Molecular biology of calcific aortic valve disease: towards new pharmacological therapies

Abstract

Calcific aortic valve disease (CAVD) is a chronic process leading to fibrosis and mineralization of the aortic valve. Investigations in the last several years have emphasized that key underlying molecular processes are involved in the pathogenesis of CAVD. In this regard, the processing of lipids and their retention has been underlined as an important mechanism that triggers inflammation. In turn, inflammation promotes/enhances the mineralization of valve interstitial cells, the main cellular component of the aortic valve. On the other hand, transformation of valve interstitial cells into myofibroblasts and osteoblast-like cells is determined by several signaling pathways having reciprocal cross-talks. In addition, the mineralization of the aortic valve has been shown to rely on ectonucleotidase and purinergic signaling. In this review, the authors have highlighted key molecular underpinnings of CAVD that may have significant relevance for the development of novel pharmaceutical therapies.

Keywords::

• aortic stenosis
• bone morphogenetic protein
• calcific aortic stenosis
• calcific aortic valve disease
• calcification
• ectonucleotidase
• lipid
• Lp-PLA2
• notch
• ox-LDL
• TGF-β
• Wnt

Financial & competing interests disclosure

The authors are supported by HSFC grant, CIHR grants MOP245048, MOP114893 and the Quebec Heart and Lung Institute Fund. P Mathieu is a research scholar from the Fonds de Recherche en Santé du Québec, Montreal, Québec, Canada and holds a patent application for the use of ectonucleotidases and Lp-PLA2 inhibitors in the treatment of CAVD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Calcific aortic valve disease (CAVD) is the most common heart valve disorder with a high prevalence in our aging societies.

• The development of novel pharmaceutical therapies for CAVD would represent a major breakthrough.

• The retention and modification of different lipid species during CAVD play an important role in promoting inflammation/mineralization of the aortic valve.

• Inflammation and the production of cytokines play a role in enhancing mineralization of the aortic valve.

• The renin angiotensin system promotes the remodeling of the aortic valve.

• TGF-β and serotonergic system have interrelationships in promoting activation of valve interstitial cells and in triggering a profibrotic response in CAVD.

• Osteogenic transdifferentiation of valve interstitial cells and the modulation of ectonucleotidases/purinergic receptors are important mechanisms involved in the mineralization of the aortic valve.

Notes