SHMT2 Protein Drives Pulmonary Hypertension Via Newly Discovered Pathway
A mitochondrial enzyme found upregulated in pulmonary hypertension patients triggers vascular damage through a noncanonical mechanism — and a known drug can block it.
Summary
Researchers discovered that a mitochondrial enzyme called SHMT2 is abnormally elevated in the blood vessel lining of pulmonary hypertension patients. Rather than acting through its known metabolic role, SHMT2 works via an unexpected mechanism: it blocks the normal disposal of a protein called RhoB, causing it to accumulate and damage the blood vessel barrier in the lungs. When scientists deleted SHMT2 specifically in endothelial cells of mice, pulmonary vascular scarring and right heart damage were significantly reduced. Overexpressing it worsened disease. Using computer-assisted drug screening, the team identified Namodenoson — an existing small molecule — as an inhibitor of this pathway, showing both preventive and therapeutic effects in rodent models. This research opens a new therapeutic angle for a deadly disease with limited treatment options.
Detailed Summary
Pulmonary hypertension (PH) is a progressive and often fatal disease in which the blood vessels of the lungs become thickened and narrowed, forcing the right side of the heart to work harder until it fails. Despite existing therapies, outcomes remain poor and the underlying molecular drivers are incompletely understood. This study from Shandong University identifies a new culprit and a druggable pathway that could change that.
Using proteomic analysis of human pulmonary artery endothelial cells exposed to hypoxia — a key trigger of PH — researchers identified serine hydroxymethyltransferase 2 (SHMT2) as significantly upregulated. Normally a mitochondrial enzyme involved in one-carbon metabolism, SHMT2 was found to be elevated in lung tissue from PH patients and across multiple rodent PH models.
The key mechanistic insight is that SHMT2 acts noncanonically here — not through its enzymatic metabolic function, but by interfering with protein degradation. Specifically, SHMT2 blocks K63-ubiquitin-mediated lysosomal breakdown of RhoB, a Rho GTPase protein. RhoB accumulation then disrupts endothelial barrier integrity, promoting the vascular remodeling central to PH pathology.
In vivo, endothelial-specific deletion of Shmt2 in mice substantially reduced pulmonary vascular remodeling and right ventricular dysfunction. Conversely, overexpression worsened disease. AAV9-mediated knockdown in rats replicated the protective effects. These converging lines of evidence establish the endothelial SHMT2–RhoB axis as causally important.
Critically, virtual drug screening identified Namodenoson — a compound with an existing safety profile — as a small-molecule inhibitor of this pathway. It showed both preventive and therapeutic efficacy in rodent PH models. While human trials are needed, this study offers a well-characterized target and a candidate drug, representing a meaningful step toward new PH therapies. The summary is based on the abstract only.
Key Findings
- SHMT2 is upregulated in pulmonary endothelium of PH patients and multiple rodent models.
- Endothelial-specific SHMT2 deletion markedly reduces vascular remodeling and right heart damage in mice.
- SHMT2 acts noncanonically by blocking lysosomal degradation of RhoB, not through its metabolic function.
- RhoB accumulation drives endothelial barrier dysfunction central to PH pathology.
- Namodenoson, identified via virtual screening, shows preventive and therapeutic effects against PH in rodents.
Methodology
The study combined proteomic analysis of hypoxia-treated human pulmonary artery endothelial cells, endothelial-specific conditional knockout and AAV9-mediated gene modulation in mice and rats, and in vitro mechanistic studies in HPAECs and HEK-293T cells. Virtual drug screening was used to identify Namodenoson, which was then validated in multiple rodent PH models including monocrotaline and Sugen5416/hypoxia-induced rats.
Study Limitations
The summary is based on the abstract only, limiting evaluation of full methodology, data quality, and statistical rigor. All therapeutic findings are from rodent models and require validation in human clinical trials. The noncanonical mechanism of SHMT2 and its interaction with RhoB ubiquitination need independent replication.
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