Correlation between MMP-9 and extracellular cytokine HMGB1 in prediction of human ischemic stroke outcome

Sapojnikova, Nelly; Kartvelishvili, Tamar; Asatiani, Nino; Zinkevich, Vitaly; Kalandadze, Iagor; Gugutsidze, Darejan; Shakarishvili, R; Tsiskaridze, Alexander

doi:10.1016/j.bbadis.2014.04.031

Cited by 52 publications

(39 citation statements)

References 26 publications

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“…MMPs, one kind of matrix-degrading enzymes, including MMP-9, cause cerebral neuroinflammation [33,34]. In the present study, we found that thrombin induced MMP-9 expression associated with cell migration of SK-N-SH cells.…”

Section: Discussionsupporting

confidence: 56%

Thrombin Enhanced Matrix Metalloproteinase-9 Expression and Migration of SK-N-SH Cells via PAR-1, c-Src, PYK2, EGFR, Erk1/2 and AP-1

2016

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Neuroinflammation is a hallmark of neurodegenerative disorders in the central nerve system (CNS). Thrombin has been known as one of the factors in pathological processes including migration, blood-brain barrier breakdown, brain edema formation, neuroinflammation, and neuronal death. Thrombin has been shown to be a regulator of matrix metalloproteinase (MMPs) expression leading to cell migration. Among MMPs, the elevated expression of MMP-9 has been observed in patients with brain diseases, which may contribute to the pathology of neuroinflammatory and neurodegenerative diseases. However, the mechanisms underlying thrombin-induced MMP-9 expression in SK-N-SH cells were not completely understood. Here, we used gelatin zymography, Western blot, real-time PCR, promoter activity assay, and cell migration assay to demonstrate that thrombin induced the expression of pro-form MMP-9 protein and messenger RNA (mRNA), and promoter activity in SK-N-SH cells, which were attenuated by pretreatment with the pharmacological inhibitor of protease-activated receptor-1 (PAR-1, SCH79797), Gi-coupled receptor (GPA2), c-Src (PP1), Pyk2 (PF431396), EGFR (AG1478), PI3K (LY294002), Akt (SH-5), MEK1/2 (U0126), or AP-1 (TanshinoneIIA) and transfection with small interfering RNA (siRNA) of PAR-1, Gi, c-Src, Pyk2, EGFR, Akt, p44, p42, or c-Jun. Moreover, thrombin-stimulated c-Src, Pyk2, EGFR, Akt, p42/p44 MAPK, or c-Jun phosphorylation was attenuated by their respective inhibitor of PP1, PF431396, AG1478, SH-5, U0126, or TanshinoneIIA. Finally, pretreatment with these inhibitors also blocked thrombin-induced SK-N-SH cell migration. Our results concluded that thrombin binding to PAR-1 receptor activated Gi-protein/c-Src/Pyk2/EGFR/PI3K/Akt/p42/p44 MAPK cascade, which in turn elicited AP-1 activation and ultimately evoked MMP-9 expression and cell migration in SK-N-SH cells.

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Section: Discussionsupporting

confidence: 56%

Thrombin Enhanced Matrix Metalloproteinase-9 Expression and Migration of SK-N-SH Cells via PAR-1, c-Src, PYK2, EGFR, Erk1/2 and AP-1

2016

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“…Previous studies show that HMGB1 increases in patients with ischemic stroke and correlates with the number of circulating leukocytes, 27 stroke severity (NIHSS score, infarct size), and inflammatory markers (TNF-a, IL-1, IL-6, MMP9). [28][29][30][31] These findings are consistent with our study whereby a decrease in let7i was associated with a rise in HMGB1 as well as an increase in inflammatory response, MMP9, and infarct size.…”

Section: Neurology 87 November 22 2016supporting

confidence: 91%

Leukocyte response is regulated by microRNA let7i in patients with acute ischemic stroke

