Sodium tanshinone IIA sulfonate protects vascular relaxation in ApoE-knockout mice by inhibiting the SYK-NLRP3 inflammasome-MMP2/9 pathway

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Abstract

Background

Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia.

Methods

In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation.

Results

Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression.

Conclusions

These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12872-024-03990-0.

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Most cited references 33

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Atherosclerosis

Peter Libby, Julie E. Buring, Lina Badimon … (2019)

Atherosclerosis, the formation of fibrofatty lesions in the artery wall, causes much morbidity and mortality worldwide, including most myocardial infarctions and many strokes, as well as disabling peripheral artery disease. Development of atherosclerotic lesions probably requires low-density lipoprotein, a particle that carries cholesterol through the blood. Other risk factors for atherosclerosis and its thrombotic complications include hypertension, cigarette smoking and diabetes mellitus. Increasing evidence also points to a role of the immune system, as emerging risk factors include inflammation and clonal haematopoiesis. Studies of the cell and molecular biology of atherogenesis have provided considerable insight into the mechanisms that link all these risk factors to atheroma development and the clinical manifestations of this disease. An array of diagnostic techniques, both invasive (such as selective coronary arteriography) and noninvasive (such as blood biomarkers, stress testing, CT and nuclear scanning), permit assessment of cardiovascular disease risk and targeting of therapies. An expanding armamentarium of therapies that can modify risk factors and confer clinical benefit is available; however, we face considerable challenge in providing equitable access to these treatments and in maximizing adherence. Yet, the clinical application of the fruits of research has advanced preventive strategies, enhanced clinical outcomes in affected individuals, and improved their quality of life. Rapidly accelerating knowledge and continued research promise to provide further progress in combating this common chronic disease.

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The SYK tyrosine kinase: a crucial player in diverse biological functions.

Jürgen Ruland, Attila Mócsai, Victor L. J. Tybulewicz (2010)

Spleen tyrosine kinase (SYK) is known to have a crucial role in adaptive immune receptor signalling. However, recent reports indicate that SYK also mediates other, unexpectedly diverse biological functions, including cellular adhesion, innate immune recognition, osteoclast maturation, platelet activation and vascular development. SYK is activated by C-type lectins and integrins, and activates new targets, including the CARD9-BCL-10-MALT1 pathway and the NLRP3 inflammasome. Studies using Drosophila melanogaster suggest that there is an evolutionarily ancient origin of SYK-mediated signalling. Moreover, SYK has a crucial role in autoimmune diseases and haematological malignancies. This Review summarizes our current understanding of the diverse functions of SYK and how this is being translated for therapeutic purposes.

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Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects.

Wen-Qi Ma, Xue-Jiao Sun, Yi. Zhu … (2021)

Ferroptosis is a form of regulated cell death that involves metabolic dysfunction resulting from iron-dependent excessive lipid peroxidation. Elevated plasma levels of free fatty acids are tightly associated with cardiometabolic risk factors in patients with obesity, diabetes mellitus, and metabolic syndrome. Metformin (Met) is an antidiabetic drug with beneficial cardiovascular disease effects. The aim of this study was to determine the effects of Met on ferroptosis induced by lipid overload and the effects of these changes on vascular smooth muscle cells (VSMCs) calcification. We developed a hyperlipidaemia-related vascular calcification in vivo model with rats fed a high-fat diet combined with vitamin D3 plus nicotine, and palmitic acid (PA), the most abundant long-chain saturated fatty acid in plasma, was used to induce lipid overload and develop an oxidative stress-related calcification model in vitro. The results showed that Met inhibits hyperlipidaemia-associated calcium deposition in the rat aortic tissue. In vitro, treatment of VSMCs with PA stimulates ferroptosis concomitant with increased calcium deposition in VSMCs, while pretreatment with Met attenuates these effects. Furthermore, PA also promotes the protein expression of the extracellular matrix protein periostin (POSTN) and its secretion into the extracellular environment. More importantly, upregulation of POSTN increased the sensitivity of cells to ferroptosis. Mechanistically, upregulation of POSTN suppresses SLC7A11 expression through the inhibition of p53 in VSMCs, which contributes to a decrease in glutathione synthesis and therefore triggers ferroptosis. Interestingly, overexpression of p53 attenuates the inhibitory effect of POSTN on SLC7A11 expression, accompanied by increased Gpx4 expression. Furthermore, p53 knockdown suppresses Met-mediated anti-ferroptosis effects in PA-treated VSMCs, which may be related to the downregulation of SLC7A11 expression. In addition, supplementation of VSMCs with Met enhances the antioxidative capacity of VSMCs through Nrf2 signalling activation. Collectively, targeting POSTN in VSMCs may provide a new strategy for vascular calcification prevention or treatment.

