Oligogalacturonic Acid Inhibits Vascular Calcification by Two Mechanisms

Abstract

Objective— Cardiovascular diseases constitute the leading cause of mortality worldwide. Calcification of the vessel wall is associated with cardiovascular morbidity and mortality in patients having many diseases, including diabetes mellitus, atherosclerosis, and chronic kidney disease. Vascular calcification is actively regulated by inductive and inhibitory mechanisms (including vascular smooth muscle cell adaptation) and results from an active osteogenic process. During the calcification process, extracellular vesicles (also known as matrix vesicles) released by vascular smooth muscle cells interact with type I collagen and then act as nucleating foci for calcium crystallization. Our primary objective was to identify new, natural molecules that inhibit the vascular calcification process. Approach and Results— We have found that oligogalacturonic acids (obtained by the acid hydrolysis of polygalacturonic acid) reduce in vitro inorganic phosphate–induced calcification of vascular smooth muscle cells by 80% and inorganic phosphate–induced calcification of isolated rat aortic rings by 50%. A specific oligogalacturonic acid with a degree of polymerization of 8 (DP8) was found to inhibit the expression of osteogenic markers and, thus, prevent the conversion of vascular smooth muscle cells into osteoblast-like cells. We also evidenced in biochemical and immunofluorescence assays a direct interaction between matrix vesicles and type I collagen via the GFOGER sequence (where single letter amino acid nomenclature is used, O=hydroxyproline) thought to be involved in interactions with several pairs of integrins. Conclusions— DP8 inhibits vascular calcification development mainly by inhibition of osteogenic marker expression but also partly by masking the GFOGER sequence—thereby, preventing matrix vesicles from binding to type I collagen.

Flavonoid‐Rich Apple Improves Endothelial Function in Individuals at Risk for Cardiovascular Disease: A Randomized Controlled Clinical Trial

“…Although we have focused on the flavonoids found in apple skin, it is possible that other bioactive phytochemicals and nutrients found in apple skin may contribute to observed effects. Apple skin contains damascone‐related norisoprenoid aroma compounds, which have been shown to induce Nrf2 and hence may possibly mediate the induction of Hmox‐1, soluble fibers such as oligogalacturonic acid, and minerals such as potassium and magnesium. A limitation of the present study is that it was not feasible for participants to be blinded to the treatment they were receiving.…”

Roles and Regulation of Extracellular Vesicles in Cardiovascular Mineral Metabolism

“…In both 3D hydrogels and human plaques, there is an inverse relationship between collagen content and microcalcification size: as collagen degrades, EVs can accumulate, aggregate, nucleate hydroxyapatite, and form microcalcifications (19). Recent work from Hodroge and colleagues has identified specific regions on collagen fibers to which EVs bind: isoforms of 8-degree-polymerized oligogalacturonic acid mask the GFOGER sequence, inhibit vesicle-collagen binding, and impair the development of calcification (68).…”

Protection Effect of Exogenous Fibroblast Growth Factor 21 on the Kidney Injury in Vascular Calcification Rats

“…[ 7 ] With the characteristic of calcium and phosphorus depositing in vessel walls, VC is motivated by a phenotypic modulation from vascular cell to osteoblast-like cell, which can be observed in many diseases including diabetes, atherosclerosis, and CKD. [ 8 ] In patients with CKD, clinical studies have found the morbidity of VC is much higher than healthy people, which results from the disorder of calcium and phosphorus metabolism caused by renal function impairment. [ 9 10 11 ] Meanwhile, hypertension and intraglomerular high pressure due to VC, together with micro-VC in kidney, may accelerate the progress of CKD.…”