Upregulated Autophagy in Calcific Aortic Valve Stenosis Confers Protection of Valvular Interstitial Cells.

Miguel Carracedo,Oscar Persson,Ewa Ehrenborg,Peter Saliba-Gustafsson,Anders Franco-Cereceda,Magnus Bäck,Per Eriksson,Gonzalo Artiach

doi:10.3390/ijms20061486

Abstract

Autophagy serves as a cell survival mechanism which becomes dysregulated under pathological conditions and aging. Aortic valve thickening and calcification causing left ventricular outflow obstruction is known as calcific aortic valve stenosis (CAVS). CAVS is a chronic and progressive disease which increases in incidence and severity with age. Currently, no medical treatment exists for CAVS, and the role of autophagy in the disease remains largely unexplored. To further understand the role of autophagy in the progression of CAVS, we analyzed expression of key autophagy genes in healthy, thickened, and calcified valve tissue from 55 patients, and compared them with nine patients without significant CAVS, undergoing surgery for aortic regurgitation (AR). This revealed a upregulation in autophagy exclusively in the calcified tissue of CAVS patients. This difference in autophagy between CAVS and AR was explored by LC3 lipidation in valvular interstitial cells (VICs), revealing an upregulation in autophagic flux in CAVS patients. Inhibition of autophagy by bafilomycin-A1 led to a decrease in VIC survival. Finally, treatment of VICs with high phosphate led to an increase in autophagic activity. In conclusion, our data suggests that autophagy is upregulated in the calcified tissue of CAVS, serving as a compensatory and pro-survival mechanism.

Highlights

Thickening and calcification of the aortic valve is known as aortic valve sclerosis, eventually causing left ventricular outflow obstruction, and referred to as calcific aortic valve stenosis (CAVS) [1]
We included aortic valves derived from nine patients with aortic sclerosis, but without significant CAVS, undergoing surgery for aortic regurgitation (AR) for comparison
Gene expression analysis of the transcription factor EB (TFEB) revealed no significant differences in CAVS nor AR

Summary

Introduction

Thickening and calcification of the aortic valve is known as aortic valve sclerosis, eventually causing left ventricular outflow obstruction, and referred to as calcific aortic valve stenosis (CAVS) [1]. CAVS is characterized by inflammatory processes, extracellular matrix remodeling, and trans-differentiation of valvular interstitial cells (VICs), the most abundant cell type in the aortic valve [2]. CAVS incidence and severity increase with age [4,5] along with several cardiovascular risk factors, e.g., obesity [6], smoking [7], and renal dysfunction [8]. While valve replacement or percutaneous intervention can reverse this dismal prognosis, these interventions are not without risk in an elderly, fragile CAVS population. Understanding the underlying molecular mechanisms behind increased susceptibility as the disease progresses is of uttermost importance in order to develop a medical treatment to halt or reverse the calcification process of the aortic valve

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Conclusion