Differences in Functional Expression of Connexin43 and NaV1.5 by Pan- and Class-Selective Histone Deacetylase Inhibition in Heart

Zhang, Xian; Patel, Dakshesh; Xu, Qin; Veenstra, Richard D.

doi:10.3390/ijms19082288

Cited by 3 publications

(3 citation statements)

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“…For further investigations of the molecular mechanisms involved, STAT3 was silenced by siRNA transfection; meanwhile, some STAT3‐associated signaling inhibitors dissolved in dimethyl sulphoxide were also used for the investigation of molecular mechanisms: Smyd2 inhibitor LLY‐507 (5 μmol/L for 24 hours), HDAC6 inhibitor ACY‐1215 (0.5 μmol/L for 24 hours), ErbB2 inhibitor AG825 (10 μmol/L for 24 hours), and JAK2 inhibitor AG490 (10 μmol/L for 6 hours). 19 , 20 , 21 , 22 H9c2 cells, purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China), were also used in this study. H9c2 cells were cultured in DMEM (Gibco) supplemented with 10% fetal bovine serum.…”

Section: Methodsmentioning

confidence: 99%

SENP1 Protects Against Pressure Overload‐Induced Cardiac Remodeling and Dysfunction Via Inhibiting STAT3 Signaling

Yang

Fan

Guo

et al. 2022

JAHA

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Background SENP1 (sentrin/small ubiquitin‐like modifier‐specific protease 1) has emerged as a significant modulator involved in the pathogenesis of a variety of human diseases, especially cancer. However, the regulatory roles of SENP1 in cardiovascular biology and diseases remain controversial. Our current study aims to clarify the function and regulation of SENP1 in pressure overload‐induced cardiac remodeling and dysfunction. Methods and Results We used a preclinical mouse model of transverse aortic constriction coupled with in vitro studies in neonatal rat cardiomyocytes to study the role of SENP1 in cardiac hypertrophy. Gene delivery system was used to knockdown or overexpress SENP1 in vivo. Here, we observed that SENP1 expression was significantly augmented in murine hearts following transverse aortic constriction as well as neonatal rat cardiomyocytes treated with phenylephrine or angiotensin II. Cardiac‐specific SENP1 knockdown markedly exacerbated transverse aortic constriction‐induced cardiac hypertrophy, systolic dysfunction, fibrotic response, and cellular apoptosis. In contrast, adenovirus‐mediated SENP1 overexpression in murine myocardium significantly attenuated cardiac remodeling and dysfunction following chronic pressure overload. Mechanistically, JAK2 (Janus kinase 2) and STAT3 (signal transducer and activator of transcription 3) acted as new interacting partners of SENP1 in this process. SENP1‐JAK2/STAT3 interaction suppressed STAT3 nuclear translocation and activation, ultimately inhibiting the transcription of prohypertrophic genes and the initiation of hypertrophic response. Furthermore, cardiomyocyte‐specific STAT3 knockout mice were generated to validate the underlying mechanisms, and the results showed that STAT3 ablation blunted the cardiac hypertrophy‐promoting effects of SENP1 deficiency. Additionally, pharmacological inhibition of SENP1 by Momordin Ic amplified cardiac remodeling post‐transverse aortic constriction. Conclusions Our study provided evidence that SENP1 protected against pressure overload‐induced cardiac remodeling and dysfunction via inhibiting STAT3 signaling. SENP1 supplementation might constitute a new promising treatment against cardiac hypertrophy. Notably, cardiovascular side effects should be seriously considered while applying systemic SENP1 blockers to suppress tumors.

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Section: Methodsmentioning

confidence: 99%

SENP1 Protects Against Pressure Overload‐Induced Cardiac Remodeling and Dysfunction Via Inhibiting STAT3 Signaling

Yang

Fan

Guo

et al. 2022

JAHA

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“…Conversely, in the heart tissue, SIRT1 has been reported to deacetylate Na V 1.5 at lysine 1479 (K1479), stimulating inward depolarizing cardiac Na+ current (I Na ) via lysine-deacetylation-mediated trafficking of Na V 1.5 to the plasma membrane [ 58 ]. Moreover, pan-HDACi have been shown to decrease peak I Na density, without significantly altering SCN5A mRNA levels, but strongly reducing Na V 1.5 protein levels [ 59 , 60 ].…”

