Sodium Nitroprusside Stimulation of Elastic Matrix Regeneration by Aneurysmal Smooth Muscle Cells

Bastola, Suraj; Kothapalli, Chandrasekhar R.; Ramamurthi, Anand

doi:10.1089/ten.tea.2022.0169

Cited by 3 publications

(1 citation statement)

References 74 publications

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“…4,32 Attenuation or deletion of JNK2 gene leads to upregulated elastogenesis. 1,33 JNK-mediated improvement in elastogenesis occurs by (a) reduction in proteolytic activity of MMP2 resulting in a net decrease of elastic matrix degradation, 34 and (b) upregulation of elastic fiber assembly genes and proteins such as ELN, LOX, fibulins, and fibrillins. While the primary goal of this project was to assess the potential of LNPs as JNK2 siRNA carrier for efficient knockdown of JNK2 thereby regulating the proteolytic activity of downstream MMP2 in EaRASMCs, we also assessed additional downstream effects on elastic fiber assembly genes (ELN, LOX).…”

Section: Discussionmentioning

confidence: 99%

JNK2 silencing lipid nanoparticles for elastic matrix repair

Dahal,

Bastola,

Ramamurthi

2023

J Biomedical Materials Res

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The over‐expression of c‐Jun N‐terminal kinase (JNK2), a stress activated mitogen kinase, in the aortic wall plays a critical role in the formation and progression of abdominal aortic aneurysm (AAA). This triggers chronic downstream upregulation of elastolytic matrix metalloproteinases (MMPs), MMPs2 and 9 to cause progressive proteolytic breakdown of the wall elastic matrix. We have previously shown that siNRA knockdown of JNK2 gene expression in an AAA culture model stimulates downstream elastin gene expression, elastic fiber formation, crosslinking and reduces elastolytic MMPs2 and 9. Since naked siRNA poorly routes to intracellular targets, has poor stability in blood, and could be potentially toxic and immunogenic, this project is aimed to develop PEGylated lipid nanoparticles (LNPs) for delivery of JNK siRNA and to generate evidence of successful JNK2 knockdown and downstream attenuation of MMP2 gene and protein expressions. LNPs were formulated using thin‐film hydration technique and had the size of 100–200 nm with zeta‐potential ranging between 30 and 40 mV. JNK siRNA loaded PEGylated LNPs successfully knocked down JNK2 in cytokine‐activated rat aneurysmal smooth muscle (EaRASMC) cultures. This resulted in a downstream decrease in MMP2 gene and protein expression and an upward trend in expression of genes for proteins critical for elastic fiber assembly such as elastin (ELN) and lysyl oxidase (LOX). Our result indicates cationic LNPs to be potential carriers for JNK siRNA delivery improving potency for elastin homeostasis required for AAA repair which could possibly provide benefits in preventing the progression of small AAAs.

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Section: Discussionmentioning

confidence: 99%

JNK2 silencing lipid nanoparticles for elastic matrix repair

Dahal,

Bastola,

Ramamurthi

2023

J Biomedical Materials Res

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Integrative analysis of gene expression, protein abundance, and metabolomic profiling elucidates complex relationships in chronic hyperglycemia-induced changes in human aortic smooth muscle cells

