Self-eating and Heart: The Emerging Roles of Autophagy in Calcific Aortic Valve Disease

Abstract

Autophagy is a self-degradative pathway by which subcellular elements are broken down intracellularly to maintain cellular homeostasis. Cardiac autophagy commonly decreases with aging and is accompanied by the accumulation of misfolded proteins and dysfunctional organelles, which are undesirable to the cell. Reduction of autophagy over time leads to aging-related cardiac dysfunction and is inversely related to longevity. However, despite the increasing interest in autophagy in cardiac diseases and aging, the process remains an undervalued and disregarded object in calcific valvular disease. Neither the nature through which autophagy is triggered nor the interplay between autophagic machinery and targeted molecules during aortic valve calcification are fully understood. Recently, the upregulation of autophagy has been shown to result in cardioprotective effects against cell death as well as its origin. Here, we review the evidence that shows how autophagy can be both beneficial and detrimental as it pertains to aortic valve calcification in the heart.

Keywords: autophagy; calcific aortic valve disease; calcification; cell death; heart aging.

Figure 1.

Overview of major components and modulating sites in mammalian autophagy. Autophagy can be activated by AMPK, which directly stimulate the ULK complex or indirectly stimulate through mTORC1 inhibition. Various autophagic molecules participate in subsequent formation, elongation, fusion, and ultimately, degradation. In addition, pharmacological and nutritional interventions are accessible to induce/inhibit autophagy activities through multistage validation mechanism. Abbreviations: 3-MA:, 3-methyladenine; AMPK, AMP-activated protein kinase; FIP200, focal adhesion kinase family interacting protein of 200 kDa; Mdivi-1, mitochondrial division inhibitor; mTORC1, mechanistic target of rapamycin complex 1; PE, phosphatidylethanolamine; PI3K-III, class III phosphatidylinositol-3-kinase; ULK1, UNC51- like autophagy activating kinase 1.

Figure 2.

Schematic presentation of calcified aortic valve progression. The structure of the aortic valve leaflet consists of three-layer extracellular matrix (ECM): the fibrosa, the spongiosa, and the ventricularis; with valvular interstitial cells (VIC) scattering in all three layers and a monolayer of valve endothelial cells (VEC) overlaying in both sides. Blood flow (haemodynamics) in ventricular side is steady-going and laminar, whereas is oscillatory and mussy in fibrosa side, from which the lesion is vulnerable to initiate. Endothelial damage can be triggered by several factors including hemodynamic stress, reactive oxygen species, and inflammatory cytokine, followed by lipid accumulation, inflammation infiltration, cell phenotype transformation, and extracellular matrix remodeling. Finally, fibrotic remodeling and valve mineralisation lead to leaflet thickness and valve dysfunction. Abbreviations: BMP-2, bone morphogenetic protein-2; EndMT, endothelial-to-mesenchymal transition; LDL, low-density lipoprotein; OxLDL, oxidized LDL; TGF-β, transforming growth factor- β; VIC, valve interstitial cell.

Figure 3.

Protective versus detrimental role of autophagy in CAVD. Upon stimuli, cell undergoes different events depending on the grades of the impairment and the sensitivity of the cell: Basal autophagy defends cell against toxic molecules which result from harmful stimuli insult via the lysosomal-degrading pathway, thus cell grows and remains homeostasis (A). Stimulating autophagy in relatively mild perturbation setting is expected to hasten the removal of damaged components and favors phenotype maintenance and survival (B). In response to very harsh environmental condition, autophagy is not sufficient for the removal of cellular damage, followed by phenotype alteration and senescence (C). Under a long-term chronic state of stimuli, severe oxidative stress combined with excessive autophagic flux may also lead to DNA damage and promote cell death (D).