFs, western blotting showed that LBH knockout partially inhibited TGF-β1-induced CF activation, while LBH-CRYAB signaling affected TGF-β1 expression and secretion through a positive feedback loop. The administration of a Smad3 phosphorylation inhibitor to LBHKO CFs under TGF-β1 stimulation indicated that Smad3 phosphorylation partially accounted for TGF-β1-induced LBH upregulation. In conclusion, LBH upregulation in CMs in post-MI peri-infarct areas correlated with a hypoxic cardiac microenvironment and led to elevated exosomal LBH levels, promoting the activation of recipient CFs, which brings new insights into the studies and therapeutic strategies of post-MI cardiac repair.

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“…Nevertheless, as stated, the EMT refers to a phenomenon that is, based on an increasingly developed body of evidence, recognized to be similarly involved in the pathogenesis of cardiac fibrosis ( 36 – 38 , 85 – 88 ). Numerous soluble factors, predominantly TGF-β ( 36 – 38 , 86 – 88 ), and extracellular matrix components act synergistically to elicit EMT programming in various tissues, including the heart, whereas MAPKs signals (p38, ERK 1/2, and JNK), upregulate transcription factors for epithelial-mesenchymal transition ( 87 , 88 ). Additional evidence that renalase (in vivo) inhibits EMT via direct suppression of ERK 1/2 signaling ( 17 , 21 , 68 , 69 , 84 ), likewise in the aforementioned research, indirectly impeding the source for myofibroblasts, suggests scientific plausibility for renalase to be involved in cardiac fibrosis scrutiny.…”

Section: The Identification Of Renalase As a Relevant Antifibrotic Mo...mentioning

confidence: 99%

The Scientific Rationale for the Introduction of Renalase in the Concept of Cardiac Fibrosis

Stojanović

Mitić

Stojanović

et al. 2022

Front. Cardiovasc. Med.

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Cardiac fibrosis represents a redundant accumulation of extracellular matrix proteins, resulting from a cascade of pathophysiological events involved in an ineffective healing response, that eventually leads to heart failure. The pathophysiology of cardiac fibrosis involves various cellular effectors (neutrophils, macrophages, cardiomyocytes, fibroblasts), up-regulation of profibrotic mediators (cytokines, chemokines, and growth factors), and processes where epithelial and endothelial cells undergo mesenchymal transition. Activated fibroblasts and myofibroblasts are the central cellular effectors in cardiac fibrosis, serving as the main source of matrix proteins. The most effective anti-fibrotic strategy will have to incorporate the specific targeting of the diverse cells, pathways, and their cross-talk in the pathogenesis of cardiac fibroproliferation. Additionally, renalase, a novel protein secreted by the kidneys, is identified. Evidence demonstrates its cytoprotective properties, establishing it as a survival element in various organ injuries (heart, kidney, liver, intestines), and as a significant anti-fibrotic factor, owing to its, in vitro and in vivo demonstrated pleiotropy to alleviate inflammation, oxidative stress, apoptosis, necrosis, and fibrotic responses. Effective anti-fibrotic therapy may seek to exploit renalase’s compound effects such as: lessening of the inflammatory cell infiltrate (neutrophils and macrophages), and macrophage polarization (M1 to M2), a decrease in the proinflammatory cytokines/chemokines/reactive species/growth factor release (TNF-α, IL-6, MCP-1, MIP-2, ROS, TGF-β1), an increase in anti-apoptotic factors (Bcl2), and prevention of caspase activation, inflammasome silencing, sirtuins (1 and 3) activation, and mitochondrial protection, suppression of epithelial to mesenchymal transition, a decrease in the pro-fibrotic markers expression (’α-SMA, collagen I, and III, TIMP-1, and fibronectin), and interference with MAPKs signaling network, most likely as a coordinator of pro-fibrotic signals. This review provides the scientific rationale for renalase’s scrutiny regarding cardiac fibrosis, and there is great anticipation that these newly identified pathways are set to progress one step further. Although substantial progress has been made, indicating renalase’s therapeutic promise, more profound experimental work is required to resolve the accurate underlying mechanisms of renalase, concerning cardiac fibrosis, before any potential translation to clinical investigation.

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Limb-bud and Heart (LBH) mediates proliferation, fibroblast-to-myofibroblast transition and EMT-like processes in cardiac fibroblasts

Cited by 10 publications

References 57 publications

Exosomal LBH inhibits epithelial-mesenchymal transition and angiogenesis in nasopharyngeal carcinoma via downregulating VEGFA signaling

Exosomal LBH inhibits epithelial-mesenchymal transition and angiogenesis in nasopharyngeal carcinoma via downregulating VEGFA signaling

Limb-Bud and Heart (LBH) Upregulation in Cardiomyocytes under Hypoxia Promotes the Activation of Cardiac Fibroblasts via Exosome Secretion

The Scientific Rationale for the Introduction of Renalase in the Concept of Cardiac Fibrosis

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