Section: Hdacs and Vgics Potential Functional Interaction In Cancermentioning

confidence: 99%

From HDAC to Voltage-Gated Ion Channels: What’s Next? The Long Road of Antiepileptic Drugs Repositioning in Cancer

Pellegrino

Ricci

Ceraldi

et al. 2022

Cancers

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Cancer is a major health burden worldwide. Although the plethora of molecular targets identified in the last decades and the deriving developed treatments, which significantly improved patients’ outcome, the occurrence of resistance to therapies remains the major cause of relapse and mortality. Thus, efforts in identifying new markers to be exploited as molecular targets in cancer therapy are needed. This review will first give a glance on the diagnostic and therapeutic significance of histone deacetylase (HDAC) and voltage gated ion channels (VGICs) in cancer. Nevertheless, HDAC and VGICs have also been reported as molecular targets through which antiepileptic drugs (AEDs) seem to exert their anticancer activity. This should be claimed as a great advantage. Indeed, due to the slowness of drug approval procedures, the attempt to turn to off-label use of already approved medicines would be highly preferable. Therefore, an updated and accurate overview of both preclinical and clinical data of commonly prescribed AEDs (mainly valproic acid, lamotrigine, carbamazepine, phenytoin and gabapentin) in breast, prostate, brain and other cancers will follow. Finally, a glance at the emerging attempt to administer AEDs by means of opportunely designed drug delivery systems (DDSs), so to limit toxicity and improve bioavailability, is also given.

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“…The Fluor de Lys assay is a commonly employed fluorometric method for assessing the in vitro enzymatic activity of deacetylases (Gurvich, Tsygankova, Meinkoth, & Klein, 2004; Joshi et al, 2013; Li et al, 2015; Miteva & Cristea, 2014; Zhang, Patel, Xu, & Veenstra, 2018; Zhou, Marks, Rifkind, & Richon, 2001), including HDACs and sirtuins (Fig. 4).…”

Section: Using the Fluor De Lys Assay To Measure In Vitro The Enzymatmentioning

confidence: 99%

Methods for characterizing protein acetylation during viral infection

Murray

Combs

Rekapalli

et al. 2019

Methods in Enzymology

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Lysine acetylation is a prevalent posttranslational modification that acts as a regulator of protein function, subcellular localization, and interactions. A growing body of work has highlighted the importance of temporal alterations in protein acetylation during infection with a range of human viruses. It has become clear that both cellular and viral proteins are decorated by lysine acetylations, and that these modifications contribute to core host defense and virus replication processes. Further defining the extent and dynamics of protein acetylation events during the progression of an infection can provide an important new perspective on the intricate mechanisms underlying the biology and pathogenesis of virus infections. Here, we provide protocols for identifying, quantifying, and probing the regulation of lysine acetylations during viral infection. We describe the use of acetyl-lysine immunoaffinity purification and quantitative mass spectrometry for assessing the cellular acetylome at different stages of an infection. As an alternative to traditional antibody-mediated western blotting, we discuss the benefits of targeted mass spectrometry approaches for detecting and quantifying site-specific acetylations on proteins of interest. Specifically, we provide a protocol using parallel reaction monitoring (PRM). We further discuss experimental considerations that are specific to studying viral infections. Finally, we provide a brief overview of the types of assays that can be employed to characterize the function of an acetylation event in the context of infection. As a method to interrogate the regulation of acetylation, we describe the Fluor de Lys assay for monitoring the enzymatic activities of deacetylases.

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Differences in Functional Expression of Connexin43 and NaV1.5 by Pan- and Class-Selective Histone Deacetylase Inhibition in Heart

Cited by 3 publications

References 50 publications

SENP1 Protects Against Pressure Overload‐Induced Cardiac Remodeling and Dysfunction Via Inhibiting STAT3 Signaling

SENP1 Protects Against Pressure Overload‐Induced Cardiac Remodeling and Dysfunction Via Inhibiting STAT3 Signaling

From HDAC to Voltage-Gated Ion Channels: What’s Next? The Long Road of Antiepileptic Drugs Repositioning in Cancer

Methods for characterizing protein acetylation during viral infection

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