MMP-2 knockdown blunts age-dependent carotid stiffness by decreasing elastin degradation and augmenting eNOS activation

Diaz-Canestro, C. et al. (2022) MMP-2 knockdown blunts age-dependent carotid stiffness by decreasing elastin degradation and augmenting eNOS activation. Cardiovascular Research, 118(10), pp. 2385-2396. (doi: 10.1093/cvr/cvab300) (PMID:34586381)

Abstract

Aims: Arterial stiffness is a hallmark of vascular ageing that precedes and strongly predicts the development of cardiovascular diseases. Age-dependent stiffening of large elastic arteries is primarily attributed to increased levels of matrix metalloproteinase-2 (MMP-2). However, the mechanistic link between age-dependent arterial stiffness and MMP-2 remains unclear. Thus, we aimed to investigate the efficacy of MMP-2 knockdown using small-interfering RNA (siRNA) on age-dependent arterial stiffness. Methods and results: Pulse wave velocity (PWV) was assessed in right carotid artery of wild-type (WT) mice from different age groups. MMP-2 levels in the carotid artery and plasma of young (3 months) and old (20–25 months) WT mice were determined. Carotid PWV as well as vascular and circulating MMP-2 were elevated with increasing age in mice. Old WT mice (18- to 21-month old) were treated for 4 weeks with either MMP-2 or scrambled (Scr) siRNA via tail vein injection. Carotid PWV was assessed at baseline, 2 and 4 weeks after start of the treatment. MMP-2 knockdown reduced vascular MMP-2 levels and attenuated age-dependent carotid stiffness. siMMP-2-treated mice showed increased elastin-to-collagen ratio, lower plasma desmosine (DES), enhanced phosphorylation of endothelial nitric oxide synthase (eNOS), and higher levels of vascular cyclic guanosine monophosphate (cGMP). An age-dependent increase in direct protein–protein interaction between MMP-2 and eNOS was also observed. Lastly, DES, an elastin breakdown product, was measured in a patient cohort (n = 64, 23–86 years old), where carotid-femoral PWV was also assessed; here, plasma levels of DES directly correlated with age and arterial stiffness. Conclusion: MMP-2 knockdown attenuates age-dependent carotid stiffness by blunting elastin degradation and augmenting eNOS bioavailability. Given the increasing clinical use of siRNA technology, MMP2 knockdown should be investigated further as a possible strategy to mitigate age-dependent arterial stiffness and related CV diseases.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Guzik, Professor Tomasz
• Authors: Diaz-Canestro, C., Puspitasari, Y. M., Liberale, L., Guzik, T. J., Flammer, A. J., Bonetti, N. R., Wüst, P., Constantino, S., Paneni, F., Akhmedov, A., Varga, Z., Ministrini, S., Beer, J. H., Ruschitzka, F., Hermann, M., Lüscher, T. F., Sudano, I., and Camici, G. G.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Cardiovascular Research
• Publisher: Oxford University Press
• ISSN: 0008-6363
• ISSN (Online): 1755-3245
• Published Online: 29 September 2021