Hydroxysafflor Yellow A Protects Against Myocardial Ischemia/Reperfusion Injury  via  Suppressing NLRP3 Inflammasome and Activating Autophagy

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Abstract

Myocardial ischemia/reperfusion (MI/R) injury is a serious threat to human health. Hydroxysafflor yellow A (HSYA), the main water-soluble ingredient extracted from Carthami flos ( Carthamus tinctorius L.), has therapeutic potential for treating MI/R injury. However, the mechanisms of HSYA−mediated protection from MI/R injury are incompletely understood. In the present study, we investigated the effects and the underlying mechanisms of HSYA during MI/R. Adult Sprague-Dawley rats were subjected to left anterior descending artery ligation for 30 min followed by 24 h of reperfusion with or without HSYA treatment. The protective effect of HSYA was detected by 2,3,5-triphenyl tetrazolium chloride (TTC) staining, hematoxylin eosin (HE) staining, and myocardial enzymes detections. Serum levels of inflammatory factors such as TNF-α, interleukin (IL)-1β, and IL-18, were detected using ELISA kits. The expression of NLRP3 and other related proteins in the myocardium was detected by western blot and immunohistochemistry. The expression of autophagy-related proteins, including Atg5, BECN1, P62, and LC3B, was detected by western blot to evaluate the effect of HSYA on autophagy. Results showed that HSYA decreased the myocardial infarct size and attenuated the cardiac dysfunction in rats after I/R. In addition, HSYA inhibited myocardial apoptosis compared with the I/R group, decreased the levels of inflammatory cytokines in rat serum, reduced NLRP3 inflammasome expression, and induced autophagy. Mechanistically, our results demonstrated that HSYA can activate AMPK to improve autophagy and inhibit NLRP3 inflammasome by inhibiting the mTOR pathway. This work provides strong data supporting for the clinical applications of HSYA in MI/R injury.

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NLRP3 inflammasome and its inhibitors: a review

Bo-zong Shao, Zhe-Qi Xu, Bin-ze Han … (2015)

Inflammasomes are newly recognized, vital players in innate immunity. The best characterized is the NLRP3 inflammasome, so-called because the NLRP3 protein in the complex belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as “pyrin domain-containing protein 3”. The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic fever syndrome, as well as other auto-immune and auto-inflammatory diseases. Several NLRP3 inflammasome inhibitors have been described, some of which show promise in the clinic. The present review will describe the structure and mechanisms of activation of the NLRP3 inflammasome, its association with various auto-immune and auto-inflammatory diseases, and the state of research into NLRP3 inflammasome inhibitors.

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Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease

Dominic Del Re, Dulguun Amgalan, Andreas Linkermann … (2019)

Twelve regulated cell death programs have been described. We review in detail the basic biology of nine including death receptor-mediated apoptosis, death receptor-mediated necrosis (necroptosis), mitochondrial-mediated apoptosis, mitochondrial-mediated necrosis, autophagy-dependent cell death, ferroptosis, pyroptosis, parthanatos, and immunogenic cell death. This is followed by a dissection of the roles of these cell death programs in the major cardiac syndromes: myocardial infarction and heart failure. The most important conclusion relevant to heart disease is that regulated forms of cardiomyocyte death play important roles in both myocardial infarction with reperfusion (ischemia/reperfusion) and heart failure. While a role for apoptosis in ischemia/reperfusion cannot be excluded, regulated forms of necrosis, through both death receptor and mitochondrial pathways, are critical. Ferroptosis and parthanatos are also likely important in ischemia/reperfusion, although it is unclear if these entities are functioning as independent death programs or as amplification mechanisms for necrotic cell death. Pyroptosis may also contribute to ischemia/reperfusion injury, but potentially through effects in non-cardiomyocytes. Cardiomyocyte loss through apoptosis and necrosis is also an important component in the pathogenesis of heart failure and is mediated by both death receptor and mitochondrial signaling. Roles for immunogenic cell death in cardiac disease remain to be defined but merit study in this era of immune checkpoint cancer therapy. Biology-based approaches to inhibit cell death in the various cardiac syndromes are also discussed.

