Cardiac Fibroblast Activation Induced by Oxygen–Glucose Deprivation Depends on the HIF-1α/miR-212-5p/KLF4 Pathway

Li, Hongbing; Li, Chenxing; Zheng, Tao; Wang, Yaning; J, Wang; Fan, Xiaojuan; Zheng, Xueyang; Tang, Gang; Yuan, Zuyi; Chen, Tao

doi:10.1007/s12265-023-10360-2

Cited by 3 publications

(3 citation statements)

References 30 publications

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“…Since we had observed increased KLF4 protein in cilia KO endocardium, we analyzed whether this is reflected in expression levels of known KLF4 targets in the endocardial cluster. These comprise genes that are activated by KLF4 including Lama3 (Laminin subunit) 52 , Malat1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) 53 , Vegfa , and Vegfc (Vascular Endothelial Growth Factors) 54–56 , and genes known to be repressed by KLF4 including Col3a1 (Collagen) 57 , Pdgfrα (Platelet-derived growth factor receptor) 58 , Wnt4 59 , and Cdkn1c ( p57, cyclin dependent kinase inhibitor) 55 . In Ift20 −/− endocardium (high KLF4 protein), we observed increased levels of KLF4-activated genes and decreased levels of KLF4-repressed genes, consistent with increased KLF4 expression in the absence of cilia that we previously observed through HCR-WISH and IF analysis (Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Defects In Ciliogenesis Block Endomtmentioning

confidence: 99%

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Endocardial primary cilia and blood flow are required for regulation of EndoMT during endocardial cushion development

Berg,

Gorham,

Lundt

et al. 2024

Preprint

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Blood flow is critical for heart valve formation, and cellular mechanosensors are essential to translate flow into transcriptional regulation of development. Here, we identify a role for primary cilia in vivo in the spatial regulation of cushion formation, the first stage of valve development, by regionally controlling endothelial to mesenchymal transition (EndoMT) via modulation of Kruppel-like Factor 4 (Klf4). We find that high shear stress intracardiac regions decrease endocardial ciliation over cushion development, correlating with KLF4 downregulation and EndoMT progression. Mouse embryos constitutively lacking cilia exhibit a blood-flow dependent accumulation of KLF4 in these regions, independent of upstream left right abnormalities, resulting in impaired cushion cellularization. snRNA-seq revealed that cilia KO endocardium fails to progress to late-EndoMT, retains endothelial markers and has reduced EndoMT/mesenchymal genes that KLF4 antagonizes. Together, these data identify a mechanosensory role for endocardial primary cilia in cushion development through regional regulation of KLF4.

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Section: Resultsmentioning

confidence: 99%

Section: Defects In Ciliogenesis Block Endomtmentioning

confidence: 99%

Endocardial primary cilia and blood flow are required for regulation of EndoMT during endocardial cushion development

Berg,

Gorham,

Lundt

et al. 2024

Preprint

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“…Given the poor results with viral targeting of the cardiac scar and our success with cardiac cell grafting, we explored the utility of combining ex vivo gene therapy, MNP loading and magnet-assisted cell injection into cardiac lesions as a novel cardiac targeting and treatment strategy. Cardiac mFB are a large cell population in the mammalian heart, they can be harvested and expanded in vitro and are reported to be more tolerant towards the adverse local conditions (8)(9)(10). Moreover, for translational purposes human cardiac mFB can be obtained from donors or generated from human induced pluripotent stem cells (hiPSCs) (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Efficient targeting of heart lesions with cardiac myofibroblasts: Combined gene and cell therapy enhanced by magnetic steering

Schiffer,

Wagner,

Carls

et al. 2024

Preprint

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1AbstractThe cardiac scar is a collagen-rich area, which is populated by myofibroblasts and has proven little amenable for therapeutic interventions. Herein, we have established an efficient targeting strategy for cardiac lesions by genetically manipulating embryonic cardiac myofibroblasts (mFB)in vitro, load the cells with magnetic nanoparticles and inject these into infarcted mouse hearts using magnetic steering. This yields strongly increased numbers (∼4 fold compared to other cell types) of engrafted mFB. The injected mFB and endogenous myofibroblast (endoFB) population remain separate in the scar, but grafted mFB enhance the proliferation rate of endoFB by ∼4 fold. We also tested the functional impact of this approach by grafting lentiviral (LV)-transduced Connexin43 (Cx43) overexpressing mFB into the cardiac lesion. Prominent engraftment of Cx43+mFB provides strong protection against post-infarct ventricular tachycardia (VT)in vivo, as VT incidence is reduced by ∼50 % at two and eight weeks after cell injection. Thus,ex vivogene and subsequentin vivocell therapy combined with magnetic steering of cardiac mFB enable efficient functional targeting of the cardiac scar.

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Inhibition of miR-25 Ameliorates Cardiac Dysfunction and Fibrosis by Restoring Krüppel-like Factor 4 Expression

Lee

Cho

Jeong

2023

IJMS

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Cardiac hypertrophy is an adaptive response to various pathological insults, including hypertension. However, sustained hypertrophy can cause impaired calcium regulation, cardiac dysfunction, and remodeling, accompanied by cardiac fibrosis. Our previous study identified miR-25 as a regulator of SERCA2a, and found that the inhibition of miR-25 improved cardiac function and reduced fibrosis by restoring SERCA2a expression in a murine heart failure model. However, the precise mechanism underlying the reduction in fibrosis following miR-25 inhibition remains unclear. Therefore, we postulate that miR-25 may have additional targets that contribute to regulating cardiac fibrosis. Using in silico analysis, Krüppel-like factor 4 (KLF4) was identified as an additional target of miR-25. Further experiments confirmed that KLF4 was directly targeted by miR-25 and that its expression was reduced by long-term treatment with Angiotensin II, a major hypertrophic inducer. Subsequently, treatment with an miR-25 inhibitor alleviated the cardiac dysfunction, fibrosis, and inflammation induced by Angiotensin II (Ang II). These findings indicate that inhibiting miR-25 not only enhances calcium cycling and cardiac function via SERCA2a restoration but also reduces fibrosis by restoring KLF4 expression. Therefore, targeting miR-25 may be a promising therapeutic strategy for treating hypertensive heart diseases.

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Cardiac Fibroblast Activation Induced by Oxygen–Glucose Deprivation Depends on the HIF-1α/miR-212-5p/KLF4 Pathway

Cited by 3 publications

References 30 publications

Endocardial primary cilia and blood flow are required for regulation of EndoMT during endocardial cushion development

Endocardial primary cilia and blood flow are required for regulation of EndoMT during endocardial cushion development

Efficient targeting of heart lesions with cardiac myofibroblasts: Combined gene and cell therapy enhanced by magnetic steering

Inhibition of miR-25 Ameliorates Cardiac Dysfunction and Fibrosis by Restoring Krüppel-like Factor 4 Expression

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