Heart Attack: METRNL stimulates vascularization and reduces scarring


Secreted proteins play a crucial role in both pathological and physiological processes and have a natural advantage for application in the diagnosis and treatment of clinical diseases [1].

Metrnl (Meteorin-like, Subfatin, Cometin) was previously discovered by us as an adipokine [2] and is abundant in subcutaneous white adipose tissue [2] and barrier tissues [3], such as the skin, intestinal, and respiratory tract epithelium [4].

Research has shown that Metrnl can promote neurite extension [5], enhance white fat browning [6], regulate insulin sensitivity [7], modify the inflammatory immune response [3], alter blood lipids [8], etc. Most of the research on the function of Metrnl has been reviewed by us before [9].

These results suggest that Metrnl could be a promising biomarker and a potential therapeutic target for related clinical diseases. However, the exact relationship between Metrnl and related clinical diseases needs to be confirmed, and whether Metrnl could be applied in the diagnosis and treatment of clinical diseases should be carefully verified.

Recently, many clinical studies related to Metrnl have been carried out. Since Metrnl is abundantly expressed in metabolism-related organ and barrier tissues and shows regulatory functions in metabolism and inflammation in animal studies [3, 6, 7, 10], most clinical studies focus on the relationship between Metrnl and metabolism or inflammation-related diseases, such as type 2 diabetes [11–13], coronary heart disease [14, 15], colitis [16], arthritis [3, 17], etc.

All these clinical studies are helpful for understanding the clinical effects of Metrnl and demonstrate its potential as a new therapeutic target. Here, in this paper, we will mainly introduce the progress of recent clinical research on Metrnl.

Now a research team led by Professor Dr. Kai Wollert, Head of Molecular and Translational Cardiology at the Department of Cardiology and Angiology at Hannover Medical School (MHH), has found out which cells are involved in heart repair and how they communicate with each other. The researchers have discovered a new messenger substance that controls wound healing, thus revealing an approach for a new therapy. The research has been published in Science.

New mechanism of cell communication found

The focus of the study is the receptor KIT. The protein is produced by various cells, including the hematopoietic stem cells in the bone marrow. Here, KIT plays an important role as a binding site for the so-called stem cell factor. This messenger substance activates the KIT-positive stem cells and causes them to develop into the various cells of the blood. KIT-positive cells are also found in the heart.

“However, these are not stem cells, as long suspected, but vascular cells,” explains Dr. Marc Reboll, research associate in Molecular and Translational Cardiology and first author of the study. The KIT-positive vascular cells ensure that new heart vessels form after a heart attack.

However, the stem cell factor necessary for KIT activation can barely be detected in the heart. The researchers have now resolved this contradiction. They discovered a new messenger substance in the heart that can also bind precisely to the KIT receptor and set the repair process in motion: the protein meteorin-like (METRNL).

METRNL stimulates vascularization and reduces scarring

“After a heart attack, the immune system reacts with an inflammatory response,” Professor Wollert explains. “The inflammatory cells produce METRNL, which stimulates the KIT-positive vascular cells to form new blood vessels.”

Studies in the mouse model showed that without METRNL, heart repair no longer worked. In contrast, when mice were treated with METRNL, new vessels formed in the infarct area. “This alleviates scarring and prevents severe heart failure,” says the cardiologist. The newly discovered messenger substance could now be the decisive building block to a drug that specifically supports heart repair.

. . . .

Metrnl in coronary heart disease and atherosclerosis
Coronary heart disease is one of the major causes of death worldwide and mainly arises from atherosclerosis [31]. The major risk factors for atherosclerosis include dyslipidemia, inflammation and insulin resistance [31, 32]. Previous research shows that Metrnl plays a role in regulating insulin resistance and inflammatory responses [3, 6, 7].

Our recent work shows that global knockout of Metrnl can not only increase blood triglycerides but also decrease high-density lipoprotein (HDL)-cholesterol in mice. Combined with the results from a tissue-specific knockout animal model, we conclude that adipose Metrnl contributes to its regulatory function on blood triglycerides and that liver Metrnl contributes to its regulatory effects on cholesterol metabolism [8]. Thus, it is speculated that a relationship between blood Metrnl and coronary heart disease could exist in the clinic.

Liu et al. showed that a decreased blood Metrnl concentration is significantly related to coronary heart disease in patients with diabetes or nondiabetics [15]. According to their regression analysis, the optimal cutoff value of Metrnl for predicting coronary heart disease is 123.5 pg/mL, with a low sensitivity (44.04%) and a high specificity (95.51%). Meanwhile, they also carried out research on the relationship between Metrnl levels and the severity of coronary heart disease.

The severity of coronary heart disease is assessed with the Gensini score system based on the degree of luminal narrowing and its geographic importance. The results show that serum Metrnl is significantly negatively correlated with the Gensini score and the number of stenosed vessels, indicating that lower Metrnl levels are associated with the severity of coronary heart disease [15].

A similar phenomenon was also observed in the study of Dadmanesh et al., which showed that blood Metrnl was significantly lower in patients with coronary heart disease [14]. These results suggest that low blood Metrnl is related to coronary heart disease and that Metrnl may have a protective role in coronary heart disease.

There are some clues to explain the mechanism; for example, lower blood Metrnl is associated with LDL cholesterol, carotid intima media thickness, brachial-ankle pulse wave velocity, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E selectin [23]. However, the comprehensive explanation of why lower blood Metrnl is associated with coronary heart disease and the exact function of Metrnl in coronary heart disease need to be explored further.

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More information: Marc R. Reboll et al, Meteorin-like promotes heart repair through endothelial KIT receptor tyrosine kinase, Science (2022). DOI: 10.1126/science.abn3027


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