Changes of Necroptosis in Irbesartan Medicated Cardioprotection in Diabetic Rats

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Abstract

Background

Diabetic cardiomyopathy (DCM) is strongly linked to microvascular disease, renin-angiotensin system (RAS) activation, cardiac inflammation and cell apoptosis. Irbesartan is an angiotensin II (Ang II) receptor antagonist in RAS system, which inhibited the conversion of Ang I into Ang II, while the specific mechanism is still obscure.

Objective

This study aims to investigate the expressions necroptosis RIP1-RIP3-MLKL pathway in myocardium of diabetic rats, and the protective action of irbesartan on myocardial damage.

Materials and Methods

In our study, 30 Sprague–Dawley rats were divided into 5 groups: CON4W, high glucose and high caloric (HC4W), diabetes mellitus 4 weeks (DM4W group), diabetes mellitus 8 weeks (DM8W group), and irbesartan diabetes 8 weeks (Ir DM8W group).

Results

We discovered that as diabetes progresses, the rats gradually lost weight, the HW/BW ratio were increased gradually, and the cardiac function became worse accompanied with the aggravation of inflammatory injury. Meanwhile, the myocardial fibers and cells were disordered, and the expression of positive substances, RIP1 and RIP3 increased significantly. The mRNA and protein levels of myocardial RIP1, RIP3 and MLKL were all increased with the progression of DM. After the intervention of irbesartan in diabetic rats, the cardiac function was improved, whereas inflammatory injury and HW/BW ratio were decreased. Also, the myocardial fibrosis injury was attenuated, and the PAS positive substances, RIP1 and RIP3 were significantly decreased. The curative effect of irbesartan was related to decreased myocardial RIP1, RIP3 and MLKL mRNA and protein levels.

Conclusion

In conclusion, irbesartan has a cardioprotective effect on the diabetic rats, and its mechanism may be connected with inhibition of RIP1-RIP3-MLKL pathway.

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Most cited references 37

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Inflammation, metaflammation and immunometabolic disorders

Gökhan S. Hotamisligil (2017)

Proper regulation and management of energy, substrate diversity and quantity, as well as macromolecular synthesis and breakdown processes, are fundamental to cellular and organismal survival and are paramount to health. Cellular and multicellular organization are defended by the immune response, a robust and critical system

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Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities

Nikolaos G Frangogiannis (2019)

Cardiac fibrosis is a common pathophysiologic companion of most myocardial diseases, and is associated with systolic and diastolic dysfunction, arrhythmogenesis, and adverse outcome. Because the adult mammalian heart has negligible regenerative capacity, death of a large number of cardiomyocytes results in reparative fibrosis, a process that is critical for preservation of the structural integrity of the infarcted ventricle. On the other hand, pathophysiologic stimuli, such as pressure overload, volume overload, metabolic dysfunction, and aging may cause interstitial and perivascular fibrosis in the absence of infarction. Activated myofibroblasts are the main effector cells in cardiac fibrosis; their expansion following myocardial injury is primarily driven through activation of resident interstitial cell populations. Several other cell types, including cardiomyocytes, endothelial cells, pericytes, macrophages, lymphocytes and mast cells may contribute to the fibrotic process, by producing proteases that participate in matrix metabolism, by secreting fibrogenic mediators and matricellular proteins, or by exerting contact-dependent actions on fibroblast phenotype. The mechanisms of induction of fibrogenic signals are dependent on the type of primary myocardial injury. Activation of neurohumoral pathways stimulates fibroblasts both directly, and through effects on immune cell populations. Cytokines and growth factors, such as Tumor Necrosis Factor-α, Interleukin (IL)-1, IL-10, chemokines, members of the Transforming Growth Factor-β family, IL-11, and Platelet-Derived Growth Factors are secreted in the cardiac interstitium and play distinct roles in activating specific aspects of the fibrotic response. Secreted fibrogenic mediators and matricellular proteins bind to cell surface receptors in fibroblasts, such as cytokine receptors, integrins, syndecans and CD44, and transduce intracellular signaling cascades that regulate genes involved in synthesis, processing and metabolism of the extracellular matrix. Endogenous pathways involved in negative regulation of fibrosis are critical for cardiac repair and may protect the myocardium from excessive fibrogenic responses. Due to the reparative nature of many forms of cardiac fibrosis, targeting fibrotic remodeling following myocardial injury poses major challenges. Development of effective therapies will require careful dissection of the cell biological mechanisms, study of the functional consequences of fibrotic changes on the myocardium, and identification of heart failure patient subsets with overactive fibrotic responses.

