The Protective Effects and Mechanisms of Apelin/APJ System on Ischemic Stroke: A Promising Therapeutic Target

Now we just need whomever is running the stroke strategy to see what followup research needs to be done. Oops, that will never occur. WE HAVE NO STROKE LEADERSHIP AND NO STROKE STRATEGY. 

Until we get stroke survivors in charge nothing useful is going to happen to get to 100% recovery. No one in stroke is even thinking about that goal. 

The Protective Effects and Mechanisms of Apelin/APJ System on Ischemic Stroke: A Promising Therapeutic Target

Yanjun Tian^1†, Ruijiao Chen^1†, Yunlu Jiang^2,3, Bo Bai³, Tongju Yang^4* and Haiqing Liu^5*

• ¹Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, Jining, China
• ²School of Mental Health, Jining Medical University, Jining, China
• ³Institute of Neurobiology, Jining Medical University, Jining, China
• ⁴Department of Pharmacy, People's Hospital of Zoucheng City, Jining, China
• ⁵Department of Physiology, Shandong First Medical University (Shandong Academy of Medical Sciences), Taian, China

The orphan receptor APJ and its endogenous ligand apelin, which are expressed in the brain, are the major components of the apelin/APJ system. Growing evidence shows that the apelin/APJ system plays a vital role in the pathophysiology of cerebral ischemic injury. Targeting the apelin/APJ system may have protective effects on cerebral ischemic injury. In this review, we sum up the latest research progress relating to the actions and therapeutic potential of the apelin/APJ system in ischemic stroke. An in-depth knowledge of the pathophysiological effects of the apelin/APJ system and the underlying mechanisms will help to develop novel therapeutic interventions for ischemic stroke.

Introduction

In 1993, O'Dowd discovered the orphan G protein–coupled receptor (GPCR) APJ while searching for vasopressin receptor subtypes (1). APJ is encoded by a gene located on chromosome 11q12. Although APJ shares 54% homology with angiotensin II receptor type-1 (AT1R) in the hydrophobic transmembrane region, there's no binding site for angiotensin II (1). Tatemoto et al. isolated apelin, the cognate ligand for APJ receptor, from bovine stomach tissue extracts in 1998 (2). The apelin gene, which is located on chromosome Xq25-26.1, encodes the preproapelin of 77 amino acids (apelin-77). Various bioactive isoforms of apelin are derived from apelin-77, including apelin-55, apelin-36, apelin-17, apelin-13, and apelin-12 (3, 4). Recently Chng et al. discovered apela, another endogenous ligand for APJ, which is encoded by a gene located on chromosome 11 and is critical in embryonic development (5, 6). However, in humans, the apela is only expressed in pluripotent cells and kidney (7). The apelin/APJ system mainly refers to APJ and its endogenous ligand, apelin.

Stroke, which is mainly caused by cerebral vascular occlusion and cerebral blood supply disorder, is one of the leading causes of death and disability worldwide, and 87% of cases are ischemic stroke (8). The cerebral infarction area is composed of the ischemic core and penumbra; apoptosis is the main cause of neuronal damage in the penumbra region, which also provides an opportunity for the treatment of ischemic stroke and makes it possible to use drugs to alleviate neuronal injury since the apoptosis is delayed and reversible (9, 10). Neuronal apoptosis in ischemic penumbra is triggered by diffusion of toxic substances released by the dead neurons of the ischemic core in the acute stage of ischemia, while ischemia injury is aggravated after reperfusion, namely ischemia/reperfusion (I/R) injury, which contributes to the neuron apoptosis in the penumbra via numerous biological mechanisms, including excitotoxicity, oxidative and nitrative stress, inflammatory responses, endoplasmic reticulum stress (ERS), and so on (11–14).

The apelin/APJ system is widely expressed in the central nervous system, especially in neurons and oligodendrocytes (15, 16). Growing evidence indicates that the apelin/APJ system is involved in the pathophysiology of ischemic stroke (17, 18). Targeting the apelin/APJ system may have protective effects on cerebral ischemic injury. In this review, we mainly focus on the latest research progress related to the biological functions and therapeutic potential of the apelin/APJ system in ischemic stroke.