Identification of a New Therapeutic Target for the Intractable Disease Pulmonary Hypertension - Protein MYL9/12 Induces Vascular Remodeling

A research group led by Professor Kiyoshi Hirahara, Associate Professor Chiaki Iwamura, and Visiting Researcher Sachiko Kuriyama from the Graduate School of Medicine, Chiba University, in collaboration with Juntendo University, has revealed that the protein MYL9/12 (Note 1) plays a role in inducing vascular remodeling (Note 3) and inflammation in the intractable disease pulmonary hypertension (Note 2). This research achievement was published online on July 2, 2026 (US Eastern Time) in Circulation Research, an international medical journal published by the American Heart Association. (Paper here: 10.1161/CIRCRESAHA.125.327791)

Figure: Research Achievements and Future Prospects

Background of the Research

Pulmonary hypertension is an intractable disease in which the walls of the pulmonary arteries thicken and harden, narrowing the blood vessels. Current treatments make it difficult to restore the thickened blood vessels to their original state. It was known that the hypoxic state of blood vessels was deeply involved in the onset of the disease, but the mechanism by which vascular changes and inflammation were caused remained unclear. Furthermore, a "right heart catheterization" procedure, which involves inserting a thin tube from the blood vessels to the heart, is necessary for the definitive diagnosis and assessment of pulmonary hypertension, but it places a significant burden on patients.

Therefore, the key challenges were: 1) elucidating the mechanism of disease onset and exploring new therapeutic methods, and 2) developing biomarkers that can complement right heart catheterization and allow for simpler assessment of the disease state or measurement of its severity.

Key Research Findings

● Identification of a protein crucial for the worsening of pulmonary hypertension: It was discovered that when blood vessels are in a hypoxic state, the protein MYL9/12 is released from platelets and abnormal pulmonary vascular endothelial cells. The accumulation of MYL9/12 in thrombi within the pulmonary vessels causes thickening of the vessel walls and inflammation.

● Symptom improvement with "antibody" administration: When an antibody that inhibits the function of MYL9/12 was administered to mice with pulmonary hypertension, not only was the thickening of the blood vessels reduced, but thrombi and inflammation were also suppressed, leading to improved blood flow.

● MYL9 concentration in patient blood correlates with the severity of pulmonary hypertension: The blood MYL9 concentration confirmed in this study is expected to serve as a new evaluation index for measuring the severity of pulmonary hypertension in the future.

Future Prospects (Researcher Comments)

This research has shown that MYL9/12 is a groundbreaking therapeutic target and can serve as a useful biomarker. Our research group has previously filed an international patent for "Methods for detecting pulmonary hypertension and therapeutic or prophylactic agents for pulmonary hypertension," and has succeeded in producing a humanized antibody targeting human MYL9/12. Furthermore, through joint research with a company, we are developing a system for measuring blood MYL9 concentration in clinical settings. Based on these research findings, we aim to contribute to the advancement of patient care and medical treatment for pulmonary hypertension by developing new therapeutic and diagnostic methods for the disease.

Glossary

Note 1) MYL9/12: A group of proteins belonging to myosin light chains that control cell "movement, force, and shape." MYL9 and MYL12 have very similar functions and are often difficult to distinguish, hence they are referred to as "MYL9/12."

Note 2) Pulmonary hypertension: Pulmonary arteries are normally structured to allow blood to flow at low pressure. However, in pulmonary hypertension, the pulmonary arteries become narrow and stiff, making blood flow difficult and placing a strong burden on the heart that pumps the blood.

Note 3) Vascular remodeling: Refers to the structural changes in blood vessels that make them "hard, thick, and narrow." In pulmonary hypertension, the progression of this vascular remodeling leads to worsening symptoms.

Paper Information

Title: Hypoxia-induced Epas1-Myl9/12 axis shapes the pathology of pulmonary hypertension

Authors: Sachiko Kuriyama, Chiaki Iwamura, Masahiro Kiuchi, Tetsutaro Nagaoka, Akane Kurosugi, Atsushi Sasaki, Yuiko Masuda, Kohei Kusakari, Yuichi Nagata, Si Jing Chen, Naoya Takayama, Yoshifumi Suzuki, Takashi Yoshida, Naoko Mato, Shinichi Yamamoto, Toshiro Niki, Kohei Takahashi, Yuki Shiko, Jungo Kakuta, Kenzo Muramoto, Koji Eto, Motoko Y. Kimura, Yuzuru Ikehara, Kazuhisa Takahashi, Kiyoshi Hirahara, and Toshinori Nakayama

Journal: Circulation Research

DOI: 10.1161/CIRCRESAHA.125.327791

About the Research Project

This research was conducted with the support of the following:

Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (JSPS KAKENHI): JP19H05650, JP20H03685, JP23H02916, JP22K08251, JP25K11462, JP20K17227, JP22K15485, JP21H05120, JP21H05121, JP19K23838

Japan Agency for Medical Research and Development (AMED): "Practical Research Project for Allergy-Related Diseases" Development of therapeutic methods for intractable allergic airway inflammation by elucidating novel regulatory mechanisms of IL-33 activation, Development of therapeutic methods for intractable allergic diseases by elucidating the induction mechanism of pathogenic Th2 cells in vivo, Development of therapeutic methods for intractable allergic diseases by elucidating the mechanism of acquisition of tissue residency by pathogenic Th2 cells in vivo, "Core Research for Evolutional Science and Technology (CREST)" Elucidation of the mechanism of pathological remodeling (fibrosis) in airway tissues and establishment of a basic strategy for pathological control therapy, Elucidation of the mechanism of formation of tissue inflammatory memory by external environmental stimuli and establishment of a basic strategy for pathological control therapy for intractable allergic diseases, "Cutting-edge Research and Development on Next Generation Infrastructure (LEAP)" Development of therapeutic and diagnostic methods for kidney diseases targeting tertiary lymphoid tissues, "Program for the Promotion of Global Research Network on Vaccines" Global Research Network Program for Vaccine Development Chiba Synergy Campus

Japan Science and Technology Agency (JST): "Emerging Research Grant" Integrated elucidation of the four-dimensional control mechanism of tissue inflammatory memory in the lungs (Project Number JPMJFR200R) Naito Foundation, Takeda Science Foundation