Loss of natriuretic peptide receptor C (NPR-C) in vascular smooth muscle cells, combined with high salt intake, triggered thoracic aortic dissection in mice — and a peptide agonist helped prevent it.
Peptide agonist prevented aortic dissectionC-ANP4-23, an NPR-C agonist, mitigated thoracic aortic dissection progression in mouse disease models
What the researchers found
NPR-C was downregulated in aortas of acute thoracic aortic dissection (TAD) patients and in mouse models. Smooth muscle cell-specific NPR-C knockout mice developed TAD when treated with angiotensin II plus high salt diet, but not angiotensin II alone — revealing high salt as a critical trigger.
Mechanistically, NPR-C loss activated the ERK1/2 pathway, which decreased PPARγ activity and suppressed HADHB expression, impairing mitochondrial fatty acid oxidation. The NPR-C agonist peptide C-ANP4-23 mitigated TAD progression in disease model mice, and spermidine (which activates the mitochondrial trifunctional protein) also effectively prevented TAD formation.
Why it matters
Aortic dissection kills up to 50% of patients and currently has no effective pharmacological prevention or treatment. This study identifies NPR-C as a protective factor and demonstrates that a peptide agonist can prevent disease progression. It also reveals that high salt intake is a critical environmental trigger — a modifiable risk factor that could inform dietary recommendations for at-risk individuals.
How the study worked
Researchers analyzed human TAD transcriptome and single-cell sequencing datasets to identify NPR-C downregulation. They generated vascular smooth muscle cell-specific and endothelial cell-specific NPR-C knockout mice, treating them with angiotensin II with or without high salt diet. RNA-sequencing identified affected pathways. Mechanistic studies examined the ERK1/2-PPARγ-HADHB signaling axis. Therapeutic potential was tested using the NPR-C agonist peptide C-ANP4-23 and spermidine in mouse models.
What this study cannot tell us
This is a preclinical study using genetically modified mice, which may not fully replicate human aortic dissection. The BAPN-induced and angiotensin II-induced mouse models are widely used but do not capture all aspects of human disease. The therapeutic effects of C-ANP4-23 and spermidine were demonstrated only in mice. The study did not address long-term safety or optimal dosing of NPR-C agonists. Human genetic studies linking NPR-C variants to aortic dissection risk would strengthen the translational relevance.
How to read the evidence
Published in Cardiovascular Research, a leading cardiovascular journal, this is a rigorous preclinical study combining human transcriptomic data with multiple mouse genetic models and mechanistic pathway analysis. However, all therapeutic data is from animal models, placing this at the preclinical evidence stage.
When this study was published
Published in 2025, this is a very recent study that identifies a novel therapeutic target and mechanism for a condition that currently lacks pharmacological treatment.
The bigger picture
Natriuretic peptides are well-known cardiovascular hormones, but the specific role of their clearance receptor (NPR-C) in aortic health was previously unclear. This study redefines NPR-C as an active protective signaling receptor rather than just a peptide clearance mechanism. The finding that high salt intake interacts with genetic vulnerability to trigger aortic dissection has implications for both personalized medicine and public health dietary guidelines.
Questions still open
- Could NPR-C genetic variants in humans identify individuals at higher risk for aortic dissection, especially those with high salt diets?
- Is the C-ANP4-23 peptide agonist suitable for development as a clinical therapeutic, or would modified versions be needed?
- How much does salt intake contribute to aortic dissection risk in the general population beyond this genetic mouse model?
Common questions
What is thoracic aortic dissection and why is it so dangerous?
Does eating too much salt increase the risk of aortic dissection?
Read the original research
Deficiency of NPR-C triggers high salt-induced thoracic aortic dissection by impairing mitochondrial homeostasis.
Cardiovascular research, 121(7), 1121-1134
Citation
Wei, Jin-Qiu; Yang, Yi; Zhai, Wen-Hui; Zhao, Jia-Jia; Yang, Yi-Hang; Kang, Yuan-Yuan; Huang, Qi-Fang; Zhang, Wei; Rong, Wu-Wei; Deng, Qian-Wan; Chen, Jing; Ye, Xiao-Fei; Gao, Ping-Jin; Wang, Zhe; Li, Xiao-Dong; Wang, Ji-Guang. (2025). Deficiency of NPR-C triggers high salt-induced thoracic aortic dissection by impairing mitochondrial homeostasis.. Cardiovascular research, 121(7), 1121-1134. https://doi.org/10.1093/cvr/cvaf085