Targeting myeloid cell coagulation signaling blocks MAP kinase/TGF-β1–driven fibrotic remodeling in ischemic heart failure

Garlapati, Venkata; Molitor, Michael; Michna, Thomas; Harms, Gregory S.; Finger, Stefanie; Jung, Rebecca; Lagrange, Jérémy; Efentakis, Panagiotis; Wild, Johannes; Knorr, Maike; Karbach, Susanne; Wild, S P; Münzel, Thomas; Daiber, Andreas; Brandt, Moritz; Gori, Tommaso; Milting, Hendrik; Ruf, Wolfram; Wenzel, Philip

doi:10.1172/jci156436

Cited by 22 publications

(12 citation statements)

References 70 publications

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“…Similarly, TF-PAR2 signaling has been linked to ischemia-mediated heart failure and fibrosis. 65 We propose coagulation-independent inhibition of TF-FVIIa-PAR2-β-arrestin signaling as a therapeutic approach for mitigating metabolic and inflammatory disturbances in CVB3 infection. The coagulation and innate immune response systems interact to form an integrated defense against tissue injury and infection.…”

Section: Discussionmentioning

confidence: 99%

TF-FVIIa PAR2-β-Arrestin Signaling Sustains Organ Dysfunction in Coxsackievirus B3 Infection of Mice

Kespohl,

Goetzke,

Althof

et al. 2024

ATVB

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BACKGROUND: Accumulating evidence implicates the activation of G-protein–coupled PARs (protease-activated receptors) by coagulation proteases in the regulation of innate immune responses. METHODS: Using mouse models with genetic alterations of the PAR2 signaling platform, we have explored contributions of PAR2 signaling to infection with coxsackievirus B3, a single-stranded RNA virus provoking multiorgan tissue damage, including the heart. RESULTS: We show that PAR2 activation sustains correlates of severe morbidity—hemodynamic compromise, aggravated hypothermia, and hypoglycemia—despite intact control of the virus. Following acute viral liver injury, canonical PAR2 signaling impairs the restoration process associated with exaggerated type I IFN (interferon) signatures in response to viral RNA recognition. Metabolic profiling in combination with proteomics of liver tissue shows PAR2-dependent reprogramming of liver metabolism, increased lipid droplet storage, and gluconeogenesis. PAR2-sustained hypodynamic compromise, reprograming of liver metabolism, as well as imbalanced IFN responses are prevented in β-arrestin coupling-deficient PAR2 C-terminal phosphorylation mutant mice. Thus, wiring between upstream proteases and immune-metabolic responses results from biased PAR2 signaling mediated by intracellular recruitment of β-arrestin. Importantly, blockade of the TF (tissue factor)-FVIIa (coagulation factor VIIa) complex capable of PAR2 proteolysis with the NAPc2 (nematode anticoagulant protein c2) mitigated virus-triggered pathology, recapitulating effects seen in protease cleavage-resistant PAR2 mice. CONCLUSIONS: These data provide insights into a TF-FVIIa signaling axis through PAR2-β-arrestin coupling that is a regulator of inflammation-triggered tissue repair and hemodynamic compromise in coxsackievirus B3 infection and can potentially be targeted with selective coagulation inhibitors.

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Section: Discussionmentioning

confidence: 99%

TF-FVIIa PAR2-β-Arrestin Signaling Sustains Organ Dysfunction in Coxsackievirus B3 Infection of Mice

Kespohl,

Goetzke,

Althof

et al. 2024

ATVB

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“…The Ras/Raf/MEK/ERK signaling pathway is one of the mitogen-activated protein kinase (MAPK) signaling pathways. The MAPK pathway is associated with diseases including excessive fibrosis of human body tissues . Substances acting on the RAS/MAPK pathway can be designed for the purpose of curing diseases and improving health …”

Section: Discussionmentioning

confidence: 99%

“…The MAPK pathway is associated with diseases including excessive fibrosis of human body tissues. 37 Substances acting on the RAS/MAPK pathway can be designed for the purpose of curing diseases and improving health. 38 Ras is a proto-oncogene of the GTP/GDP binding protein.…”

