Oxidative stress and autophagy in cardiovascular homeostasis - PubMed (original) (raw)
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Oxidative stress and autophagy in cardiovascular homeostasis
Cyndi R Morales et al. Antioxid Redox Signal. 2014.
Abstract
Significance: Autophagy is an evolutionarily ancient process of intracellular protein and organelle recycling required to maintain cellular homeostasis in the face of a wide variety of stresses. Dysregulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) leads to oxidative damage. Both autophagy and ROS/RNS serve pathological or adaptive roles within cardiomyocytes, depending on the context.
Recent advances: ROS/RNS and autophagy communicate with each other via both transcriptional and post-translational events. This cross talk, in turn, regulates the structural integrity of cardiomyocytes, promotes proteostasis, and reduces inflammation, events critical to disease pathogenesis.
Critical issues: Dysregulation of either autophagy or redox state has been implicated in many cardiovascular diseases. Cardiomyocytes are rich in mitochondria, which make them particularly sensitive to oxidative damage. Maintenance of mitochondrial homeostasis and elimination of defective mitochondria are each critical to the maintenance of redox homeostasis.
Future directions: The complex interplay between autophagy and oxidative stress underlies a wide range of physiological and pathological events and its elucidation holds promise of potential clinical applicability.
Figures
**FIG. 1.
The process of autophagy. Beclin 1 localizes to the phagophore to promote autophagosome formation and recruit ATGs. Then, ATG7 mediates the conjugation of ATG12 to ATG5, which then bind ATG16 to promote autophagosome elongation. In parallel, LC3 is converted to LC3I by ATG4, and LC3I is subsequently lipidated to form LC3II by ATG7 and ATG3. The mature autophagosome fuses with a lysosome, an event that culminates in cargo degradation. ATG, autophagy-related protein. To see this illustration in color, the reader is referred to the web version of this article at
**FIG. 2.
Balance of ROS/RNS and antioxidants in cardiac stress. A critical balance between oxidants and antioxidants is essential to maintain normal cardiac signaling and function. Similarly, adequate basal autophagic flux is required for homeostasis. A variety of cardiac insults can lead to ROS accumulation and the decline of antioxidant systems. This loss of redox balance is related to the development of maladaptive remodeling. In this context, autophagy may be induced as a bulk anti-oxidative response. GSH, glutathione; NOX, NADPH oxidase; XO, xanthine oxidase; eNOS, endothelial NOS; iNOS, inducible isoform NOS; nNOS, neuronal NOS; SOD, superoxide dismutase; TRX, thioredoxin; ROS, reactive oxygen species; RNS, reactive nitrogen species. To see this illustration in color, the reader is referred to the web version of this article at
**FIG. 3.
Effects of elevated ROS in heart disease. A variety of cardiac insults can lead to ROS accumulation, provoking oxidative damage in cardiomyocytes. In a feed-forward manner, accumulation of oxidative damage can result in exacerbation of disease-related stress. MMP, metalloproteinase. To see this illustration in color, the reader is referred to the web version of this article at
**FIG. 4.
Reciprocal ROS-induced activation of autophagy and autophagic elimination of ROS sources. ROS activate autophagic flux via a variety of inducers. Meanwhile, autophagy can eliminate mitochondrial sources of ROS, as well as ROS-oxidized protein aggregates, which can contribute to cardiomyopathy. FoxO, Forkhead box-O; IKK, IκB kinase; Keap1, Kelch-like ECH-associated protein-1; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor (erythroid-derived 2)-like 2; SIRT, sirtuin (silent mating type information regulation 2 homolog) 1. To see this illustration in color, the reader is referred to the web version of this article at
**FIG. 5.
Differential regulation of autophagy by ROS and RNS. ROS can induce autophagic degradation in cardiomyocytes. However, the role of specific RNS in autophagy in cardiomyocytes remains relatively less well characterized. Recently, it was shown in neurons that NO leads to S-nitrosylation and inhibition of JNK1 and IKKβ. In consequence, downstream signaling events inhibit autophagy. JNK1, c-Jun N-terminal kinase-1; mTOR, mammalian target of rapamycin. To see this illustration in color, the reader is referred to the web version of this article at
**FIG. 6.
Balance between redox state and autophagic activation. ROS, RNS, and autophagy must each be maintained within a narrow range; too little, or too much, of each can be maladaptive. To see this illustration in color, the reader is referred to the web version of this article at
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