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    • br Direct effect of HDACs on contractile function by deacety

    2022-03-31


    Direct effect of HDACs on contractile function by deacetylating cytoskeletal and contractile proteins
    Role of HDACs in electropathology by transcriptional reprogramming Next to deacetylation of α-tubulin by HDAC6 in experimental and human AF, there is also evidence for transcriptional reprogramming to underlie AF susceptibility and progression [6,75,76]. Transcriptional reprogramming refers to the phenomenon of global changes in gene Manidipine 2HCl receptor initiated by transcription factors [77]. During transcriptional reprogramming, the expression of specific genes is elevated, whereas other genes are repressed compared to the previous state. During cardiac transcriptional reprogramming, especially pathological and fetal gene expression is activated, leading to structural and metabolic changes, such as cardiomyocyte dedifferentiation, fibrosis, hypertrophy, atrial dilation, ion channel remodeling and metabolic remodeling, all of which have been identified as important mechanisms underlying the onset and progression of AF (Fig. 3) [7,60,[78], [79], [80]]. HDACs, especially class I and class IIa HDACs, play a key role in the transcriptional reprogramming which underlies AF onset and progression (Table 3).
    Therapeutic implications for AF Present drug therapies for AF have moderate efficacy and important limitations [109]. Thus, pharmacological approaches preventing or limiting electropathology in AF are warranted [13]. HDACs have an important role in the development of cardiac electropathology. Therefore, various HDAC inhibitors have been tested in experimental animal model systems for AF and revealed protective effects against cardiac electropathology and AF promotion (Table 4). Furthermore, pan-HDAC inhibitors, including class I/II HDAC inhibitors and class I HDAC inhibitors, protect against hypertension [22,23], hypertrophy, heart failure (especially HFpEF) [[24], [25], [26]], and obesity and diabetes [[27], [28], [29]] (Table 4), all risk factors for the development of AF. Several of these class I and/or II pan-HDAC inhibitors are FDA approved drugs or are in clinical trials for the treatment of cancer (Table 4). Importantly, the generally well-tolerated pan-HDAC inhibitors reveal toxicities when administered at comparatively high chemotherapeutic doses [24]. At present it is uncertain whether the liabilities of current HDAC inhibitors may preclude their use as therapeutics in AF. In this context, future in vivo studies aimed at defining the therapeutic window of HDAC inhibitors for the treatment of AF will be essential. We recently screened the role of individual HDACs in AF and identified a specific role for HDAC3, HDAC5 and HDAC6 in AF [4,7]. Overexpression of HDAC3 revealed detrimental effects on the cardiomyocytes, whereas HDAC5 protected against tachypacing-induced cardiomyocyte remodeling. This highlights a need for isoform-selective HDAC drug design to limit unwanted side-effects through inhibition of protective HDACs. Isoform-selective HDAC inhibition will definitely be safer than pan- HDAC inhibition in the setting of AF. The specific inhibitor of HDAC3, such as RGFP966, prevented contractile dysfunction in both cardiomyocyte and Drosophila models for AF, suggesting HDAC3 as an very interesting therapeutic target for AF [4]. In addition, AF results in HDAC6 activation, which results in α-tubulin deacetylation, microtubule disruption and consequently AF progression. In line, proof of concept for HDAC6 as a druggable target in AF was provided by demonstrating that tubastatin A protects against electropathology and thereby attenuates AF onset and progression in tachypaced dogs [8]. Therefore, pharmacological inhibition of the major α-tubulin deacetylating enzyme HDAC6 represents a potentially promising target for AF therapy. A clinical HDAC6 inhibitor, ricolinostat (ACY-1215) has been developed and is in clinical phase II for the treatment of multiple myeloma, breast cancer, and leukemia [8]. Since the specific inhibition of HDAC6 by ricolinostat has not been associated with any serious side effects so far [91], this drug may be an interesting candidate to test in patients with AF. Preventing phosphorylation and nuclear export of HDAC5 is accomplished by inhibiting upstream kinases and therefore may also benefit AF patients. We have showed that the PKC inhibitor Go6983 can prevent tachypacing-induced contractile dysfunction in experimental models for AF [6]. Whether PKC is activated in AF patients is the subject for further investigation. Importantly, all the HDAC inhibitors listed in Table 4 can not efficiently cross the blood brain barrier (BBB) except RGFP966. On one hand, this limits possible side effect on central nervous system; on the other hand, for patients with neurological diseases in combination with AF, it may be more appropriate to use a drug with efficient BBB crossing such as RGFP966 [110].