Abstract
Elastin plays an important role in maintaining blood vessel integrity. Proteolytic degradation of elastin in the vascular system promotes the development of atherosclerosis, including blood vessel calcification. Cysteine cathepsins have been implicated in this process, however, their role in disease progression and associated complications remains unclear. Here, we showed that the degradation of vascular elastin by cathepsins (Cat) K, S, and V directly stimulates the mineralization of elastin and that mineralized insoluble elastin fibers were ~25–30% more resistant to CatK, S, and V degradation when compared to native elastin. Energy dispersive X-ray spectroscopy investigations showed that insoluble elastin predigested by CatK, S, or V displayed an elemental percentage in calcium and phosphate up to 8-fold higher when compared to non-digested elastin. Cathepsin-generated elastin peptides increased the calcification of MOVAS-1 cells acting through the ERK1/2 pathway by 34–36%. We made similar observations when cathepsin-generated elastin peptides were added to ex vivo mouse aorta rings. Altogether, our data suggest that CatK-, S-, and V-mediated elastolysis directly accelerates the mineralization of the vascular matrix by the generation of nucleation points in the elastin matrix and indirectly by elastin-derived peptides stimulating the calcification by vascular smooth muscle cells. Both processes inversely protect against further extracellular matrix degradation.
Highlights
Vascular calcification is recognized as an important risk factor that significantly increases the mortality rate by a factor of 3 to 4 in atherosclerosis and up to 60-fold when associated with chronic kidney diseases (CKD) or type II diabetes mellitus[1]
Previous work showed that vascular smooth muscle cells (VSMCs), macrophages, and multinucleated cells participate in atheroma plaque formation and progression and are involved in the regulation of vascular mineralization[6,7]
Mineralized elastin revealed less degradation (~25–30%) after being subjected to CatK, S, and V when compared to non-calcified elastin (p < 0.025) based on the respective remaining weights of the digested and undigested samples (Fig. 1c)
Summary
Vascular calcification is recognized as an important risk factor that significantly increases the mortality rate by a factor of 3 to 4 in atherosclerosis and up to 60-fold when associated with chronic kidney diseases (CKD) or type II diabetes mellitus[1]. Previous work showed that vascular smooth muscle cells (VSMCs), macrophages, and multinucleated cells participate in atheroma plaque formation and progression and are involved in the regulation of vascular mineralization[6,7] These plaque-forming cells contribute to the progression of the pathology through the secretion of elastolytic proteases, including matrix metalloproteinases (MMP-2, -9 and -12) and cysteine cathepsins (CatK, S, and V)[8,9,10]. CatK, S, and V are among the most potent mammalian elastases and previous work has demonstrated that they represent about 60% of the total elastase activity in plaque-associated VSMCs and macrophages[12] These cathepsins contribute to the progression of atherosclerosis and to the outcome of several associated complications, such as medial calcification, valvular calcific aortic stenosis, and plaque rupture[10,13,14,15]. Soluble elastin peptides released after digestion of elastin by CatK, S, and V have a stimulatory effect on the calcification of VSMCs
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