Protein linked to worsening pulmonary hypertension identified

A research group including Professor Kiyoshi Hirahara, Specially Appointed Associate Professor Chiaki Iwamura, and Guest Researcher Sachiko Kuriyama of the Graduate School of Medicine at Chiba University, in cooperation with Juntendo University, clarified that the protein Myl9/12 plays a role in inducing vascular remodeling and inflammation in pulmonary hypertension, an intractable disease. It is expected to become a diagnostic marker and a therapeutic target. Hirahara commented, "To socially implement it as a biomarker within 4 years, we are advancing joint research and development with a reagent manufacturer." The findings were published online in Circulation Research.

Pulmonary hypertension is a designated intractable disease common among young women, and there are 4,682 patients in Japan (as of fiscal year 2023). The wall of the pulmonary artery extending from the right ventricle becomes thick and hard, which results in pulmonary artery stenosis and right ventricular hypertrophy (vascular remodeling). More than 20% of patients die within 3 years even with treatment. Currently, there is no effective treatment for abnormal proliferation of vascular endothelial cells or fibrosis of the vascular adventitia.

The disease cannot be identified by blood tests or ultrasound tests. For a definitive diagnosis and evaluation of the medical condition, a right heart catheterization test, which inserts a thin tube from a blood vessel into the heart, is necessary, but it is highly invasive, and the test cost is also high.

To clarify the cause of the disease and search for biomarkers, the research group focused on platelet-derived Myl9 (myosin light chain 9), which serves as an indicator of vascular inflammation. When vascular damage due to inflammation occurs, platelets are activated and Myl9 is released, forming a thrombus-like net of Myl9 on the vascular lumen wall.

Past research has clarified that in severe COVID-19 patients, the concentration of Myl9 in plasma rises, among other findings. In this research, it was found that Myl9 was detected not only in microthrombi but also from abnormal vascular endothelial cells of patients and is involved in the formation of the pathology. It was also clarified that when human microvascular endothelial cells are cultured under hypoxic conditions, they release Myl9.

In vascular endothelial cells, hypoxic stimulation stabilized EPAS1, leading to the induction and release of Myl9. It was found that even in actual patients, the more severe the condition becomes, the higher the blood Myl9 concentration becomes, and Myl9 becomes an indicator of the severity of pulmonary hypertension. Furthermore, when an anti-Myl9 antibody was administered to pulmonary hypertension model mice, the pulmonary microthrombi containing Myl9 disappeared, by which both pulmonary blood flow and the load on the heart improved. The abnormal proliferation of vascular endothelial cells was also suppressed.

Myl9 in plasma has become a strong candidate for a severity marker of pulmonary hypertension, and this is likely to lead to the development of a new treatment method targeting Myl9 as a therapeutic target. While advancing the marker development, the research group is developing a human anti-Myl9 antibody and will accelerate efforts toward social implementation in the future.

Journal Information
Publication: Circulation Research
Title: Hypoxia-Induced Epas1-Myl9/12 Axis Shapes the Pathology of Pulmonary Hypertension
DOI: 10.1161/CIRCRESAHA.125.327791