Evaluation of plasma CD36 and glutathione as potential biomarkers for intracranial aneurysm.

doi:10.21203/rs.3.rs-2425740/v1

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Evaluation of plasma CD36 and glutathione as potential biomarkers for intracranial aneurysm.

https://doi.org/10.21203/rs.3.rs-2425740/v1

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The underlying mechanisms of intracranial aneurysm (IA) formation and rupture are still unclear. Evidence has proved that it might be closely related to inflammatory response and oxidative stress. Our objective was to identify novel inflammatory and oxidative stress related biomarkers to assist IA management. In this study, the enzyme-linked immunosorbent assay was performed to measure the expression levels of CD36 and glutathione (GSH) in the plasma of 30 IA patients and 30 healthy controls. Then, correlation analysis and receiver operating characteristic (ROC) curve, and logistic regression analysis were applied to investigate CD36 and GSH as potential biomarker for IA. The expression level of plasma CD36 in the IA patients was significantly higher than that in the control group (P < 0.0001), and the level of plasma GSH in the IA patients was significantly lower than that in the control group (P < 0.0001). The plasma level of CD36 and GSH did not show significant correlation with age, Glasgow Coma Scale (GCS), Hunter-Hess score, aneurysm size, aneurysm height, aneurysm neck, and aspect ratio. ROC analysis showed that CD36 and GSH had high sensitivity (90.0%, 96.6%) and specificity (96.6%, 86.6%) for IA diagnosis. And the combined sensitivity and specificity achieved 100% and 100%, respectively. The AUC of logistic regression model based on CD36 and GSH was 0.505. Our results suggested that CD36 and GSH might participate in the process of IA formation and rupture but did not affect its morphology. Moreover, the combination plasma CD36 and GSH could serve as potential biomarker for IA rupture.

Intracranial aneurysm

Inflammation

Oxidative stress

CD36

Glutathione

Biomarker

An intracranial aneurysm (IA) is an abnormal bulge of blood vessel caused by damage to the intracranial artery wall [1]. IA has an incidence of 3% in the general population. With the advances in medical imaging, more and more patients with IA are diagnosed [2]. Patients with IA usually accompanied by neurological dysfunction, and the mortality rate resulting from ruptured IA is as high as 50% [3, 4]. Until now, the pathological mechanisms of IA formation and rupture remain unclear, which deserves deeper exploration for biomarker identification and therapeutic targets discovery [5].

Previous studies have demonstrated that the formation and rupture of IA was closely related to several factors including hemodynamics, inflammation, oxidative stress, endothelial dysfunction, and vascular remodeling [6, 7]. Among them, inflammatory response and oxidative stress might be crucial pathophysiological processes for its occurrence, development, and rupture [8]. In order to identify new therapeutic targets and determine their prognostic roles to assist IA management, we selected a panel of inflammatory and oxidative stress-related markers, involved in vascular dysfunction. In this study, we focused on CD36 and glutathione (GSH) that are reported participated in vascular remodeling under different pathological of cardiovascular disease [9, 10]. As a membrane glycoprotein, CD36 has been evidenced to play an essential role in physiological processes and cellular events such as inflammation, lipid metabolism, endothelial dysfunction, smooth muscle cell dysfunction, and foam cell formation [11]. GSH, a non-protein thiol, is involved in various redox reactions in the body and plays a vital role in protecting cells from oxidative damage and maintaining redox homeostasis [12, 13].

The literatures have documented that CD36 and GSH paly crucial role in processes such as inflammation and oxidative stress responses of arterial walls in cardiovascular disease such as atherosclerosis [14, 15]. CD36 expressed by macrophages promotes the inflammatory response and the formation of foam cells leading to the development of atherosclerosis [16]. The activation inflammatory response and the upregulated expression of CD36 could also increase the production of reactive oxygen species (ROS), which would deplete GSH to trigger the occurrence of oxidative stress. Decreased GSH levels could further increase CD36 expression [17]. Recent studies have shown that IA is also a macrophage-mediated chronic inflammatory disease and that IA may have atherosclerotic wall properties [18, 19]. Here, we proposed that CD36 and GSH might play significant role in IA rupture. To our knowledge, however, there is no study that has evaluated their expression profile in IA.

