Targeting the renin-angiotensin-aldosterone system in fibrosis

Qudah, Mohammad Al; Hale, Taben M.; Czubryt, Michael P.

doi:10.1016/j.matbio.2020.04.005

Cited by 87 publications

(51 citation statements)

References 157 publications

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“… 13 The core component of classic RAAS is Ang II, which is mediated by the type‑1 Ang II (AT1) receptor to activate many pro-inflammatory and fibrotic effects in vascular, heart, kidney, and other tissues. 14 A non-classical RAAS component is an enzyme called angiotensin‑converting enzyme 2 (ACE2), which has high Ang II affinity, and can transform this peptide to Ang-(1-7), and which binds to a G‑protein‑coupled receptor called Mas receptor. This ACE2-Ang-(1-7)-Mas axis has been reported to function as a counterbalance to the classic ACE-Ang II-AT1 axis, with opposite effects than those mediated by the classic axis.…”

Section: Introductionmentioning

confidence: 99%

The ACE2-Ang-(1‑7)-Mas Axis Modulates M1/M2 Macrophage Polarization to Relieve CLP-Induced Inflammation via TLR4-Mediated NF-кb and MAPK Pathways

Pan¹,

Huang²,

Wang³

et al. 2021

JIR

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has been identified as an important anti-inflammatory and anti-fibrotic factor. This study determined how the ACE2-Ang-(1-7)-Mas axis affected M1/ M2 macrophage polarization and thus contributed to anti-inflammatory processes in the cecal ligation and puncture (CLP)-induced inflammation model. Materials and Methods: ELISA, western blotting, and qRT-PCR were used to verify that Ang-(1-7) decreased the expression of pro-inflammatory cytokines and increased anti-inflammatory cytokines. The differentiation of M1/M2 macrophages was assessed by flow cytometry for assessing the cell-surface markers, CD86 and CD206. The related key receptors and pathways were analyzed by Western blotting, qRT-PCR, and immunofluorescence. CLP-induced inflammatory mice models were used for in vivo studies. Hematoxylin and eosin and immunohistochemical and immunofluorescence staining protocols were used to analyze histological changes in the spleen, and the related key pathway proteins were analyzed by western blotting. Results: Ang-(1-7) decreased the expressions of the TNF-α and IL-6 pro-inflammatory cytokines and increased the expressions of the IL-4 and IL-10 anti-inflammatory cytokines. INOS and TNFα, which represented M1 macrophage polarization, were decreased by Ang-(1-7). ARG1 and CD163, which represented M2 macrophage polarization, were increased by Ang-(1-7). Both Mas receptor and ACE2 are expressed on macrophages. Furthermore, the ACE2-Ang-(1-7)-MAS axis modulated macrophage polarization by ameliorating TLR4 expression and regulating the NF-кB and MAPK pathways. In addition, splenomegaly and macrophage infiltration were observed in the spleen of the CLP-induced mouse models and macrophages in the spleen suspension of CLP models were shifted to M1 phenotype and were effectively inhibited by Ang-(1-7) via the TLR4mediated NF-кB and MAPK pathways, which could be partially rescued by A-779. Ang-(1-7) inhibited inflammatory responses in vivo and in vitro, and repressed macrophage polarization toward the M1 phenotype and promoted it toward the M2 phenotype, which provided new evidence for the anti-inflammation activity of the ACE2-Ang -(1-7)-MAS axis. Conclusion:

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Section: Introductionmentioning

confidence: 99%

The ACE2-Ang-(1‑7)-Mas Axis Modulates M1/M2 Macrophage Polarization to Relieve CLP-Induced Inflammation via TLR4-Mediated NF-кb and MAPK Pathways

Pan¹,

Huang²,

Wang³

et al. 2021

JIR

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“…Previous studies have found that Ang II cause hypertension and hypertensive cardiac hypertrophy and fibrosis. 23 , 24 SIRT3 can protect the heart from multiple types of diseases which cause cardiac hypertrophy and fibrosis, through the regulation of oxidative stress, metabolism and aging. 14 , 25 , 26 , 27 It was consistent with the previous study that SIRT3 deficiency aggravated Ang II‐induced heart injury.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 3 deficiency aggravates angiotensin II‐induced hypertensive cardiac injury by the impairment of lymphangiogenesis

