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  • Numerous strategies of cardiomyocyte protection are effectiv

    2021-10-16

    Numerous strategies of cardiomyocyte protection are effective in preclinical, animal models and in small clinical trials. However, most have disappointed in large clinical trials [4,5]. Failures of cyclosporine and post-conditioning to mitigate reperfusion injury are recent examples [[6], [7], [8]]. Although numerous pathways have been uncovered as mediators of reperfusion injury, there remains a substantial gap in effective clinical translation [4,5]. Nonetheless, pre-clinical studies have revealed that multiple signaling pathways converge to confer cardioprotection during I/R injury [8], so efforts to translate these to the clinical context remain relevant.
    Difficulty in designing therapy targeting reperfusion injury With this challenge in mind, the NIH-sponsored Cardioprotection Consortium CESAR analyzed failed therapies for I/R injury and suggested multiple design and efficacy criteria that must be fulfilled before a large-scale clinical trial should be launched [5]. Among the criteria to be met are: the agent must be tested at the time of reperfusion, not simply pre-injury, as this is the time at which the patient encounters the healthcare system; efficacy must be confirmed in large animal models; therapeutic agent must be safe and pharmaceutical grade; agent efficacy must be verified across multiple laboratories; protective response must be robust; preclinical studies must be conducted in a randomized, blinded fashion; agent must be tested in animal models with comorbidities [5]. A thoughtful review emerging subsequently suggested additional requirements, including evaluation of long-term effects beyond infarct size reduction, appropriate phase II dosing and timing studies, and focus on patient populations most likely to benefit from adjunct cardioprotection [9]. Recently, inhibition of histone deacetylase (HDAC) TC-I 15 receptor has emerged as a promising candidate to reduce reperfusion injury. Here, we discuss the prospect of targeting HDAC activity as a novel therapy for reperfusion injury using compounds approved for human use in rare cancers.
    HDAC activity is induced during I/R and promotes cardiomyocyte injury Many proteins undergo reversible protein acetylation, a highly regulated series of responses that govern protein stability, function, and subcellular localization [10]. These reactions are accomplished by proteins termed “writers” (histone acetyltransferases, HATs) and “erasers” (HDACs). Importantly, despite the presence of the word “histone” in each name, a reflection of the context in which these enzymes were first discovered, a wide range of proteins within the cell are regulated by reversible acetylation [11]. HATs catalyze the transfer of an acetyl-group from AcCoA (acetyl-coenzyme A) to the ɛ-amino group of a lysine residue within a protein. Conversely, HDACs remove the acetyl groups. Importantly, histones are not the only targets of these enzymes; indeed, this post-translational modification of reversible acetylation takes place on many other proteins. Thus, the arguably more appropriate terms lysine acetyltransferase (KAT) and lysine deacetylases (KDAC) have been introduced [12]. Nevertheless, given the role of histones in DNA packaging, the acetylation state of histone proteins governed by HATs and HDACs regulates chromatin function and subsequently gene transcription [13]. HATs are divided into 2 families, Gcn5 and MYST, named for their founding members [14]. Other proteins, such as p300/CBP, Taf1, and nuclear receptor coactivators also have acetyltransferase catalytic activity, but they do not harbor true consensus HAT domains and are categorized as an orphan class [15]. There are four classes of HDACs. HDACs 1, 2, 3, and 8 comprise the class I HDACs. Class II HDACs are subgrouped into class IIa (HDACs 4, 5, 7, and 9), and class IIb HDACs (HDACs 6 and 10), all of which are dependent on zinc for enzymatic activity. Class III HDACs are the sirtuin family, differentiated from the other classes because they use NAD+ as a cofactor. HDAC11, another zinc-dependent enzyme, is the sole known class IV HDAC [16].