Amyloid and collagen templates in aortic valve calcification

Calcified areas in aortic valves often co-localize with amyloid fibrils that can promote calcification. Patient-derived amyloid fibrils contain arrays of acidic residues that can bind calcium and organize calcium phosphate nucleation clusters, while collagen fibrils guide crystal growth. This process is akin to functional biomineralization guided by Ca entrapment by acidic arrays in proteins, including amyloids. High shear stress and turbulent blood flow across the aortic valve, which are exacerbated in calcific aortic valve disease (CAVD), augment amyloid formation by plasma proteins. The main amyloid protein is probably apolipoprotein A-I (apoA-I), yet other proteins can also be involved. Lipoprotein(a) [Lp(a)], a genetic risk factor for CAVD, contributes to calcification. Enzymatic hydrolysis of oxidized phospholipids in Lp(a) helps generate orthophosphate, whereas apo(a) blocks collagen and amyloid fibril degradation by plasmin. Calcific aortic valve disease (CAVD) is a widely prevalent heart disorder in need of pharmacological interventions. Calcified areas in aortic valves often contain amyloid fibrils that promote calcification in vitro. This opinion paper suggests that amyloid contributes to CAVD development; amyloid-assisted nucleation can accelerate hydroxyapatite deposition onto collagen matrix. Notably, acidic arrays in amyloid match calcium–calcium spacing in the amorphous hydroxyapatite precursor, while oscillating hemodynamic perturbations promote amyloid deposition in the valve. Lipoprotein(a), a genetic risk factor for CAVD, augments calcification via several mechanisms, wherein hydrolysis of oxidized phospholipids (oxPLs) by Lp(a)-associated enzymes helps generate orthophosphate, and apolipoprotein(a) blocks plasmin-induced fibril degradation. Current studies of amyloid–calcium–collagen interactions in solution and in fibrillar complexes allow deeper insight into the role of amyloid in calcification. Calcific aortic valve disease (CAVD) is a widely prevalent heart disorder in need of pharmacological interventions. Calcified areas in aortic valves often contain amyloid fibrils that promote calcification in vitro. This opinion paper suggests that amyloid contributes to CAVD development; amyloid-assisted nucleation can accelerate hydroxyapatite deposition onto collagen matrix. Notably, acidic arrays in amyloid match calcium–calcium spacing in the amorphous hydroxyapatite precursor, while oscillating hemodynamic perturbations promote amyloid deposition in the valve. Lipoprotein(a), a genetic risk factor for CAVD, augments calcification via several mechanisms, wherein hydrolysis of oxidized phospholipids (oxPLs) by Lp(a)-associated enzymes helps generate orthophosphate, and apolipoprotein(a) blocks plasmin-induced fibril degradation. Current studies of amyloid–calcium–collagen interactions in solution and in fibrillar complexes allow deeper insight into the role of amyloid in calcification. a 40- to 42-residue peptide that forms extracellular amyloid fibrils in Alzheimer's disease brain. the precursor of crystalline hydroxyapatite in the bone and bone-like materials. a major structural and functional protein in a lipoprotein. a major Lp(a) protein of variable length. The length of the protein is genetically predetermined and relates inversely to the number of circulating Lp(a) particles and the risk of CAVD. a multistep protein-guided process generating composite organic–inorganic materials. a method of choice for detailed structural analysis of large macromolecular assemblies. Cryo-EM 'resolution revolution' (Nobel prize in 2017) revolutionized structural biology and enabled structural determination of many patient-derived amyloid fibrils. an age-related process which generates organic–inorganic materials that are deposited in various body parts and can contribute to disease pathology. Examples include bone-like calcific deposits in coronary artery disease, CAVD, Alzheimer's disease, and certain cancers. a network of proteins (e.g., collagens, non-collagenous proteins, and enzymes), polysaccharides (glycosaminoglycans), and minerals (hydroxyapatite) providing structural and biochemical support to surrounding cells. a tightly controlled process that generates organic–inorganic materials with specific mechanical and functional properties, such as the bone and dental enamel in animals and humans, or shell, eggshell, and nacre in animals. a particle (8–12 nm) with apoA-I as the major structural and functional protein. crystalline calcium phosphate with formula Ca10(PO4)6(OH)2, which is the major mineral in the bone, dental enamel, and bone-like calcified deposits in cardiovascular and other diseases. an enzyme that preferentially hydrolyses oxidized phospholipids in lipoproteins. The lyso-phospholipids generated in this process are rapidly hydrolyzed by autotaxin on Lp(a). This generates lyso-phosphatidic acid, a precursor of inorganic phosphate. a proinflammatory and pro-calcific LDL-like particle that contains apo(a) covalently linked to apoB as its major proteins. Lp(a) is the major lipoprotein carrier of oxidized phospholipids; it also carries Lp-PLA2 and autotaxin, which hydrolyze oxidized phospholipids to generate substrates for alkaline phosphatase. Inorganic phosphate, which is ultimately produced in this process, contributes to calcification. protein–lipid nanoparticles that transport lipids in the circulation and direct lipid metabolism in plasma, lymph, and cerebrospinal fluid. a particle (~22 nm) that carries a copy of apoB as its major protein. LDL is the major carrier of plasma cholesterol. preferred substrates for phospholipases and important contributors to cardiovascular disease, including CAVD. Lp(a) is the major lipoprotein carrier of oxPL in blood. a nanometer-sized cluster with the formula Ca9(PO4)6 that comprises ACP. Prenucleation clusters, Ca2(HPO4)32–, take up Ca2+ and coalesce into nucleation (Posner's) clusters that aggregate to form ACP. In these ACP clusters, the closest Ca–Ca spacing is 4.7 Å. a particle (40–100 nm) containing apoB and other apolipoproteins. VLDL is the major carrier of fat in blood and the metabolic precursor of LDL.