et al. 2016

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Objective: To evaluate microRNA let7i in ischemic stroke and its regulation of leukocytes.Methods: A total of 212 patients were studied: 106 with acute ischemic stroke and 106 controls matched for risk factors. RNA from circulating leukocytes was isolated from blood collected in PAXgene tubes. Let7i microRNA expression was assessed using TaqMan quantitative reverse transcription PCR. To assess let7i regulation of gene expression in stroke, messenger RNA (mRNA) from leukocytes was measured by whole-genome Human Transcriptome Array Affymetrix microarray. Given microRNAs act to destabilize and degrade their target mRNA, mRNAs that inversely correlated with let7i were identified. To demonstrate let7i posttranscriptional regulation of target genes, a 39 untranslated region luciferase assay was performed. Target protein expression was assessed using ELISA.Results: Let7i was decreased in patients with acute ischemic stroke (fold change 21.70, p , 0.00001). A modest inverse correlation between let7i and NIH Stroke Scale score at admission (r 5 20.32, p 5 0.02), infarct volume (r 5 20.21, p 5 0.04), and plasma MMP9 (r 5 20.46, p 5 0.01) was identified. The decrease in let7i was associated with increased expression of several of its mRNA targets, including CD86, CXCL8, and HMGB1. In vitro studies confirm let7i posttranscriptional regulation of target genes CD86, CXCL8, and HMGB1. Functional analysis predicted let7i regulates pathways involved in leukocyte activation, recruitment, and proliferation including canonical pathways of CD86 signaling in T helper cells, HMGB1 signaling, and CXCL8 signaling.Conclusions: Let7i is decreased in circulating leukocytes of patients with acute ischemic stroke.Mechanisms by which let7i regulates inflammatory response post stroke include targeting CD86, CXCL8, and HMGB1. Neurology ® 2016;87:2198-2205 GLOSSARY cDNA 5 complementary DNA; HTA 5 Human Transcriptome Array; IL 5 interleukin; mRNA 5 messenger RNA; NIHSS 5 NIH Stroke Scale; 39UTR 5 39 untranslated region; TNF-a 5 tumor necrosis factor a.Ischemic stroke remains a leading cause of disability. Although early reperfusion therapy can improve outcomes, it is available to a minority of stroke patients. Specific therapies are needed to reduce brain injury and improve outcomes after stroke. The immune system responds rapidly following cerebral ischemia. A range of damage-associated molecular patterns, cytokines, and chemokines are released to activate circulating leukocytes, vasculature, and brain cells.

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“…In the early phase subsequent to cerebral ischemia, MMPs disrupt the BBB, leading to BBB leakage, leukocyte infiltration, brain edema and hemorrhage (41). Within the MMP family, MMP-2 and MMP-9 have been regarded as the key enzymes associated with secondary damage following ischemic cerebral stroke (42).…”

Section: Discussionmentioning

confidence: 99%

“…Within the MMP family, MMP-2 and MMP-9 have been regarded as the key enzymes associated with secondary damage following ischemic cerebral stroke (42). Clinical data support that the activated MMP-9 can be considered as an effective marker for negative outcome within the early phase of ischemic stroke development (41). Therefore, MMP-9 is a potential therapeutic target for BBB disruption following thrombolysis (43).…”

Section: Discussionmentioning

confidence: 99%

Tissue kallikrein protects against ischemic stroke by suppressing TLR4/NF-κB and activating Nrf2 signaling pathway in rats

Yang

Wan

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Brain damage following cerebral ischemia-reperfusion (I/R) is a complicated pathophysiological course, in which inflammation and oxidative stress have been suggested to serve an important role. Toll-like receptor 4 (TLR4) has been suggested to be involved in secondary inflammatory process in cerebral ischemia. Nuclear factor erythroid 2-related factor 2 (Nrf2), an important regulator of the antioxidant host defense, maintains the cellular redox homeostasis. Tissue kallikrein (TK) has been proven to elicit a variety of biological effects in ischemic stroke through its anti-inflammatory and anti-oxidant properties. However, the mechanisms underlying its beneficial effects remain poorly defined. The present study examined the hypothesis that TK attenuates ischemic cerebral injury via the TLR4/nuclear factor-κB (NF-κB) and Nrf2 signaling pathways. Using a transient rat middle cerebral artery occlusion (MCAO) model, the effects of immediate and delayed TK treatment subsequent to reperfusion were investigated. The neurological deficits, infarct size, and the expression of TLR4/NF-κB and Nrf2 pathway in ischemic brain tissues were measured at 24 following MCAO. The results indicated that TK immediate treatment significantly improved neurological deficits and reduced the infarct size, accompanied by the inhibition of TLR4 and NF-κB levels, and the activation of Nrf2 pathway. Furthermore, TK delayed treatment also exerted neuroprotection against I/R injury. However, the neuroprotective effect of TK immediate treatment was better compared with that of TK delayed treatment. In conclusion, the results indicated that TK protected the brain against ischemic injury in rats after MCAO through its anti-oxidative and anti-inflammatory effects. Suppression of TLR4/NF-κB and activation of the Nrf2 pathway contributed to the neuroprotective effects induced by TK in cerebral ischemia. Therefore, TK may provide an effective intervention with a wider therapeutic window for ischemic stroke.

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Correlation between MMP-9 and extracellular cytokine HMGB1 in prediction of human ischemic stroke outcome

Cited by 52 publications

References 26 publications

Thrombin Enhanced Matrix Metalloproteinase-9 Expression and Migration of SK-N-SH Cells via PAR-1, c-Src, PYK2, EGFR, Erk1/2 and AP-1

Thrombin Enhanced Matrix Metalloproteinase-9 Expression and Migration of SK-N-SH Cells via PAR-1, c-Src, PYK2, EGFR, Erk1/2 and AP-1

Leukocyte response is regulated by microRNA let7i in patients with acute ischemic stroke

Tissue kallikrein protects against ischemic stroke by suppressing TLR4/NF-κB and activating Nrf2 signaling pathway in rats

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