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Numerous strategies of cardiomyocyte protection are effectiv
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) Polydatin 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].