Vitamin K-Dependent Inhibition Mechanisms in Human Aortic Valve Calcification

Abstract

Introduction: Stenosis of the aortic valve is a leading cause of severe cardiovascular lesions. Progressive calcification, rheumatic modifications and also congenital events are the main etiopathogenetic factors. Extended fibrotic changes and aberrant ectopic calcification of the specific aortic valve interstitial cells are the most recognizable histopathological features. In fact, the previously referred cells are transformed from their initial myofibroblast phenotype to an osteoblast-like cell formation mediated by an inflammatory process. Concerning the potentially effective anti-calcification, inhibition strategies, some molecules are under investigation. Among them, vitamins seem to be involved in this process by preventing aortic wall extensive calcification. Objective: The purpose of the current review was to explore the involvement of Vitamin K complex in the inhibition mechanisms of the human aortic valve calcification process. Material and method: A systematic retrospective review of the literature was carried out based on PubMed international medical database. The following keywords were used: vitamin, calcification, cardiovascular, stenosis, aorta. Results: A broad spectrum of seventy (n=70) significant articles - focused on the vitamin K complex structural and functional aspects and its implication in anti-calcification mechanisms - were selected for the current review study. The majority of medical data referred to after 2015 published articles, whereas specific references of great importance and value were also included. Conclusions: Specific vitamin K members play a crucial role by regulating the activity of proteins such as osteocalcin that induces endothelial calcification. Interestingly, vitamin K also modifies the function of the matrix-Gla proteins that are implicated in this process. In fact, vitamin K-related molecular and biochemical mechanisms in the human aortic valve calcification inhibition are crucial and represent an interesting field for research.

FIGURE 1.

Stereo-chemical structure of Vit K isoforms: K1 (phylloquinone), K2 (menaquinone) and K3 (menadione). 2-methyl-1,4-naphthoquinones central ring is the core Vit K1 represents a phylloquinone characterized by a group of four isoprenoid residues. One of them only is unsaturated. In contrast, Vit K2 is chemically a menaquinone with differences in the corresponding unsaturated isoprenoid residues. Vit K3 is a menadione, a synthetic Vit K variant, which interacts with glutathione. Two enzymes are implicated in the intracellular procedure (electron reduction and oxidization) that transforms Vit K to its active form (Vit K hydroquinone): Vitamin K epoxide reductase (VKER) and gamma-glutamyl carboxylase (Vit K-dependent carboxylase) . In fact, these two enzymes regulate the Vit K biochemical cycle that includes the carboxylation and epoxidation chemical reactions.