Proteomic changes in intracranial blood during human ischemic stroke

Maglinger, Benton; Frank, Jacqueline A.; McLouth, Christopher J.; Trout, Amanda L; Roberts, Jill; Grupke, Stephen; Turchan–Cholewo, Jadwiga; Stowe, Ann M.; Fraser, Justin F.; Pennypacker, Keith R.

doi:10.1136/neurintsurg-2020-016118

Cited by 28 publications

(22 citation statements)

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“…Considering how REG3A mainly acts within the entero‐hepatic system, we hypothesized that REG3A may be predictive of these outcomes by networking with other systemic proteins, such as IL6 and IL17. A previous study found that IL6 and IL17 were up‐regulated in BACTRAC subjects (Fraser et al, 2019, Maglinger, Frank et al 2020). In ischemic stroke, IL6 is a biomarker for poor outcomes, such as increased infarct and edema volume (Vila et al, 2000).…”

Section: Resultsmentioning

confidence: 94%

“…A common thread between the gut‐brain, immune, and brain inflammatory responses are the acute‐phase proteins, chemokines, and cytokines introduced at the time of stroke (Krishnan & Lawrence, 2019; Selvaraj & Stowe, 2017). One such molecule, Regenerating Family Member 3 Alpha (REG3A), also referred to as Pancreatitis Associated Protein (PAP1/PAP) and Hepatocarcinoma‐Intestine‐Pancreatic Protein (HIP), is an acute‐phase inflammatory and antimicrobial protein that was previously reported to be elevated systemically in arterial blood sampled during mechanical thrombectomy (MT) of BACTRAC subjects (Maglinger, Frank et al 2020). In non‐pathologic states, REG3A is produced within the entero‐hepatic system and is variable expressed within central nervous tissue (Uhlen et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Antimicrobial protein REG3A and signaling networks are predictive of stroke outcomes

Sands

Frank

Maglinger

et al. 2021

Journal of Neurochemistry

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Regenerating Family Member 3 Alpha (REG3A) is a multifunctional protein with antimicrobial activity, and primarily secreted by the intestine and pancreas. Studies have shown an increased expression of REG3A in systemic inflammatory responses to acute injury and infection, but studies investigating REG3A during the pathogenesis of ischemic stroke are limited. The aims of this study were to examine the associations between arterial expression of REG3A and other arterial inflammatory proteins implicated in stroke pathogenesis, as well as associations between REG3A and markers of poor outcome for ischemic stroke. The University of Kentucky Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) protocol (clinicaltrials.gov NCT03153683) utilizes thrombectomy to isolate intracranial arterial blood (i.e. distal to thrombus) and systemic arterial blood (i.e. carotid). Samples were analyzed by Olink Proteomics for N = 42 subjects. Statistical analyses of plasma proteins included 2‐sample t‐tests, spearman and biserial correlations, and robust regression models to elucidate network signaling and association to clinical outcomes. Results indicated that levels of systemic REG3A were positively correlated with inflammatory proteins interleukin IL6 (R = 0.344, p = 0.030) and IL17C (R = 0.468, p = 0.002). 2‐sided t‐ tests examining differences of systemic REG3A within quartiles of NIHSS admission score depicted significant differences between quartiles. Those with NIHSS scores corresponding to moderate and moderate‐severe neurofunctional deficits had significantly higher levels of systemic REG3A compared to those with NIHSS scores corresponding to mild and mild‐moderate neurofunctional deficits (p = 0.016). STRING analyses of proteins in each robust regression model demonstrated substantial networking between REG3A and other systemic proteins highly relevant to ischemic stroke. The present study provides novel data on systemic REG3A in the context of ischemic stroke. These results demonstrate the influential role of REG3A regarding surrogate functional and radiographic outcomes of stroke severity. Additionally, they provide novel insight into the role of REG3A and related proteins during the complex neuroinflammatory process of ischemic stroke. These data provide a foundation for future studies to investigate REG3A and related networking proteins as potential biomarkers with prognostic potential, as well as potential therapeutic targets.

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Section: Resultsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Antimicrobial protein REG3A and signaling networks are predictive of stroke outcomes

Sands

Frank

Maglinger

et al. 2021

Journal of Neurochemistry

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“…From the stroke patient population, systemic (proximal to the thrombus) and intracranial (distal to the thrombus) blood samples were obtained and isolated for plasma. The tissue processing and protein isolation methods have been previously described ( 30 ). Olink (Olink Proteomics, Boston, MA) was given both intracranial and systemic plasma samples to analyze and quantify proteomic data for 184 cardiometabolic and inflammatory proteins.…”

