Aortic Valve Stenosis and Mitochondrial Dysfunctions: Clinical and Molecular Perspectives

Abstract

Calcific aortic stenosis is a disorder that impacts the physiology of heart valves. Fibrocalcific events progress in conjunction with thickening of the valve leaflets. Over the years, these events promote stenosis and obstruction of blood flow. Known and common risk factors are congenital defects, aging and metabolic syndromes linked to high plasma levels of lipoproteins. Inflammation and oxidative stress are the main molecular mediators of the evolution of aortic stenosis in patients and these mediators regulate both the degradation and remodeling processes. Mitochondrial dysfunction and dysregulation of autophagy also contribute to the disease. A better understanding of these cellular impairments might help to develop new ways to treat patients since, at the moment, there is no effective medical treatment to diminish neither the advancement of valve stenosis nor the left ventricular function impairments, and the current approaches are surgical treatment or transcatheter aortic valve replacement with prosthesis.

Keywords: Aortic stenosis; autophagy; cardiovascular disease; inflammation; mitochondria.

Figure 1

Aortic valve structure. Aortic valve is divided into three different layers: the fibrosa which faces the aorta, the spongiosa in the center and the ventricularis which faces left ventricular outflow tract. Valvular interstitial cells are the prevalent cell type and present in all layers. In addition, the tissue is characterized by a small percentage of smooth muscle cells and by valvular endothelial cells. All these cells are surrounded by extracellular matrix, including collagen, proteoglycan and elastin.

Figure 2

Aortic stenosis pathobiology: a molecular perspective. Mechanical and shear stress induces endothelial damage that leads to lipid accumulation and increased inflammation in valve tissue. These physiological impairments lead to fibrotic processes and to a step-by-step differentiation of valve interstitial cells to myofibroblasts and finally osteoblasts. The final stage of the disease is the calcification of the tissue. Abbreviations: LDL, low-density lipoprotein; oxLDL, oxidized low-density lipoprotein; mtUPR, mitochondrial unfolded protein response; ACE, angiotensin-converting enzyme; ECM, extracellular matrix; MMPs, matrix metalloproteinases; MVs, microvesicles; TNF-α, tumor necrosis factor α; BSP, bone sialoprotein; BMP-2, bone morphogenetic protein-2; LRP5, LDL receptor-related protein 5; SOX9, SRY-box 9; RUNX2, runt-related transcription factor 2; ALP, alkaline phosphatase; RANKL, receptor activator of NF-kappa B ligand; RANK, receptor activator of nuclear factor κ; OPG, osteoprotegerin; NO, nitric oxide; VEGF, vascular endothelial growth factor; TGF-β, transforming growth factor beta; ROS, reactive oxygen species; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule-1; CACNA1C, calcium voltage-gated channel subunit alpha 1 C.

Figure 3

Autophagy involvement in aortic stenosis. Immunohistochemical alizarin red staining was used to identify calcium deposits in the human aortic valve interstitial cells. The autophagic process has been associated with the calcification of aortic leaflets by several independent works, but no definitive results have been achieved. Abbreviations: AV, aortic valve; BMP-2, bone morphogenetic protein-2; ALP, alkaline phosphatase; 3-MA, 3-methyladenine; Atg7, autophagy-related 7; CAVS, calcific aortic valves; LC3-II, microtubule-associated protein 1A/1B light chain 3; ULK1, unc-51-like kinase; Pi, inorganic phosphate.