Abstract
The cardiac-specific overexpression of the adenine nucleotide translocase 1 (ANT1) has cardioprotective effects in various experimental heart disease models. Here, we analyzed the link between ANT1 expression and heat shock protein 27 (HSP27)-mediated toll-like receptor 4 (TLR4) signaling, which represents a novel communication pathway between mitochondria and the extracellular environment. The interaction between ANT1 and HSP27 was identified by co-immunoprecipitation from neonatal rat cardiomyocytes. ANT1 transgenic (ANT1-TG) cardiomyocytes demonstrated elevated HSP27 expression levels. Increased levels of HSP27 were released from the ANT1-TG cardiomyocytes under both normoxic and hypoxic conditions. Extracellular HSP27 stimulated TLR4 signaling via protein kinase B (AKT). The HSP27-mediated activation of the TLR4 pathway was more pronounced in ANT1-TG cardiomyocytes than in wild-type (WT) cardiomyocytes. HSP27-specific antibodies inhibited TLR4 activation and the expression of HSP27. Inhibition of the HSP27-mediated TLR4 signaling pathway with the TLR4 inhibitor oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) reduced the mitochondrial membrane potential (∆ψm) and increased caspase 3/7 activity, which are both markers for cell stress. Conversely, treating cardiomyocytes with recombinant HSP27 protein stimulated TLR4 signaling, induced HSP27 and ANT1 expression, and stabilized the mitochondrial membrane potential. The activation of HSP27 signaling was verified in ischemic ANT1-TG heart tissue, where it correlated with ANT1 expression and the tightness of the inner mitochondrial membrane. Our study shows a new mechanism by which ANT1 is part of the cardioprotective HSP27-mediated TLR4 signaling.
Highlights
Adenine nucleotide translocase (ANT) plays a central role in the cellular energy supply, facilitating the transfer of intramitochondrial ATP and extramitochondrial ADP across the inner mitochondrial membrane [1]
We previously demonstrated that adenine nucleotide translocase 1 (ANT1) overexpression resulted in the attenuation of cell death under hypoxic conditions, as demonstrated by reductions in cellular lactate dehydrogenase release, caspase 3 activity, and DNA fragmentation, and the stabilization of the mitochondrial membrane potential (∆ψm ) [12]
While heat shock protein 27 (HSP27) expression levels remained stable in hypoxic ANT1 transgenic (ANT1-TG) cardiomyocytes, they decreased in hypoxic WT cardiomyocytes
Summary
Adenine nucleotide translocase (ANT) plays a central role in the cellular energy supply, facilitating the transfer of intramitochondrial ATP and extramitochondrial ADP across the inner mitochondrial membrane [1]. It regulates the opening of the mitochondrial permeability transition pore (MPTP), which mediates apoptotic and necrotic processes [2]. Knockout of ANT1 results in hypertrophic cardiomyopathy and sudden cardiac death in mice [3]. ANT1 gene expression is reduced, resulting in impaired mitochondrial. Disturbed ANT1 function leads to insufficient energy supply, increased oxidative stress and cell death [6,7]. ANT1 is significantly involved in the pathophysiology of cardiac disease
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