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- Title
Pentosan polysulfate, an aggrecanase inhibitor modulates arterial stiffness in spontaneously hypertensive rats.
- Authors
Klosinska, Miss Aleksandra; Siew, Keith; Tao Luo; Figg, Nichola; Cleary, Sarah; Sharif, Isam; Williams, Colin; Wilkinson, Ian; Sutcliffe, Michael; O'Shaughnessy, Kevin; Yasmin, Y.
- Abstract
Background: Arterial stiffness is an independent predictor of all-cause and cardiovascular mortality in many populations. Our recent research showed that loss of aggrecan integrity associates with age-related arterial stiffening (ARAS) in humans1, and others have shown that inhibition of ADAMTS/aggrecanase enzymes, which degrade aggrecan, improves cardiac function 2. Currently, there are no drugs that specifically target arterial stiffening in humans. We hypothesise that ADAMTS inhibitor, Pentosan Polysulfate (PPS), represents an attractive molecule that can be repurposed as a first-in-class drug treatment for ARAS. Methods: We performed an in vivo pharmacological experiment using 15wk-old spontaneous hypertensive male rats (SHR) that were administered either PPS or vehicle control (n = 7 per group) subcutaneously 3 times per week for 4 weeks. Animals were sacrificed and fully intact aortae including blood, cartilage, etc. were harvested and stored at - 800 °C. Arterial wall thickness, stress-strain and failures stress were measured, and tensile elasticity calculated ex vivo. Results: Preliminary analysis showed that PPS significantly reduced aortic wall thickening normally associated with arterial stiffening in hypertension (Vehicle 225 ± 6 μm vs 204 ± 6 μm, p = 0.0143). PPS also decreased aortic stiffening significantly at supraphysiological pressures in treated rats, and treated rats had a higher failure stress relative to vehicle controls. Conclusions: This proof-of-principle study demonstrated that an aggrecanase inhibitor can modulate aortic stiffness markers in SHR, but the short treatment period may not be adequate to reveal clinically significant differences. Further longitudinal studies are therefore, needed to establish if longer exposure to PPS can reduce aortic stiffness at clinically significant levels in older animals.
- Subjects
PENTOSANS; ARTERIAL diseases; CARTILAGE
- Publication
Artery Research, 2023, Vol 29, Issue 1, pS2
- ISSN
1872-9312
- Publication type
Article
- DOI
10.1007/s44200-022-00028-8