Targeting the Translocator Protein (18 kDa) in Cardiac Diseases: State of the Art and Future Opportunities

Abstract

Mitochondria dysfunctions are typical hallmarks of cardiac disorders (CDs). The multiple tasks of this energy-producing organelle are well documented, but its pathophysiologic involvement in several manifestations of heart diseases, such as altered electromechanical coupling, excitability, and arrhythmias, is still under investigation. The human 18 kDa translocator protein (TSPO) is a protein located on the outer mitochondrial membrane whose expression is altered in different pathological conditions, including CDs, making it an attractive therapeutic and diagnostic target. Currently, only a few TSPO ligands are employed in CDs and cardiac imaging. In this Perspective, we report an overview of the emerging role of TSPO at the heart level, focusing on the recent literature concerning the development of TSPO ligands used for fighting and imaging heart-related disease conditions. Accordingly, targeting TSPO might represent a successful strategy to achieve novel therapeutic and diagnostic strategies to unravel the fundamental mechanisms and to provide solutions to still unanswered questions in CDs.

Transcriptional landscape of a hypoxia response identifies cell-specific pathways for adaptation

“…Our studies of human cardiomyocytes link HIF-1α activation with TSPO, which has been suggested to function in myriad processes, including intracellular cholesterol transport and steroid hormone biosynthesis. 82 We speculate that some of the well-established responses of cardiomyocytes to hypoxia in developmental, physiological, and pathophysiological contexts 66,76,104,105 involve TSPO. First, TSPO in cardiomyocytes has been reported to influence heart rate and muscle contractile force by modulating voltage-dependent Ca 2+ channels.…”

“…In particular, these mammalian homologs modulate both the heart rate and the contractility of cardiomyocytes. 64–66 In this study, we asked if tspo-1 functions in the hypoxia response in muscle cells.…”

“…First, TSPO in cardiomyocytes has been reported to influence heart rate and muscle contractile force by modulating voltage-dependent Ca 2+ channels. 64,66 Second, mitochondrial cholesterol dynamics can influence mitochondrial homeostasis, including the balance between fission and fusion, 106,107 and might directly influence cardiomyocyte contractility. 108 The fission-fusion balance is critical for maintaining mitochondrial quality and function and has been shown to be modulated by hypoxia and HIF-1α activation.…”