In this study, we measured the expression level of plasma CD36 and GSH in IA patients and healthy controls by using enzyme-linked immunosorbent assay (ELISA). We further investigated the correlation between clinical parameters of IA patients and CD36, GSH expression level. Further, we evaluated their potential utility as biomarkers for IA rupture.

Study Population

In this study, we recruited 30 IA patients from the Department of Neurosurgery, Affiliated Hospital of Hebei University. The exclusion criteria were diabetes mellitus, metabolic syndrome, cardiovascular disease, severe systemic dysfunction, or other serious medical conditions. Inclusion criteria for IA group: at least one ruptured intracranial aneurysm was found by digital subtraction angiography (DSA) or cerebral CT angiography (CTA) in the patients with subarachnoid hemorrhage, no relevant symptoms, receiving non-operative and conservative observation treatment, Signing the informed consent. In parallel, another 30 age- and sex-matched healthy volunteers with no history of IA. Healthy volunteers underwent CTA before joining the control group, which recruited healthy volunteers with negative examination results. All protocols in this study were approved by the Institutional Review Board for human studies at Affiliated Hospital of Hebei University, Hebei, China (HDFYLL-KY-2022-014). All participants signed informed consent of this study.

Standardized Clinical Assessment

Standard clinical scores were employed in this study: neurological status was assessed using the Glasgow Coma Scale (GCS) and the Hunt-Hess scale. The lower the GCS score and the higher the Hunt-Hess scale grading, the worse the patient's state of consciousness. Meanwhile, the demographics of all participants were collected. Aneurysm parameters include aneurysm location, aneurysm size, aneurysm height, aneurysm width, and aspect ratio (aneurysm height/aneurysm width) [20]. The aneurysm parameters were measured by analyzing the original and three-dimensional reconstruction images of the imaging examinations of CTA or DSA (Fig. 1). Aneurysm height was measured as the maximum perpendicular distance between the dome and the neck plane [21]. The aneurysm width was measured as the maximal horizontal length of the aneurysm [22]. The aneurysm parameters of collected by two experienced neurosurgeons. All differences were resolved by consensus.

Blood Sample Collection

Blood samples were collected from patients within 12h of admission. 10 mL of venous blood from patients and healthy volunteers were collected, placed in EDTA tubes, stored at 4℃, and processed within 4 h. The venous blood was put into a centrifuge and centrifuged at 1,600 g for 10 min at 4℃. The plasma obtained after centrifugation of the venous blood was then stored in a -80℃ freezer until further analysis [23].

Measurement Of Cd36 And Gsh

The GSH and CD36 expression level in plasma of IA and healthy control were measured by using enzyme-linked immunosorbent assay (ELISA) as described previously [24, 25]. In the measurement of GSH and CD36 a pool of EDTA plasma was aliquoted, analyzed at seven different dilutions, and used as a standard concentration curve. The colorimetric reaction was initiated by the addition of yellow para-nitrophenylphosphatase (pNPP; Sigma) to each well, and absorbance values at 405 and 603 nm were measured on a ELISA microplate reader (Bio-Tek, Winooski, VT, USA). Two dilutions of another EDTA pool served as internal controls, each of which was reproduced four times on each ELISA plate.

Construction Of The Logistic Regression Model

To investigate the reliable of GSH and CD36 as the biomarker for IA, the logistic regression models were constructed by using the glm function in R language [26]. In this logistic regression model, the expression value of GSH and CD36 was considered as predictive variables, and the clinical characteristics, aneurysm parameters were considered as a binary responsive variable. A receiver operating characteristic curve (ROC) analysis was performed to evaluate the performance of the model.