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Author and article information

Contributors

Wei Wei: jaywei@czmc.edu.cn

Journal

Journal ID (nlm-ta): BMC Cardiovasc Disord

Journal ID (iso-abbrev): BMC Cardiovasc Disord

Title: BMC Cardiovascular Disorders

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2261

Publication date (Electronic): 12 July 2024

Publication date PMC-release: 12 July 2024

Publication date Collection: 2024

Volume: 24

Electronic Location Identifier: 354

Affiliations

[1 ]Department of Endocrinology, Heping Hospital Affiliated to Changzhi Medical College, ( https://ror.org/0340wst14) No.110, Yan’an South Road, Changzhi, 046000 Shanxi China

[2 ]Department of Pharmacology, Changzhi Medical College, ( https://ror.org/0340wst14) No.161, Jiefang East Street, Changzhi, 046000 Shanxi China

[3 ]Department of Clinical Center Laboratory, Heping Hospital Affiliated to Changzhi Medical College, ( https://ror.org/0340wst14) No.110, Yan’an South Road, Changzhi, 046000 Shanxi China

[4 ]Department of Stomatology, Changzhi Medical College, ( https://ror.org/0340wst14) No.161, Jiefang East Street, Changzhi, 046000 Shanxi China

[5 ]Department of Anesthesia, Changzhi Medical College, ( https://ror.org/0340wst14) No.161, Jiefang East Street, Changzhi, 046000 Shanxi China

[6 ]Department of Medical Imageology, Changzhi Medical College, ( https://ror.org/0340wst14) No.161, Jiefang East Street, Changzhi, 046000 Shanxi China

[7 ]Department of Nephrology Heping Hospital, Changzhi Medical College, ( https://ror.org/0340wst14) No.110, Yanan Road South, Changzhi, 046000 Shanxi China

Article

Publisher ID: 3990

DOI: 10.1186/s12872-024-03990-0

PMC ID: 11241843

PubMed ID: 38992615

SO-VID: 194c6673-b785-4938-ad9e-86c4a8ca647d

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 22 January 2024

Date accepted : 19 June 2024

Funding

Funded by: Heping Hospital Affiliated to Changzhi Medical College, China

Award ID: HPYJ202210

Award ID: HPYJ202218

Award ID: HPYJ201921

Funded by: Education department of Shanxi, China

Award ID: 2021L351

Funded by: Changzhi Medical College, China

Award ID: BS202115

Funded by: Department of Science and Technology of Shanxi

Award ID: 202203021211107

Funded by: FundRef http://dx.doi.org/10.13039/100017949, Health Commission of Shanxi Province;

Award ID: 2022021

Custom metadata

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: hyperlipidemia,vascular relaxation,nlrp3 inflammasome,mmp2/9,sodium tanshinone iia sulfonate

Data availability:

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: hyperlipidemia, vascular relaxation, nlrp3 inflammasome, mmp2/9, sodium tanshinone iia sulfonate

Sodium tanshinone IIA sulfonate protects vascular relaxation in ApoE-knockout mice by inhibiting the SYK-NLRP3 inflammasome-MMP2/9 pathway

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Abstract

Background

Methods

Results

Conclusions

Supplementary Information

Related collections

Cardiovascular Innovations and Applications

Most cited references 33

Atherosclerosis

The SYK tyrosine kinase: a crucial player in diverse biological functions.

Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects.

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