Zhang¹,

Li²,

Suo³

et al. 2021

J Cellular Molecular Medi

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Lymphangiogenesis is possibly capable of attenuating hypertension‐induced cardiac injury. Sirtuin 3 (SIRT3) is an effective mitochondrial deacetylase that has the potential to modulate this process; however, its role in hypertension‐induced cardiac lymphangiogenesis to date has not been investigated. Our experiments were performed on 8‐week‐old wild‐type (WT), SIRT3 knockout (SIRT3‐KO) and SIRT3 overexpression (SIRT3‐LV) mice infused with angiotensin II (Ang II) (1000 ng/kg per minute) or saline for 28 days. After Ang II infusion, SIRT3‐KO mice developed a more severe cardiac remodelling, less lymphatic capillaries and lower expression of lymphatic marker when compared to wild‐type mice. In comparison, SIRT3‐LV restored lymphangiogenesis and attenuated cardiac injury. Furthermore, lymphatic endothelial cells (LECs) exposed to Ang II in vitro exhibited decreased migration and proliferation. Silencing SIRT3 induced functional decrease in LECs, while SIRT3 overexpression LECs facilitated. Moreover, SIRT3 may up‐regulate lymphangiogenesis by affecting vascular endothelial growth factor receptor 3 (VEGFR3) and ERK pathway. These findings suggest that SIRT3 could promote lymphangiogenesis and attenuate hypertensive cardiac injury.

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“…Upon injury of myocardial tissue, transforming growth factor-beta 1 (TGF-b1) augments ECM through (myo)fibroblast proliferation and activation (Liu et al 2009). TGF-b1 expression can also be enhanced by angiotensin II (AngII) via the angiotensin II type 1 receptor (AT1); both cardiomyocyte hypertrophy and the development of cardiac fibrosis can develop through the activation of this pathway (Gao et al 2009;Yokono et al 2020;AlQudah et al 2020).…”

Section: Cardiotoxicity Induced By Radiotherapymentioning

confidence: 99%

Preliminary pre-clinical studies on the side effects of breast cancer treatment

Salata

deAlmeida

Ferreira-Machado

et al. 2021

International Journal of Radiation Biology

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Purpose: Technological advancement in the treatment of cancer together with early detection and diagnosis have considerably improved the survival of breast cancer patients. On the other hand, the potential of patients developing side effects from cancer treatment are not negligible. Despite the progress that has been made in terms of early diagnosis, therapy, and survival, including improvements in the chemotherapeutic agents, radiation and molecular targeted therapies, cardiotoxicity of cancer therapy is still cause for concern. Radiation therapy for breast cancer is associated with increased risk of heart disease and myocardial infarction. Furthermore, the association of radiation therapy to chemotherapy is an important aspect to be considered in the development of cardiac disease, as this could play an additional role as a risk factor. Besides the heart effect, other side effects can be observed in the bone, ovary, uteri, and other organs. This paper aims to review the recent literature to present the current understanding of side effects associated with breast cancer treatment. The focus is on recent preclinical studies that have assessed potential changes in different organs that may be injured after breast cancer treatment, both due to both radiation and chemotherapy agents. Conclusion: Radiation-induced heart disease is one important side effect that must be considered during the treatment planning and patient follow-up. The cardiac damage can be potentialized when chemotherapy is associated to radiotherapy, and the literature findings indicate that heart fibrosis plays an important role at the radio-chemotherapy induced cardiac damage. Literature findings also showed important side effects at the bone, that can lead to ospeoporosis, due to the decrease of calcium, after radio or chemotherapy treatments. This decrease could be explained by the ovarian failure observed at rats after chemotherapy treatment. It is of great importance to acknowledge the complications originating from the treatment, so that new strategies can be developed. In this way, it will be possible to minimize side effects and improve the patients' quality of life.

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Targeting the renin-angiotensin-aldosterone system in fibrosis

Cited by 87 publications

References 157 publications

The ACE2-Ang-(1‑7)-Mas Axis Modulates M1/M2 Macrophage Polarization to Relieve CLP-Induced Inflammation via TLR4-Mediated NF-кb and MAPK Pathways

The ACE2-Ang-(1‑7)-Mas Axis Modulates M1/M2 Macrophage Polarization to Relieve CLP-Induced Inflammation via TLR4-Mediated NF-кb and MAPK Pathways

Sirtuin 3 deficiency aggravates angiotensin II‐induced hypertensive cardiac injury by the impairment of lymphangiogenesis

Preliminary pre-clinical studies on the side effects of breast cancer treatment

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