Statistical Analysis

All data were statistically analyzed and graphically displayed using GraphPad Prism 7.0 (GraphPad Software Inc., San Diego, CA, USA). The normal distribution of all data in this study was evaluated using the Shapiro-Wilk method. Paired t-test was used to compare the difference between baselines and stimuli tests. The values of CD36 and GSH expression level did not conform to the normal distribution. Thus, the Mann-Whitney U test was used to analyze the difference of CD36, GSH expression between IA and control groups. Differences between genders, and ages were evaluated by unpaired t-test. Pearson correlation was applied to evaluate the relationship between the concentrations of GSH and CD36 expression and clinical data, aneurysm parameters. The area under the receiver operating characteristic (ROC) curve was employed to evaluate potential diagnostic capability. The investigator who performed the statistical analysis was blind to the experimental groups. All experiments were performed with 30 replicates. All values are expressed as Mean ± SD. A p-value < 0.05 was considered statistically significant.

Demographic characteristics of the participants

There were 22 females and 8 males enrolled in the IA group, and the mean age of the IA patients was 56.2 ± 10.1 years (range 36–75). There were 20 females and 10 males in the healthy control group, and the mean age of the healthy control volunteers was 52.7 ± 11.6 years (range 32–72). There was no age- and gender-related difference of CD36 and GSH expression. The clinical data and aneurysm parameters of IA patients were presented in Table 1.

Table 1

Clinical data and aneurysm parameters of the study population.
	Healthy controls (n = 30)	IA patients (n = 30)
Gender (female/male)	20/10	22/8
Age, years	52.7 ± 11.6	56.2 ± 10.1
GCS
Mild (13–15)	–	22
Moderate (9–12)	–	8
Severe (3–8)	–	0
Hunt-Hess grade
Ⅰ	–	4
Ⅱ	–	23
Ⅲ—Ⅴ	–	3
Aneurysm size
< 5 mm	–	15
5–10 mm	–	12
> 10 mm	–	3
Location of Aneurysm
Middle cerebral artery	–	10
Internal carotid artery	–	10
Anterior cerebral artery	–	2
Posterior cerebral artery	–	1
Anterior communicating artery	–	5
Posterior communicating artery	–	1
Basilar artery	–	1
Aneurysm height (mm)	–	5.1 ± 2.5 (range, 1.9–12.4)
Aneurysm neck (mm)	–	3.1 ± 1.5 (range, 1.2–7.3)

Plasma Concentrations Of Cd36 And Gsh

ELISA analysis was used to measure the CD36 and GSH expression level in plasma. The CD36 and GSH were detected in the plasma of both IA and control groups. The expression level of plasma CD36 in the IA group was significantly higher than that in the healthy control group, and the difference reached statistically significant (P < 0.0001) (Fig. 2a). The expression level of plasma GSH in the IA group was significantly lower than that in the healthy control group (P < 0.0001) (Fig. 2b).

Correlation And Roc Curve Analysis

To evaluate the relationship between CD36, GSH and clinical parameters of IA patients, we analyzed the correlation between the expression level of CD36, GSH and IA clinical data, aneurysm parameters. Our results showed no significant correlation between CD36 expression level and clinical data such as patient age (p = 0.459, r = 0.140), GCS (p = 0.204, r = -0.238), Hunt-Hess (p = 0.093, r = 0.311) (Fig. 3). And there was also no significant correlation between CD36 expression level and aneurysm parameters such as aneurysm size (p = 0.101, r = -0.305), aneurysm height (p = 0.543, r = -0.115), aneurysm width (p = 0.947, r = -0.012), and aspect ratio (p = 0.849, r = 0.036) (Fig. 4). For GSH, there were no significant correlations between patient age (p = 0.822, r = 0.042), GCS (p = 0.205, r = 0.237), Hunt-Hess (p = 0.543, r = -0.115), aneurysm size (p = 0.448, r = 0.144), aneurysm height (p = 0.102, r = -0.304), aneurysm width (p = 0.637, r = 0.089), and aspect ratio (p = 0.394, r = -0.161) (Figs. 3 and 4). Among the aneurysm parameters, we found that aneurysm height and aneurysm width showed a significant correlation (p = 0.0002, r = 0.645) (Fig. 5). We further analyzed the sensitivity and specificity of CD36 and GSH for IA predicting by using ROC curves. The sensitivity and specificity of CD36 were 90.0% and 96.6%, respectively, and that of GSH was 96.6% and 86.6%, respectively. Moreover, the sensitivity and specificity of CD36 combined GSH achieved 100% and 100% (Fig. 6).

