Role of Ectonucleotidases and Purinergic Receptors in Calcific Aortic Valve Disease

Abstract

Calcific aortic valve disease (CAVD) is the most common heart valve disorders [1]. Despite intensive research effort in the last decade or so no medical therapy has emerged to treat patients with CAVD [2]. Studies have underlined that CAVD is characterized by lipid infiltration, inflammation, calcification and extensive tissue remodelling, which leads over the years to a clinically significant stenosis [3]. It should be stressed that mineralization and fibrosis are two major contributors to the development and progression of CAVD. Ectopic valve mineralization involves two mechanisms. First, it is well documented by using in vitro system of cell culture that valve interstitial cells (VICs), the main cellular component of the aortic valve, undergo an osteoblastic transition when exposed to a calcifying medium containing phosphate [4]. During this phenotypic switch VICs express several genes, which are involved in osteoblast development such as Runx2, osteopontin, osteocalcin and bone morphogenetic proteins (BMPs) [5]. It is of interest to note that these osteogenic markers are present in specimen of CAVD retrieved from patients undergoing aortic valve replacements procedures [6]. Second, there is evidence that production of phosphate (Pi), which is of prime importance in controlling mineralization of VICs, promotes apoptosis-mediated mineralization [7]. To this effect, in vitro inhibition of apoptosis prevents phosphate-induced mineralization of VICs [8]. Also, in stenotic aortic valves a high level of apoptotic cells is present in the vicinity of calcific nodules. It should be pointed out that osteoblastic transition and apoptosis-mediated mineralization are not mutually exclusive and probably occur simultaneously in different proportions to promote the calcification of the aortic valve. In this regard, studies have highlighted that the stiffness of the substrate on which VICs are grown may determine whether cells will undergo either osteoblastic transition or apoptosis. On this score, a stiffer support largely drives apoptosis of VICs whereas a more compliant matrix will promote mineralization through the expression of bone-related factors [9]. Hence, it could be speculated that during the initial stages of aortic valve mineralization, when the tissues are still relatively compliant, that osteogenic transformation of VICs is dominant, whereas when the process is more advanced apoptosis-mediated mineralization would possibly be major contributor to ectopic valve mineralization.

Disclosures

P. Mathieu has patent applications for the use of ectonucleotidase inhibitors and purinergic agonists in the treatment of CAVD.