Article

Cardioprotection by adaptation to ischemia augments autophagy in association with BAG-1 protein

Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, 06030-1110, USA.
Journal of Cellular and Molecular Medicine (Impact Factor: 4.01). 10/2008; 13(2):373-87. DOI: 10.1111/j.1582-4934.2008.00495.x
Source: PubMed

ABSTRACT

Autophagy is an intracellular process in which a cell digests its own constituents via lysosomal degradative pathway. Though autophagy has been shown in several cardiac diseases like heart failure, hypertrophy and ischaemic cardiomyopathy, the role and the regulation of autophagy is still largely unknown. Bcl-2-associated athanogene (BAG-1) is a multifunctional pro-survival molecule that binds with Hsp70/Hsc70. In this study, myocardial adaptation to ischaemia by repeated brief episodes of ischaemia and reperfusion (I/R) prior to lethal I/R enhanced the expression of autophagosomal membrane specific protein light chain 3 (LC3)-II, and Beclin-1, a molecule involved in autophagy and BAG-1. Autophagosomes structures were found in the adapted myocardium through electron microscopy. Co-immunoprecipitation and co-immunofluorescence analyses revealed that LC3-II was bound with BAG-1. Inhibition of autophagy by treating rats with Wortmannin (15 microg/kg; intraperitoneally) abolished the ischaemic adaptation-induced induction of LC3-II, Beclin-1, BAG-1 and cardioprotection. Intramyocardial injection of BAG-1 siRNA attenuated the induction of LC3-II, and abolished the cardioprotection achieved by adaptation. Furthermore, hypoxic adaptation in cardiac myoblast cells induced LC3-II and BAG-1. BAG-1 siRNA treatment attenuated hypoxic adaptation-induced LC3-II and BAG-1, and abolished improvement in cardiac cell survival and reduction of cell death. These results clearly indicate that myocardial protection elicited by adaptation is mediated at least in part via up-regulation of autophagy in association with BAG-1 protein.

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    • "Significant upregulation in the rat hearts after ischemic adaptation [27] [44] [47] [48] Significant increase in brains with HIV-1 encephalitis "
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    • "In mammals, autophagy can be induced by exogenous H 2 O 2 (Zhang et al., 2009) or internal ROS generated mainly from mitochondria (Chen et al., 2007; Scherz-Shouval et al., 2007; Moore, 2008; Azad et al., 2009). However, autophagy can serve to reduce ROS levels and reduce oxidative damage (Kaushik and Cuervo, 2006; Scherz- Shouval and Elazar, 2007; Gurusamy et al., 2009; Jain et al., 2010). "
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    • "Autophagy activation has been proposed as one mechanism of cardioprotection [15]. In isolated rat hearts, protection by ischemic preconditioning, i.e., brief episodes of coronary artery occlusion/reperfusion, was associated with enhanced myocardial expression of LC3-II, beclin-1 [16], and p62 [14] as well as with enhanced expression of parkin in the mitochondrial fraction [17]. Parkin is a requisite for autophagic removal of mitochondria [17]. "
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