Evaluation Of The Logistic Regression Model

The expressions of GSH and CD36 were used as predict variables. The logistic regression model showed a normal distribution (Fig. 7), and the GSH and CD36 values had a good linear relationship with the response variable (clinical data and aneurysm parameters). There are no extreme points that significantly affect the accuracy of the model. AUC of the logistic model was 0.505, suggesting that the logistic regression model based on GSH and CD36 could reliably distinguish the patients with IA and healthy controls, and GSH and CD36 could be used as potential biomarkers for the diagnosis of patients with IA (Fig. 8).

Although the underlying pathophysiological mechanisms of IA formation and rupture remain unclear, previous studies suggested vascular endothelial cell inflammation is one of the initiating factors for IA [27]. Oxidative stress, as a significant component in the pathophysiological mechanism of inflammation, also plays a role in the progress of IA formation and rupture [28]. Previous studies have documented that CD36 and GSH were involved in various pathological conditions related to inflammation and oxidative [29]. Whether CD36 and GSH could serve as potential biomarkers for IA rupture needs further investigation.

In this study, we aimed to compared the expression level of plasma CD36, GSH between patients with ruptured IA and healthy controls. Further, evaluate their potential roles as biomarkers for IA rupture. The results showed that the expression of plasma CD36 was elevated in the IA patients. While, the plasm GSH was significantly decreased compared with the healthy controls, which confirmed our conjecture. Evidences indicated the pro-inflammatory signaling in vascular endothelial cells could be initially activated by high wall shear stress of blood flow, resulting in abundant macrophages infiltrating the vascular endothelium [30]. Subsequently, macrophages release various cytokines, which further recruit other inflammatory cells, such as neutrophils, T cells, and mast cells [31, 27]. CD36 is a scavenger receptor expressed in monocytes, endothelial cells, platelets which plays significant roles in mediating lipid uptake, immune recognition, inflammation, molecular adhesion, and apoptosis [32]. CD36 mediates the production of reactive oxygen species (ROS) and promote the occurrence of inflammatory responses by activating the NLRP3 inflammasome [33]. On the other hand, CD36 could also upregulate the expression and phosphorylation of focal adhesion kinase, thereby promoting the expression of matrix metalloproteinases (MMPs) [34]. And MMPs are proteases most closely related to the formation and rupture of IA. As was reported that MMPs could degrade elastin on the arterial wall, resulting in loss of the inner elastic layer and weakening of the vessel wall, and eventually leading to the rupture of IA [35, 36]. Studies have showed that despite normal lipid levels in IA patients, lipid accumulation, foam cells, and oxidized lipids could be found in both unruptured and ruptured IA walls [37]. Moreover, macrophages infiltrating the vascular endothelium could internalize oxidized low-density lipoprotein (ox-LDL) via CD36 and confine it to the vascular intima, which ultimately leads to the accumulation of vascular wall lipids and the conversion of macrophages to foam cells [38]. The reduction of smooth muscle cells is characteristic of arterial remodeling, which is one of the primary causes of IA formation and rupture [39]. Evidence also demonstrated that the binding of CD36 on macrophages to ox-LDL could activate the nuclear factor-κB (NF-κB) signaling pathway to trigger an inflammatory response [40]. The NF-κB pathway is a pivotal link in the inflammatory response, and NF-κB mediated inflammation has been demonstrated to be involved in the pathogenesis of IA [41, 42]. Studies have found that inhibition of NF-κB activity can inhibit the formation and expansion of IA [43]. The above findings indicated that therapeutic targeting CD36 mediating inflammatory responses could be potential candidates for the treatment of IAs.