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Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL.

Robert W. Marquis, Jason Upton, Edward Mocarski … (2013)

Toll-like receptor (TLR) signaling is triggered by pathogen-associated molecular patterns that mediate well established cytokine-driven pathways, activating NF-κB together with IRF3/IRF7. In addition, TLR3 drives caspase 8-regulated programmed cell death pathways reminiscent of TNF family death receptor signaling. We find that inhibition or elimination of caspase 8 during stimulation of TLR2, TLR3, TLR4, TLR5, or TLR9 results in receptor interacting protein (RIP) 3 kinase-dependent programmed necrosis that occurs through either TIR domain-containing adapter-inducing interferon-β (TRIF) or MyD88 signal transduction. TLR3 or TLR4 directly activates programmed necrosis through a RIP homotypic interaction motif-dependent association of TRIF with RIP3 kinase (also called RIPK3). In fibroblasts, this pathway proceeds independent of RIP1 or its kinase activity, but it remains dependent on mixed lineage kinase domain-like protein (MLKL) downstream of RIP3 kinase. Here, we describe two small molecule RIP3 kinase inhibitors and employ them to demonstrate the common requirement for RIP3 kinase in programmed necrosis induced by RIP1-RIP3, DAI-RIP3, and TRIF-RIP3 complexes. Cell fate decisions following TLR signaling parallel death receptor signaling and rely on caspase 8 to suppress RIP3-dependent programmed necrosis whether initiated directly by a TRIF-RIP3-MLKL pathway or indirectly via TNF activation and the RIP1-RIP3-MLKL necroptosis pathway.

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Author and article information

Journal

Journal ID (nlm-ta): Diabetes Metab Syndr Obes

Journal ID (iso-abbrev): Diabetes Metab Syndr Obes

Journal ID (publisher-id): dmso

Journal ID (pmc): dmso

Title: Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy

Publisher: Dove

ISSN (Electronic): 1178-7007

Publication date (Electronic): 07 September 2021

Publication date Collection: 2021

Volume: 14

Pages: 3851-3863

Affiliations

[1 ]Department of Cardiology, The First Affiliated Hospital of Bengbu Medical College , Bengbu, Anhui, 233004, People’s Republic of China

[2 ]Department of Preventive Medicine, Bengbu Medical College , Bengbu, Anhui, 233000, People’s Republic of China

[3 ]Clinic Medical College of AnHui Medical University , Hefei, Anhui, 230000, People’s Republic of China

[4 ]Cardiovascular Disease Research Center of Bengbu Medical College , Bengbu, Anhui, 233030, People’s Republic of China

[5 ]Department of Physiology, Bengbu Medical College , Bengbu, Anhui, 233000, People’s Republic of China

Author notes

Correspondence: Pinfang Kang Department of Cardiology, The First Affiliated Hospital of Bengbu Medical College , Bengbu, Anhui, 233004, People’s Republic of ChinaTel +86 552-3086107 Email kangpinfang.1016@163.com

Article

Publisher ID: 300388

DOI: 10.2147/DMSO.S300388

PMC ID: 8434868

PubMed ID: 34522112

SO-VID: 42cd99de-dc2b-4b17-8274-3df1a4659be8

License:

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

History

Date received : 08 January 2021

Date accepted : 05 August 2021

Page count

Figures: 29, Tables: 1, References: 40, Pages: 13

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Changes of Necroptosis in Irbesartan Medicated Cardioprotection in Diabetic Rats

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Abstract

Background

Objective

Materials and Methods

Results

Conclusion

Related collections

Journal of the ASEAN Federation of Endocrine Societies

Most cited references 37

Inflammation, metaflammation and immunometabolic disorders

Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities

Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL.

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Cited by 4

Most referenced authors 422