Orosomucoid and Cerebral Stroke: A Mini Review

Introduction

Orosomucoid (ORM), or Alpha-1-Acid Glycoprotein (AGP), is one of the most abundant plasma proteins, accounting for about 1% of all plasma proteins. There are two isoforms of Orm in humans, three in mice, and one in rats. It possesses peptide moiety that is a single chain of 183 amino acids (human) or 187 amino acids (rat) with two and one disulfide bridges in humans and rats, respectively. Its molecular weight is of 37–54 kDa, low pI is of 2.8–3.8. The carbohydrate content represents 45% of the molecular weight that is attached in the form of five to six highly sialylated complex-type-N-linked glycans. Although it is mainly synthesized by the liver, many extrahepatic tissues have also been reported to produce ORM under myriad physiological and pathological conditions [1-3]. In the 1960s, the researchers from Japan firstly found Orosomucoid [4]. From then many studies were designed to explore the effect of this protein in physiological and pathological conditions, however little is known about the role of ORM in the Central Nervous System (CNS). Stroke is a common disease of the nervous system and numerous studies revealed that neuroinflammation can contribute to the pathogenesis of stroke including brain edema ,tissue and brain blood barrier injury [5-7]. In this mini review, we try to introduce the relationship between orosomucoid and stroke.

Clinical Corhort Study

ORM as one of Inflammation-Sensitive Proteins (ISPs) has been widely regarded as an essential measure in the clinical cohort study about the association of ISP, risk factors and incidence of stroke. Atherosclerotic plaque obstruction of cerebral or carotid artery is the main cause of stroke. Berntssonc indicates that elevated levels of orosomucoid are associated with increased occurrence of carotid plaque and increased incidence of ischemic stroke [6]. Hypertension, diabetes, smoking, hyperlipidemia are all involved in the development of arteriosclerosis, and they are also high risk factors for stroke. Series cohort studies was conducted on the relationship between ISPs and these high risk factors and the impact of ISPs and high risk factors on the incidence of stroke. In these studies, ORM was one of the ISPs that were assessed. The results of these studies indicated that smoking [9], diabetes [10], hyperlipidemia [11], hypertension [12], high risk of atrial fibrillation [13] are accompanied by high levels of ISPs. By observation, the researchers found that the subjects suffering from hypertension, diabetes, smoking, hyperlipidemia and high risk of atrial fibrillation with high levels of ISPs are associated with an increased cardiovascular and stroke risk.

As we known chronic low-grade inflammation and associated insulin resistance and metabolic abnormalities have been proposed as joint participation in pathological process of Diabetes Mellitus (DM) and Cardiovascular Disease (CVD). There was a prospective study exploring this hypothesis and they found that orosomucoid was associated with an increased risk of both DM and CVD [14]. And there also was an article showing that serum AGP values of the metabolic syndrome subjects were significantly higher in an adolescent population with metabolic syndrome than those of the controls [15]. A study about orosomucoid in Young Patients with Type 1 Diabetes suggesting that orosomucoid is a significant independent factor for diabetic microvascular complications and can be considered as an early marker of renal injury. High orosomucoid levels in type 1 diabetes reflect endothelial dysfunction and subclinical atherosclerosis [16]. But a populationbased cohort study reveal that there are associations between orosomucoid, haptoglobin and C Reactive Protein (CRP) and the risk of incidence of diabetes.

However, after additional adjustment for fasting glucose levels at baseline, the association stayed significant only for CRP [17]. Up to now, many studies have explored the relationship between ORM and risk factors of stroke and the incidence of stroke. Other risk factors such as insomnia, lack of exercise, high uric acid, high homocysteine, and malnutrition have also attracted widespread attention in recent years. Whether these risk factors are related to acute phase reactive protein (including ORM) and whether they jointly increase the incidence of stroke, these problems need to be further explored. The number of young people with stroke is increasing year by year. The cohort study of acute phase proteins in young people with stroke is worthy of attention.