In addition, inflammation could increase the production of ROS and lead to oxidative stress. ROS could directly increase the expression of inflammatory and adhesion factors, aggravate the inflammatory response, and promote ox-LDL formation [44, 45]. Large amounts of ROS deplete antioxidant compounds (GSH, polyphenols, and vitamins) and enzymes in the body, further unbalancing oxidative and antioxidant effects in the body toward oxidation [46]. Among them, GSH is a significant antioxidant which plays a crucial role in maintaining redox homeostasis. Glutathione-related metabolism is the principal mechanism by which cells protect themselves against oxidative stress [47]. Decreased GSH makes cells more susceptible to oxidative stress, thereby accelerating apoptosis [48]. Studies have shown that oxidative stress can stimulate cells to initiate programmed cell death through an endogenous pathway, resulting in a reduction in the number of cells on the IA wall and a weakening of the vessel wall, which accelerates aneurysm development and rupture [49]. Moreover, oxidative stress can increase CD36 expression, which may be closely related to GSH levels [50]. Studies have found that decreased GSH levels also induced CD36 expression in macrophages and enhanced ox-LDL uptake, thereby promoting lipid accumulation in the vascular wall and foam cell formation [51, 52]. Studies have shown that lipid accumulation and foam cell formation are important factors promoting aneurysm wall degeneration, and lipid accumulation in aneurysm wall has been confirmed to be related to aneurysm rupture [53]. The principal source of macrophages in the walls of IA are monocyte-differentiated macrophages, and reduced GSH levels induce monocyte differentiation into macrophages and promote inflammation response [54]. Some studies have found that certain antioxidants restore intracellular GSH levels, which could prevent the transformation of monocytes to macrophages and reduce the expression of CD36, thus playing a protective role [51, 54, 55]. These findings may provide new therapeutic ideas for antioxidant therapy to inhibit the formation and rupture of IA. Based on our observation, we suggest that CD36 and GSH involved in the pathological process of inflammation and oxidative stress which may predispose to the rupture and formation of IA.

In order to evaluate the diagnosis value of plasma CD36, GSH for IA, the ROC curve analysis was performed. The results showed their excellent predictive performance. As the previous indicated that combining multiple biomarkers could improve diagnostic accuracy compared with using a single marker [56]. And combination of biomarkers has great potentialities in identifying diseases, and the improved diagnostic accuracy could even achieve sensitivity 100.0%, specificity100.0% [57]. In this study, the ROC analysis of two biomarkers combination showed excellent sensitivity, specificity (each 100.0%) which suggested their potential for serving as biomarker for IA diagnosis. Furthermore, correlation analysis between the level of CD36, GSH and the clinical parameters was conducted to determine their roles in the diagnosis of IA. To our surprise, the results showed that CD36 and GSH had no significant correlation with GCS score, Hunt-Hess score, age, aneurysm width, aneurysm height, aneurysm neck, and aspect ratio in IA patients. Moreover, the logistic regression was used to examine their performance of IA prediction. Our results showed GSH and CD36 have a poor discrimination between IA patients and healthy control when combined clinical characteristics, aneurysm parameters. Inconsistent with previous finding showing that a panel of biomarkers display a high discriminating capacity with an AUC = 1, a specificity of 100%, and a sensitivity of 100%. We speculated that there might be several explanations for these results. First, the study population is too small to represent the predict values with the logistic regression model [58]. Second, it might be caused by the disease spectrum bias. The clinical studies with a population that lacks diagnostic uncertainty may produce a biased estimate of a test’s performance [59]. Third, our correlation analysis indicated that the expression level of CD36, GSH did significantly correlated with the aneurysm parameters which imply that they might not participate in changes in aneurysm morphology. Evidences also demonstrated a pathogenetic link between hemodynamics and inflammatory response in the development and rupture of IA [60]. As previous study suggested, hemodynamics factor might play crucial roles in the morphologic changes of IA [61]. Here, we suspected that CD36 and GSH might participate in the process of IA formation and rupture but did not affect its morphology. Further, the logistic regression model was established by combining clinical characteristics, aneurysm parameters. Although we evaluation the utility of plasma CD36 and glutathione as biomarkers for IA with small population, our result demonstrated their diagnosis power which deserves further validation with larger cohorts.