Section: Discussionmentioning

confidence: 99%

Promoted Skin Wound Healing by Tail-AmputatedEisenia foetidaProteins via the Ras/Raf/MEK/ERK Signaling Pathway

Sun

Wang

et al. 2023

ACS Omega

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Skin wound healing is an important fundamental problem in biological and medical fields. This study aimed to investigate wound healing promotion of protein extract from tail-amputated Eisenia foetida (E. foetida) and reveal the mechanism correlated with the Ras/Raf/MEK/ERK signaling pathway. Proteins extracted from tail-amputated E. foetida were applied on rats’ full-thickness excisional wounds to evaluate their regenerative efficacy. Rat skin tissues around surgical defects were analyzed by immunofluorescence staining and Western blot methods. The Ras/Raf/MEK/ERK signaling pathway was further investigated in vitro using the NIH3T3 cell line. A tail-amputated protein extract (ES2) from E. foetida significantly accelerated rat wound healing ability via higher re-epithelialization and ECM deposition in the tissue section compared to the blank control and un-amputated earthworm extract groups. Furthermore, ES2 treatment dramatically accumulated the expressions of platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), and hydroxyproline (HYP) in wound areas on day 7 without their accumulation on day 21 post-wounding, diminishing excessive scar formation. Accelerated wound healing ability with the ES2 was proved to correlate with the up-regulation of the Ras/Raf/MEK/ERK signaling pathway. The mRNA expression of this pathway increased significantly in NIH3T3 cells after being treated with the ES2 at an appropriate concentration. The tail-amputated E. foetida proteins (ES2) can significantly promote skin wound healing better than the un-amputated earthworm tissue extract without excessive scar tissue formation. This effect was related to the up-regulation of the Ras/Raf/MEK/ERK signaling pathway.

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“…To protect the heart, the TGF-β signaling system controls apoptosis, autophagy, and antifibrotic activities ( Deng et al, 2019 ; Shen et al, 2020a ; Liang et al, 2022 ). Of these, the most in-depth studies have been conducted on the effects of TGF-β1 on myocardial fibrosis ( Garlapati et al, 2023 ).…”

Section: Cardiovascular Disease-related Signal Pathwaysmentioning

confidence: 99%

Effects of scutellarin on the mechanism of cardiovascular diseases: a review

Zhang,

Yin,

Wang

et al. 2024

Front. Pharmacol.

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Cardiovascular diseases represent a significant worldwide problem, jeopardizing individuals’ physical and mental wellbeing as well as their quality of life as a result of their widespread incidence and fatality. With the aging society, the occurrence of Cardiovascular diseases is progressively rising each year. However, although drugs developed for treating Cardiovascular diseases have clear targets and proven efficacy, they still carry certain toxic and side effect risks. Therefore, finding safe, effective, and practical treatment options is crucial. Scutellarin is the primary constituent of Erigeron breviscapus (Vant.) Hand-Mazz. This article aims to establish a theoretical foundation for the creation and use of secure, productive, and logical medications for Scutellarin in curing heart-related illnesses. Additionally, the examination and analysis of the signal pathway and its associated mechanisms with regard to the employment of SCU in treating heart diseases will impart innovative resolving concepts for the treatment and prevention of Cardiovascular diseases.

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Targeting myeloid cell coagulation signaling blocks MAP kinase/TGF-β1–driven fibrotic remodeling in ischemic heart failure

Cited by 22 publications

References 70 publications

TF-FVIIa PAR2-β-Arrestin Signaling Sustains Organ Dysfunction in Coxsackievirus B3 Infection of Mice

TF-FVIIa PAR2-β-Arrestin Signaling Sustains Organ Dysfunction in Coxsackievirus B3 Infection of Mice

Promoted Skin Wound Healing by Tail-AmputatedEisenia foetidaProteins via the Ras/Raf/MEK/ERK Signaling Pathway

Effects of scutellarin on the mechanism of cardiovascular diseases: a review

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