Age-related arterial stiffening (ARAS): Biomarkers for disease stratification and identifying the molecular drivers of stiffening

Arterial stiffness predicts CV risk, and age is the key determinant of arterial stiffening.

This proposal builds on our work identifying novel proteins that change with age and affect stiffness, but whose mechanistic role in ARAS remains poorly defined. We hypothesized that degradation of aggrecan and other proteins increased stiffness due to loss of viscoelasticity.

In pilot experiments, we showed that: i) aggrecan core protein is cleaved by aggrecanases releasing fragments (NITEs and ARGs) which are present in the vessel wall and serum, associate with stiffer arteries and age, and could be used as biomarkers; ii) aggrecanses can modify biomechanical properties of the aorta, and an aggrecanse inhibitor can modulate arterial stiffness, and iii) using ‘mass spectrometry immunohistochemistry’, we labelled rapidly and cost effectively many proteins simultaneously in the same tissue sample.

We will develop this pilot work, focusing on aggrecan, its degradative enzymes and fibulins as drivers of the ARAS process using our unique collection of donor aortic tissues and ENIGMA and ACCT study serum samples.

This work will allow us to better characterise the molecules and pathways operating in ARAS (and pathways that may be druggable).