Asporin Reduces Adult Aortic Valve Interstitial Cell Mineralization Induced by Osteogenic Media and Wnt Signaling Manipulation In Vitro

Abstract

Worldwide, calcific aortic valve disease is one of the leading causes of morbidity and mortality among patients with cardiac abnormalities. Aortic valve mineralization and calcification are the key events of adult calcific aortic valve disease manifestation and functional insufficiency. Due to heavy mineralization and calcification, adult aortic valvular cusps show disorganized and dispersed stratification concomitant with deposition of calcific nodules with severely compromised adult valve function. Interestingly, shared gene regulatory pathways are identified between bone-forming cells and heart valve cells during development. Asporin, a small leucine-rich proteoglycan (43 kDa), acts to inhibit mineralization in periodontal ligament cells and is also detected in normal murine adult aortic valve leaflets with unknown function. Therefore, to understand the Asporin function in aortic cusp mineralization and calcification, adult avian aortic valvular interstitial cell culture system is established and osteogenesis has been induced in these cells successfully. Upon induction of osteogenesis, reduced expression of Asporin mRNA and increased expression of bone and osteogenesis markers are detected compared to cells maintained without osteogenic induction. Importantly, treatment with human recombinant Asporin protein reduces the mineralization level in osteogenic media-induced aortic valvular interstitial cells with the concomitant decreased level of Wnt/β-catenin signaling. Overall, all these data are highly indicative that Asporin might be a novel biomolecular target to treat patients of calcific aortic valve disease over current cusp replacement surgery.

Extracellular Matrix in Calcific Aortic Valve Disease: Architecture, Dynamic and Perspectives

“…The most important advantages of bioengineered valves consist of low propensity to mineralization and high hemodynamic performances. Bioengineered valves can be obtained from acellular non-valvular scaffolds or decellularized native valves, which can be repopulated with host cells [ 99 , 141 ]. In addition, scaffold matrices may also consist of artificial matrices synthesized from synthetic or natural polymers.…”

“…To date, more than 40 genes encoding different PGs have been identified, which have been organized in four major classes on the basis of cellular and subcellular localization [ 96 ]. Among them, only few PGs have been investigated for a role in CAVD pathogenesis and progression [ 97 , 98 , 99 , 100 , 101 , 102 ].…”

“…Conversely, in vitro studies showed that osteogenic differentiation and mineralization of VICs are characterized by a reduced expression of Asporin, also known as periodontal ligament-associated protein1 (PLAP1), suggesting an inhibitory role for this PG in the aortic valve [ 99 ]. In this case, mineralization associated to Asporin downregulation seems to involve the activation of Wnt/ β -catenin signaling.…”

Identification of Hub Diagnostic Biomarkers and Candidate Therapeutic Drugs in Heart Failure

“…ASPN is an extracellular matrix protein and a member of the leucine-rich small proteoglycan family. 40 Sasaki et al 41 showed that ASPN protected gastric tumor cells against oxidative stress by up-regulating HIF1α and reducing the levels of mitochondrial ROS. It also increased the expression of CD44 to accelerate the migration and infiltration of gastric cancer cells.…”

ASPN is a Potential Promising Biomarker for Common Heart Failure

“…Asporin (ASPN) is a member of the small leucine-rich proteoglycan family that is expressed in multiple tissues, including osteoarthritic articular cartilage, the aorta, the uterus, the heart, and the liver [40,41].…”