Bohara,

Bagheri,

Ertugral

et al. 2024

J Biol Eng

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Type 2 diabetes mellitus (T2DM) is a major public health concern with significant cardiovascular complications (CVD). Despite extensive epidemiological data, the molecular mechanisms relating hyperglycemia to CVD remain incompletely understood. We here investigated the impact of chronic hyperglycemia on human aortic smooth muscle cells (HASMCs) cultured under varying glucose conditions in vitro, mimicking normal (5 mmol/L), pre-diabetic (10 mmol/L), and diabetic (20 mmol/L) conditions, respectively. Normal HASMC cultures served as baseline controls, and patient-derived T2DM-SMCs served as disease controls. Results showed significant increases in cellular proliferation, area, perimeter, and F-actin expression with increasing glucose concentration ( p < 0.01), albeit not exceeding the levels in T2DM cells. Atomic force microscopy analysis revealed significant decreases in Young’s moduli, membrane tether forces, membrane tension, and surface adhesion in SMCs at higher glucose levels ( p < 0.001), with T2DM-SMCs being the lowest among all the cases ( p < 0.001). T2DM-SMCs exhibited elevated levels of selected pro-inflammatory markers (e.g., ILs-6, 8, 23; MCP-1; M-CSF; MMPs-1, 2, 3) compared to glucose-treated SMCs ( p < 0.01). Conversely, growth factors (e.g., VEGF-A, PDGF-AA, TGF-β1) were higher in SMCs exposed to high glucose levels but lower in T2DM-SMCs ( p < 0.01). Pathway enrichment analysis showed significant increases in the expression of inflammatory cytokine-associated pathways, especially involving IL-10, IL-4 and IL-13 signaling in genes that are up-regulated by elevated glucose levels. Differentially regulated gene analysis showed that compared to SMCs receiving normal glucose, 513 genes were upregulated and 590 genes were downregulated in T2DM-SMCs; fewer genes were differentially expressed in SMCs receiving higher glucose levels. Finally, the altered levels in genes involved in ECM organization, elastic fiber synthesis and formation, laminin interactions, and ECM proteoglycans were identified. Growing literature suggests that phenotypic switching in SMCs lead to arterial wall remodeling (e.g., change in stiffness, calcific deposits formation), with direct implications in the onset of CVD complications. Our results suggest that chronic hyperglycemia is one such factor that leads to morphological, biomechanical, and functional alterations in vascular SMCs, potentially contributing to the pathogenesis of T2DM-associated arterial remodeling. The observed differences in gene expression patterns between in vitro hyperglycemic models and patient-derived T2DM-SMCs highlight the complexity of T2DM pathophysiology and underline the need for further studies. Supplementary Information The online version contains supplementary material available at 10.1186/s13036-024-00457-w.

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A bibliometric analysis of abdominal aortic aneurysm (2014–2024)

Liu,

Yang,

et al. 2024

Front. Cardiovasc. Med.

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BackgroundAbdominal aortic aneurysm (AAA) is a localized bulge of the abdominal aorta, which mainly manifests as a pulsatile mass in the abdomen. Once an abdominal aortic aneurysm ruptures, the patient's life is seriously endangered. Surgery is the preferred treatment for abdominal aortic aneurysm. At present, there has been no comprehensive review of the current status of abdominal aortic aneurysm research. Therefore, this study aimed to identify global trends in abdominal aortic aneurysm research over the last 10 years through bibliometric analysis and to inform clinical practice, research funding allocation, and decision-making.MethodsWe downloaded research articles and reviews on abdominal aortic aneurysm from 1 January 2014, to 1 March 2024, from the Web of Science core collection. CiteSpace (version 6.2.1), RStudio and VOSviewer (version 1.6.18) were used for visual analysis of regional distribution, institutions, authors, keywords and other information.ResultsThe number of documents on abdominal aortic aneurysm research increased continuously and has stabilized in recent years. A total of 9,905 publications from 67 countries were published from 1 January 2014, to 1 March 2024. A total of 2,142 (29.52%) studies were from the United States, 1,293 (13.05%) were from China, and 919 (9.28%) were from the United Kingdom. A total of 205 studies were conducted at Stanford University, 172 were conducted at Harvard Medical School, and 165 were conducted at the Mayo Clinic. The top three coauthorship authors were Schermerhorn, Marc L (114); Golledge, Jonathan (102); and De Vries, Jean Paul P.M. (74). The most cocited reference was Chaikof EL, 2018, J Vasc Surg, v67, p. 2; the most cocited journal was the Journal of Vascular Surgery; and the most cocited author was Lederle, FA. “Abdominal aortic aneurysm” was the most frequently used author keyword (2,492). Twenty-five references with strong citation bursts were identified by “CiteSpace”. “Artificial intelligence”, “clinical outcomes” and “bridging stent” were the primary keywords of emerging research hotspots.ConclusionThis is the first bibliometric study to comprehensively summarize the research trends in abdominal aortic aneurysm research. This information can help us to identify the current research hotspots and directions. This study will provide extensive help for future research.

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Sodium Nitroprusside Stimulation of Elastic Matrix Regeneration by Aneurysmal Smooth Muscle Cells

Cited by 3 publications

References 74 publications

JNK2 silencing lipid nanoparticles for elastic matrix repair

JNK2 silencing lipid nanoparticles for elastic matrix repair

Integrative analysis of gene expression, protein abundance, and metabolomic profiling elucidates complex relationships in chronic hyperglycemia-induced changes in human aortic smooth muscle cells

A bibliometric analysis of abdominal aortic aneurysm (2014–2024)

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