How to Unharden the Heart
Understanding how blood vessels calcify could help prevent cardiovascular disease
William Aryitey |
Major cardiovascular diseases are often accompanied by calcification of arteries and valves. A recent study has revealed a key regulator in the vascular calcification process – the protein sortilin – and the new findings may aid in discovering suitable therapies for vascular calcification (1).
“There are no available therapeutic options to prevent or treat calcification in blood vessels and heart valves, so the motivation of our research was to discover therapeutic strategies,” says Elena Aikawa, principle investigator, and Director of the Vascular Biology Program at the Center of Interdisciplinary Cardiovascular Sciences at Brigham and Women's Hospital. “We used novel mass spectrometry techniques to study sortilin modifications and identified a phosphorylation site that is essential for the calcification process,” says first author Claudia Goettsch, a scientist at Brigham and Women’s Hospital. Sortilin regulates the loading of a key calcification enzyme into extracellular vesicles.
Goettsch continues, “Inhibiting the sortilin pathway could serve as a treatment strategy to prevent vascular calcification in atherosclerotic vessels, and the identified sortilin phosphorylation could serve as a potential target.”
Given its role in depositing calcium, there was concern that inhibiting sortilin might have an impact on bone formation. But the team were able to show that sortilin inhibition didn’t affect the bone phenotype in mouse models used for testing, nor did it change the cellular function of human osteoblasts or osteoclasts.
“Currently, we’re perusing the drug discovery path. We are developing assay systems to perform high-throughput screening to identify sortilin pathway inhibitors,” says Aikawa.
Goettsch adds, “We are assessing the clinical translation of our experimental findings. We also aim to determine if sortilin can be used as a surrogate marker for cardiovascular calcification by analyzing blood levels in different clinical cohorts and assessing the correlation to cardiovascular calcification.”
- C Goettsch et al., “Sortilin mediates vascular calcification via its recruitment into extracellular vesicles”, J Clin Invest, (2016). PMID: 26950419.