Section: Methodsmentioning

confidence: 99%

Short Chain Fatty Acids Taken at Time of Thrombectomy in Acute Ischemic Stroke Patients Are Independent of Stroke Severity But Associated With Inflammatory Markers and Worse Symptoms at Discharge

et al. 2022

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IntroductionShort chain fatty acids (SCFA) are gut microbiota-derived metabolites that contribute to the gut-brain axis and may impact stroke outcomes following gut dysbiosis. We evaluated plasma SCFA concentrations against stroke severity parameters and identified SCFA-associated protein networks.MethodsThe Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC), a continuously enrolling tissue bank, was used to obtain stroke samples. Arterial blood distal and proximal to the thrombus was obtained from Acute Ischemic Stroke (AIS) Patients (n=53) during thrombectomy. Patient demographics, stroke presentation and outcome parameters were reported. The SCFAs were isolated from proximal plasma via chemical derivatization UHPLC coupled tandem mass spectrometry using electrospray ionization and multiple reaction monitoring. Proteomic levels for 184 cardioembolic and inflammatory proteins was quantified from systemic and intracranial plasma by Olink. Arterial blood from cerebrovascular patients undergoing elective neurointerventional procedures was used as controls.ResultsAcetate positively correlated with time from last known normal (LKN) and was significantly lower in stroke patients compared to control. Isobutyrate, Butyrate and 2-Methylbutyrate negatively correlated with %ΔNIHSS. Isobutyrate and 2-Methylbutyrate positively correlated with NIHSS discharge. SCFA concentrations were not associated with NIHSS admission, infarct volume, or edema volume. Multiple SCFAs positively associated with systemic and pro-inflammatory cytokines, most notably IL-6, TNF-α, VCAM1, IL-17, and MCP-1.ConclusionsPlasma SCFA concentrations taken at time of stroke are not associated with stroke severity at presentation. However, higher levels of SCFAs at the time of stroke are associated with increased markers of inflammation, less recovery from admission to discharge, and worse symptom burden at discharge.

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“…This protocol allows for both intracranial (i.e., distal to thrombus) and systemic (i.e., carotid) arterial blood samples to be obtained during MT. To date, our institution has published results from BACTRAC on arterial blood gasses (ABGs), electrolyte chemistry, genomics, neuroinflammatory cells, and proteomics ( Maglinger et al., 2020 ; Martha et al., 2019 ; Martha SR et al., 2020 ; Shaw et al., 2021 ; Sands et al., 2021 ; Spears et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Influence of BMI on adenosine deaminase and stroke outcomes in mechanical thrombectomy subjects

Maglinger

McLouth

Frank

et al. 2022

Brain, Behavior, & Immunity - Health

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Background Emergent Large Vessel Occlusion (ELVO) strokes are ischemic vascular events for which novel biomarkers and therapies are needed. The purpose of this study is to investigate the role of Body Mass Index (BMI) on protein expression and signaling at the time of ELVO intervention. Additionally, we highlight the protein adenosine deaminase (ADA), which is a deaminating enzyme that degrades adenosine, which has been shown to be neuroprotective in ischemia. We investigate the relationship between ADA and BMI, stroke outcomes, and associated proteomic networks which might aid in personalizing prognosis and future treatment of ELVO stroke. Methods The Blood And Clot Thrombectomy And Collaboration (BACTRAC) study is a continually enrolling tissue bank ( clinicaltrials.gov NCT03153683) and registry from stroke patients undergoing mechanical thrombectomy (MT). N = 61 human carotid plasma samples were analyzed for inflammatory and cardiometabolic protein expression by Olink Proteomics. Statistical analyses used t-tests, linear, logistic, and robust regressions, to assess the relationship between BMI, proteomic expression, and stroke-related outcomes. Results The 61 subjects studied were broken into three categories: normal weight (BMI 18.5–24.9) which contained 19 subjects, overweight (BMI 25–30) which contained 25 subjects, and obese (BMI ≥30) which contained 17 subjects. Normal BMI group was a significantly older population (mean 76 years) when compared to overweight (mean 66 years) and obese (mean 61 years) with significance of p = 0.041 and p = 0.005, respectively. When compared to normal weight and overweight categories, the obese category had significantly higher levels of adenosine deaminase (ADA) expression (p = 0.01 and p = 0.039, respectively). Elevated levels of ADA were found to have a significant positive correlation with both infarct volume and edema volume (p = 0.013 and p = 0.041, respectively), and were associated with a more severe stroke (NIHSS on discharge) and greater stroke related disability (mRS on discharge) with significance of p = 0.053 and p = 0.032, respectively. Conclusions When examined according to BMI, subjects undergoing MT for ELVO demonstrate significant differences in the expression of certain plasma proteins, including ADA. Levels of ADA were found to be significantly higher in the obese population when compared to normal or overweight groups. Increased levels of ADA in the obese group were predictive of increased infarct volume, edema volume, and worse NIHSS scores and mRS at discharge. These data provide novel biomarker candidates as well as treatment targets while increasing the personalization of stroke prognosis and treatment.

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Proteomic changes in intracranial blood during human ischemic stroke

Cited by 28 publications

References 28 publications

Antimicrobial protein REG3A and signaling networks are predictive of stroke outcomes

Antimicrobial protein REG3A and signaling networks are predictive of stroke outcomes

Short Chain Fatty Acids Taken at Time of Thrombectomy in Acute Ischemic Stroke Patients Are Independent of Stroke Severity But Associated With Inflammatory Markers and Worse Symptoms at Discharge

Influence of BMI on adenosine deaminase and stroke outcomes in mechanical thrombectomy subjects

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