This study has some limitations. First, the sample size of this study is small, which may cause biased results to a certain extent. A large-scale cohort study is needed to validate our results in our future work. Secondly, this study is an observational study without further animal or in vitro cells experiments to their underlying mechanisms in IA pathology process. And CD36 KO or glutathione metabolism-related gene-related gene knock out IA mice model could also help for evaluating the role CD36 and CHS in AI formation. Thirdly, we did not measure the expression level of CD36 and GSH in the aneurysm wall. These limitations are subjects of future work.

This study revealed a significant increase of plasma CD36 and a decrease of plasma GSH in the patients with ruptured IA compared with healthy controls. We proposed that CD36 and GSH might be involved in the progress of IA rupture, but did not affect the aneurysm morphology. And plasma CD36 and GSH could serve as potential biomarker for IA rupture.

IA: intracranial aneurysm; GSH: glutathione; ROC: receiver operating characteristic; ROS: reactive oxygen species; DSA: digital subtraction angiography; CTA: cerebral CT angiography; GCS: Glasgow Coma Scale; ELISA: enzyme-linked immunosorbent assay

Acknowledgements Not applicable.

Author Contribution Concept of study design: Lijian Zhang, Chunhui Li, Data collection and statistics: Hanbin Wang, Luxuan Wang, Yunmei Liu, Weidong Men, Wanjiao Hao, Chuan Fan, Manuscript draft: Hanbin Wang, Luxuan Wang. Revise and editing of the manuscript: Lijian Zhang, Chunhui Li.

Funding This work was supported by China Postdoctoral Science Foundation (NO. 2022M710997); Provincial Medical Talents Project funded of Hebei Province (NO. 361007); the Hebei Natural Science Foundation Precision Medicine Joint Project (grant number H2020201206), and The Central Government Guided Local Science and Technology Development Fund Project of Hebei Province (grant number 216Z7711G).

Data availability All patient characteristics and data are available upon requests to the correspondent author.

Code Availability Not applicable.

Ethics Approval This study was approved by the ethnic committee of Affiliated Hospital of Hebei University, Hebei, China (HDFYLL-KY-2022-014). and complied with the Declaration of Helsinki. And all individuals participating in this study signed written informed consent.

Consent to Participate Not applicable.

Consent for Publication Not applicable.

Conflict of Interest The authors declare no competing interests.

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You are reading this latest preprint version

Evaluation of plasma CD36 and glutathione as potential biomarkers for intracranial aneurysm.

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Version 1

Abstract

Figures

Introduction

Materials And Methods

Study Population

Standardized Clinical Assessment

Blood Sample Collection

Measurement Of Cd36 And Gsh

Construction Of The Logistic Regression Model

Statistical Analysis

Results

Demographic characteristics of the participants

Plasma Concentrations Of Cd36 And Gsh

Correlation And Roc Curve Analysis

Evaluation Of The Logistic Regression Model

Discussion

Conclusion

Abbreviations

Declarations

References

Status:

Version 1