The reason for the worsening of ‘Moyamoya disease’, which causes narrowing of cerebral blood vessels, was discovered.

[이데일리 이순용 기자] The aggravating factor of moyamoya disease, which causes narrowing of cerebral blood vessels, was found.

Professor Hong Ji-man’s team (Researcher Shin Hee-seon) of the Department of Neurology at Ajou University Hospital revealed that one of the causes of serious progression in moyamoya disease patients is the decrease in autophagy ability of vascular endothelial cells that interacts with the RNF213 mutant gene.

The research team confirmed that in patients with moyamoya disease with the RNF213 gene mutation, the disease progresses more seriously when exposed to stressful environments such as nutritional deficiency (starvation) and hypoxia. The proportion of patients with the RNF213 gene mutation is approximately 80% in Korea and Japan.

Moyamoya disease is a rare and incurable disease in which the arteries that supply blood to the brain gradually narrow and eventually become blocked. When the blood supply to the brain becomes insufficient, abnormal microscopic blood vessels grow to compensate for this. Because these blood vessels resemble smoke, it is called ‘moyamoya’ disease, which means ‘sharp’ in Japanese. Moyamoya disease has a high prevalence and family history in Asia, including Korea, Japan, and China. Therefore, genetic factors have been assumed to be the main cause of the disease.

The research team compared 30 patients with moyamoya disease and 15 normal people. The patient group was divided into the RNF213 gene normal group (15 patients) and the mutant group (15 patients), and autophagy ability was analyzed in peripheral blood mononuclear cells.

As a result of the analysis, the endothelial cell function of the patient with the genetic modification was reduced, and autophagy was abnormally suppressed in the genetically modified cells. In addition, normal and mutant RNF213 genes were randomly overexpressed in human umbilical vein endothelial cells, and then the cells were exposed to hypoxia and glucose deprivation for 2 hours to resemble the intracranial environment of patients with moyamoya disease.

As a result, more autophagic cysts were observed in endothelial cells of RNF213 gene mutation. Autophagy cysts are a form observed when abnormal proteins are removed from the cytoplasm of our body. In particular, after exposure to hypoxia and glucose deficiency, inhibition of autophagy and decreased function of vascular endothelial cells were clearly observed, and more intracellular autophagic cysts were observed through transmission electron microscopy. The research team confirmed that the genetically modified cells recovered normal autophagy function after using an autophagy inducer.

Meanwhile, the RNF213 protein is known to play an important role in removing unnecessary or abnormal proteins from our body, and autophagy is also a physiological mechanism that maintains cellular homeostasis even under cell stress conditions through removal of unnecessary proteins.

Accordingly, the research team explained, “It is presumed that inhibition of autophagy and decline in vascular endothelial function worsens moyamoya disease by causing accumulation of abnormal proteins in cerebral blood vessels and decreased cerebral blood flow.”

Professor Hong Ji-man, the lead researcher, said, “This study is significant in that it is the first to confirm that environmental stress, such as hypoxia, seriously progresses the disease in RNF213 gene mutation moyamoya disease.”

Researcher Shin Hee-seon, the first author, said, “By identifying the relationship between autophagy and vascular cell function in the peripheral blood cells of actual moyamoya patients, we look forward to the development and clinical application of new drugs in the future.”

This study was published in the April online edition of the International Journal of Cerebral Blood Flow and Metabolism, titled ‘RNF213 variant and autophagic impairment: A pivotal link to endothelial dysfunction in moyamoya disease. It was published under the title “Pivotal involvement in endothelial dysfunction.”

This study was conducted with support from the Ministry of Health and Welfare’s research-oriented hospital development R&D project.