Dataset Information

Stressor-Induced "Inflammaging" of Vascular Smooth Muscle Cells via Nlrp3-Mediated Pro-inflammatory Auto-Loop.

ABSTRACT: Calcification of the vessel wall as one structural pathology of aged vessels is associated with high cardiovascular mortality of elderly patients. Aging is linked to chronic sterile inflammation and high burden of reactive oxygen species (ROS), leading to activation of pattern recognition receptors (PRRs) such as Nlrp3 in vascular cells. The current study investigates the role of PRR activation in the calcification of vascular smooth muscle cells (VSMCs). Therefore, in vitro cell culture of primary rat VSMCs and ex vivo aortic stimulations were used to analyze osteogenic, senescence and inflammatory markers via real-time PCR, in situ RNA hybridization, Western Blot, photometric assays and histological staining. Induction of ROS and DNA-damage by doxorubicin induces a shift of VSMC phenotype toward the expression of osteogenic, senescence and inflammatory proteins. Induction of calcification is dependent on Nlrp3 activity. Il-1β as a downstream target of Nlrp3 induces the synthetic, pro-calcifying VSMC phenotype. Inhibition of PRR with subsequent reduction of chronic inflammation might be an interesting target for reduction of calcification of VSMCs, with subsequent reduction of cardiovascular mortality of patients suffering from vessel stiffness.

SUBMITTER: Herrmann J

PROVIDER: S-EPMC8720922 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Stressor-Induced "Inflammaging" of Vascular Smooth Muscle Cells via Nlrp3-Mediated Pro-inflammatory Auto-Loop.

Herrmann Jaqueline J Xia Mengdi M Gummi Manasa Reddy MR Greco Anna A Schacke Annika A van der Giet Markus M Tölle Markus M Schuchardt Mirjam M

Frontiers in cardiovascular medicine 20211220

Calcification of the vessel wall as one structural pathology of aged vessels is associated with high cardiovascular mortality of elderly patients. Aging is linked to chronic sterile inflammation and high burden of reactive oxygen species (ROS), leading to activation of pattern recognition receptors (PRRs) such as Nlrp3 in vascular cells. The current study investigates the role of PRR activation in the calcification of vascular smooth muscle cells (VSMCs). Therefore, <i>in vitro</i> cell culture ...[more]

PMID: 34988126

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Project description:ObjectiveInflammation and its resolution are central to vascular injury and repair. Maresins comprise a new family of bioactive lipid mediators synthesized from docosahexaenoic acid, an ω-3 polyunsaturated fatty acid. They have been found to exert anti-inflammatory and pro-resolving responses in macrophages, neutrophils and bronchial epithelial cells and impart beneficial actions in murine models of peritonitis and colitis. We investigated the impact of maresin-1 (MaR1) on tumor necrosis factor alpha (TNF-α) induced inflammatory responses in human vascular endothelial (EC) and smooth muscle cells (VSMC).MethodsPrimary cultures of human saphenous vein EC and VSMC were employed. We tested the naturally occurring MaR1 as modulator of TNF-α effects, with examination of monocyte adhesion, oxidant stress, and intracellular inflammatory signaling pathways.ResultsMaR1 attenuated TNF-α induced monocyte adhesion and reactive oxygen species (ROS) generation in both EC and VSMC, associated with down-regulated expression (cell surface) of the adhesion molecule E-selectin (in EC) and NADPH-oxidases (NOX4, NOX1, NOX2). MaR1 attenuated TNF-α induced release of pro-inflammatory mediators by EC and VSMC. MaR1 caused an attenuation of TNF-α induced NF-κB activation in both cell types associated with inhibition of I-κ Kinase (IKK) phosphorylation, IκB-α degradation and nuclear translocation of the NF- κB p65 subunit. MaR1 also caused a time-dependent increase in intracellular cyclic AMP (cAMP) in both naive and TNF-α stimulated VSMC and EC.ConclusionsMaR1 has broad anti-inflammatory actions on EC and VSMC, which may be partly mediated through up-regulation of cAMP and down-regulation of the transcription factor NF-κB. The results suggest that the pro-resolving lipid mediator MaR1 exerts homeostatic actions on vascular cells that counteract pro-inflammatory signals. These findings may have direct relevance for acute and chronic states of vascular inflammation.

Project description:BackgroundGraft vascular disease (GVD), which limits the long-term survival of patients after solid-organ transplantation, is associated with both immune responses and nonimmune factors, including dyslipidemia. Recent studies have shown that inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), a U.S. Federal Drug Administration-approved treatment for hyperlipidemia, reduces cardiovascular events, regulates inflammatory responses, and enhances the efficacy of immune checkpoint therapy in cancer treatment through a cholesterol-independent mechanism. However, whether targeting PCSK9 is a potential therapeutic strategy for GVD remains unknown.MethodsSerum samples and grafts were harvested from male mice undergoing abdominal aortic transplantation. The pathological alterations in the aortic grafts were detected by hematoxylin and eosin staining, Verhoeff's Van Gieson staining, and Masson staining. Inflammatory cell infiltration and proinflammatory cytokine expression in the aortic grafts were detected by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. The regulatory effects of PCSK9 on vascular smooth muscle cell (VSMC) migration and proliferation were examined by transwell, EdU, and western blot assays. The effect of Evolocumab, a PCSK9 inhibitor, on GVD in humanized PCSK9 mice was also evaluated.ResultsPCSK9 was upregulated in the serum, grafts, and liver of mice in the allograft group subjected to abdominal aortic transplantation. Pcsk9 knockout significantly reduced vascular stenosis, the intimal hyperplasia area and collagen deposition. Pcsk9 depletion also inhibited macrophage recruitment and the mRNA expression of proinflammatory cytokines in aortic grafts. Furthermore, Pcsk9 knockout suppressed the migration and proliferation of VSMCs, which was related to the inhibition of NLRP3 inflammasome activation. Meanwhile, Evolocumab significantly ameliorated GVD in humanized PCSK9 mice.ConclusionPCSK9 is upregulated in a mouse model of GVD, and Pcsk9 knockout reduces vascular occlusion, suggesting that PCSK9 may be a promising target for the treatment of GVD.

Dataset Information

Stressor-Induced "Inflammaging" of Vascular Smooth Muscle Cells via Nlrp3-Mediated Pro-inflammatory Auto-Loop.

Publications

Stressor-Induced "Inflammaging" of Vascular Smooth Muscle Cells via Nlrp3-Mediated Pro-inflammatory Auto-Loop.

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