Preclinical Experiment

So far there has been a lot of basic research focused on ORM and stroke. Some researchers investigated 30 patients with cerebral ischaemic stroke. They found that APG and alpha-1- antichymotrypsin levels in serum of patients with cerebral ischemic stroke were statistically higher than in the control group on III and VII day of illness [18]. A study’s results revealed the change of Orosomucoid1 gene (ORM1) of peripheral whole blood gene expression in patients of ischemic stroke and control group. They explained the reason of the upregulation of ORM1 is that the acute phase response of ischemic stroke in the context of ischemic stroke, is similar to trauma, infection, and systemic tissue damage [19]. Some researcher showed that diphenyl diselenide (PhSe) (2), an organoselenium compound with antioxidant and anti-inflammatory properties, against Ischemia/Reperfusion (I/R) insult in rat brain can markedly reduce plasma levels of tissue damage markers, such as a-1-acid glycoprotein and creatine kinase [20]. Some studies have explored the specific role of ORM protein in stroke.

Anti-inflammation Obesity is a risk factor for stroke. Obesity has some association with chronic low-grade inflammation, which contributes to systemic metabolic irregularities and obesity-linked metabolic disorders. Some researchers found that adipocytokine orosomucoid resolve immoderate inflammation by suppressing proinflammatory gene expression and pathways such as NF-kappaB and mitogen-activated protein kinase signalings and reactive oxygen species generation [21]. And another study showed that ORM mRNA expression had no difference between visceral and subcutaneous adipose tissue. ORM mRNA expression correlated with mRNA expression of TNF-α, IL-6, and adiponectin [22]. Interleukin-1(IL-1) is a pro-inflammatory cytokine which involve the process of neuronal injury in ischemic brain [23]. Recently, a review article explicit the Cytokines as one of inflammatory mediators have impacts on the disruption of the brain blood barrier [24]. There was a study revealed α1-acid glycoprotein can inhibit IL-1 comitogenic activity [25]. There also has the studies explicit that AGP can down-regulate neutrophil responsiveness, an effect that depends in part on its glycan microheterogeneity [26,27].

There is a study indicating that ORM1 stimulates quiescent monocytes to polarize to M2b monocytes so that leads to opportunistic infections [28]. Jo M investigate the brain expression of ORM and its role in neuroinflammation. The results of the study reveal that astrocytes are the major cellular sources of ORM2 in the inflamed mouse brain. ORM2 may be exert anti-inflammatory effects by inhibiting C-C Chemokine Ligand 4 (CCL4)-induced microglial migration and activation by blocking the interaction of CCL4 with C-C chemokine receptor type 5 [29]. Overall, dynamic expression of ORM protein in cerebral tissue of cerebral infarction model has not been observed in animal experiments, and there are few animal experiments on the role of ORM protein in the neuroinflammatory response of cerebral infarction. The process of cerebral infarction and recovery of cerebral infarction is accompanied by changes of neuroinflammation, and the anti-inflammatory effects of ORM need to be further understood in animal models of cerebral infarction in order to provide the basis for optimizing the treatment plan.

2.2Maintaining blood-brain barrier function the breakdown of Blood-Brain Barrier (BBB) after stroke is closely related to the formation of cerebral edema. In 1999, Pichler et al. publish an article which discuss that further experiment for alpha 1-acid glycoprotein is about inhibitory effect on brain edema formation after experimental stroke [30]. Human microvascular endothelial cells have been found to synthesize ORM protein, which is essential for capillary charge selectivity [31]. Some experientments has been found that via decreasing the transport of negatively charged molecules but increasing that of positively charged ones, orosomucoid modulates the transport of charged solutes across the wall of peripheral and cerebral microvessels in vivo [32,33]. There are experimental results indicate that orosomucoid can modulate the permeability of the BBB to charged molecules by adding negative charge to the matrix components of the BBB [34]. And this results were repeated in the experientments that the bEnd3 (An Immortalized Mouse Cerebral Endothelial Cell Line )monolayer replace intact endothelium of the BBB [35]. Wu designed a study to investigate that vascular endothelial growth factor-induced blood-brain barrier leakage after ischemic stroke in transient middle cerebral artery occlusion model decreasing the orosomucoid1 expression via inhibition of the NF-κB pathway [36]. Studies on the relationship between ORM and blood-brain barrier have been carried out, but these studies have not been widely used in animal models of cerebral infarction, and the dynamic changes of ORM expression and blood-brain barrier damage have not been observed systematically. There are many imaging methods for measuring changes in blood-brain barrier damage, and subsequent studies can combine imaging with ORM expression.

Conclusion

In summary, orosomucoid associates with risk factors for stroke. It can inhibit neuroinflammation and regulate the permeability of blood-brain barrier. However, the dynamic evolution of the expression of this protein and its specific mechanism need to be further explored in the animal model of cerebral infarction.

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