Trends in Molecular Medicine
ReviewAutophagy in cardiovascular disease
Section snippets
Autophagy: survival or death pathway?
Autophagy is an evolutionarily conserved process that results in the degradation of cytosolic components inside lysosomes 1, 2, 3, 4, 5. Under normal conditions, it is a nonstop, reparative, life-sustaining mechanism for recycling cellular components, such as long-lived proteins and damaged organelles. Therefore, autophagy is thought to be involved in many physiological processes, including cellular differentiation, tissue remodeling, growth control, cell defense and adaptation to an adverse
Detection of autophagy
The identification of autophagy-specific biomarkers is highly compromised owing to the paucity of biomarkers that are expressed differentially or modified post-translationally after the induction of autophagy 10, 11, 12. Therefore, the demonstration of autophagic vacuoles by conventional electron microscopy is the ‘golden standard’ for assessing autophagy currently, both in tissues and in cultured cells 10, 11. The demonstration of granular cytoplasmic-ubiquitin inclusions by
Autophagy in heart failure
One of the first reports describing autophagy in cardiac myocytes was published in the mid-1970s, approximately one decade after the initial description of autophagy in mammalian cells [26]. In this study, Sybers et al. [27] demonstrated that fetal mouse heart in organ culture continues to beat for a period of weeks but that degenerative changes occur. Electron microscopy revealed formation of autophagic vacuoles containing damaged organelles in some cells after the first day, indicating focal
Autophagy in atherosclerosis
Transmission electron microscopy of disintegrating smooth muscle cells (SMCs) in the fibrous cap of advanced plaques reveals certain features of ‘programmed’ cell death unrelated to apoptosis but typical of autophagy, such as the formation of myelin figures [32], the accumulation of ubiquitinated inclusions in the cytosol [33] and severe vacuolization [34] (Figure 2). Severe vacuolization has already been described in dying SMCs by Stehbens [35] as granulovesicular degeneration. More recently,
Role of autophagy in cardiovascular disease
In the heart, autophagy seems to have a special housekeeping role in the turnover of cytoplasmic constituents, as demonstrated by severe cardiac dysfunction in patients and mice showing defective autophagic degradation owing to a deficiency of lysosome-associated membrane protein-2 (LAMP-2) 42, 43, a disorder also known as Danon disease [44]. In line with these findings, cardiac-specific deficiency of Atg5, a protein required for autophagy (Box 2), leads to cardiac hypertrophy, left-ventricular
Therapeutic implications
Despite the discovery of many autophagy-specific genes and the dissection of signaling pathways involved in the regulation of autophagy (Box 2), therapeutic approaches to modulating autophagy in cardiovascular disease are highly limited (Table 1). Several possibilities can explain this discrepancy. First, the few autophagy inhibitors that are used in cell culture experiments currently, in particular, the phosphatidylinositol 3-kinase inhibitor 3-methyladenine, are unsuitable for in vivo
Concluding remarks
The rapid advancement in our understanding of the mechanisms and regulation of autophagy has placed this process at the center of current research in major human disorders. Clearly, the most fundamental question for autophagy in cardiovascular disease is whether its role is harmful or protective. Based on recent findings, autophagy in the adult heart under basal conditions is cytoprotective and promotes cardiovascular function. However, stimulated autophagy has an important role in several
Acknowledgements
This work was supported by the Fund for Scientific Research (FWO)-Flanders (Belgium) (Projects G.0308.04 and G.0113.06), the University of Antwerp (NOI-BOF) and the Bekales Foundation. W.M. is a postdoctoral fellow of the FWO-Flanders.
Glossary
- Autolysosome
- an autophagosome that fuses with a lysosome.
- Autophagic vacuole
- refers to an autophagosome or an autophagic structure that has fused with an endosome (amphisome) or lysosome (autolysosome). The term ‘autophagic vacuole’ is used mainly in electron microscopy studies, because often it is not possible to distinguish between the different autophagic structures.
- Autophagosome
- autophagy starts when a flat membrane cistern wraps around a portion of cytosol and/or organelles, forming a closed
References (90)
Autophagy: a regulated bulk degradation process inside cells
Biochem. Biophys. Res. Commun.
(2004)- et al.
Development by self-digestion: molecular mechanisms and biological functions of autophagy
Dev. Cell
(2004) Autophagy: paying Charon's toll
Cell
(2007)Determination of four sequential stages during microautophagy in vitro
J. Biol. Chem.
(2004)Methods for monitoring autophagy
Int. J. Biochem. Cell Biol.
(2004)Human hibernating myocardium is jeopardized by apoptotic and autophagic cell death
J. Am. Coll. Cardiol.
(2004)- et al.
Orchestrating nuclear functions: ubiquitin sets the rhythm
Trends Biochem. Sci.
(2003) Diphtheria toxin-induced autophagic cardiomyocyte death plays a pathogenic role in mouse model of heart failure
J. Biol. Chem.
(2004)Sitosterol-containing lipoproteins trigger free sterol-induced caspase-independent death in ACAT-competent macrophages
J. Biol. Chem.
(2006)Plant sterols in serum and in atherosclerotic plaques of patients undergoing carotid endarterectomy
J. Am. Coll. Cardiol.
(2005)