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mTORC1 as the main gateway to autophagy

Yoana Rabanal-Ruiz, Elsje G. Otten, Viktor I. Korolchuk (2017)

Cells and organisms must coordinate their metabolic activity with changes in their environment to ensure their growth only when conditions are favourable. In order to maintain cellular homoeostasis, a tight regulation between the synthesis and degradation of cellular components is essential. At the epicentre of the cellular nutrient sensing is the mechanistic target of rapamycin complex 1 (mTORC1) which connects environmental cues, including nutrient and growth factor availability as well as stress, to metabolic processes in order to preserve cellular homoeostasis. Under nutrient-rich conditions mTORC1 promotes cell growth by stimulating biosynthetic pathways, including synthesis of proteins, lipids and nucleotides, and by inhibiting cellular catabolism through repression of the autophagic pathway. Its close signalling interplay with the energy sensor AMP-activated protein kinase (AMPK) dictates whether the cell actively favours anabolic or catabolic processes. Underlining the role of mTORC1 in the coordination of cellular metabolism, its deregulation is linked to numerous human diseases ranging from metabolic disorders to many cancers. Although mTORC1 can be modulated by a number of different inputs, amino acids represent primordial cues that cannot be compensated for by any other stimuli. The understanding of how amino acids signal to mTORC1 has increased considerably in the last years; however this area of research remains a hot topic in biomedical sciences. The current ideas and models proposed to explain the interrelationship between amino acid sensing, mTORC1 signalling and autophagy is the subject of the present review.

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Author and article information

Contributors

Jingxue Ye: URI : https://loop.frontiersin.org/people/446496

Shan Lu: URI : https://loop.frontiersin.org/people/990885

Min Wang: URI : https://loop.frontiersin.org/people/444620

Wenxiu Ge: URI : https://loop.frontiersin.org/people/994355

Guibo Sun: URI : https://loop.frontiersin.org/people/460785

Xiaobo Sun: URI : https://loop.frontiersin.org/people/469824

Journal

Journal ID (nlm-ta): Front Pharmacol

Journal ID (iso-abbrev): Front Pharmacol

Journal ID (publisher-id): Front. Pharmacol.

Title: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-9812

Publication date (Electronic): 30 July 2020

Publication date Collection: 2020

Volume: 11

Electronic Location Identifier: 1170

Affiliations

[1] ¹Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing, China

[2] ²College of Pharmacy, Harbin University of Commerce , Harbin, China

[3] ³Pneumology Department, Xiyuan Hospital, China Academy of Chinese Medical Sciences , Beijing, China

Author notes

Edited by: Ismail Laher, University of British Columbia, Canada

Reviewed by: Daniela Giuliani, University of Modena and Reggio Emilia, Italy; Xiang Gao, Cornell University, United States; Shunchang Li, Chengdu Sport University, China; Tapas C. Nag, All India Institute of Medical Sciences, India

*Correspondence: Bengang Zhang, bgzhang@ 123456implad.ac.cn ; Guibo Sun, sunguibo@ 123456126.com ; Xiaobo Sun, sun_xiaobo163@ 123456163.com

This article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology

†These authors have contributed equally to this work

Article

DOI: 10.3389/fphar.2020.01170

PMC ID: 7406911

PubMed ID: 32848777

SO-VID: f6025fd3-f83a-480c-8ad8-946902a5780d

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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 01 June 2020

Date accepted : 17 July 2020

Page count

Figures: 6, Tables: 0, Equations: 0, References: 61, Pages: 11, Words: 4676

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Hydroxysafflor Yellow A Protects Against Myocardial Ischemia/Reperfusion Injury via Suppressing NLRP3 Inflammasome and Activating Autophagy

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RNA drug delivery

Most cited references 49

NLRP3 inflammasome and its inhibitors: a review

Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease

mTORC1 as the main gateway to autophagy

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