Arsenic trioxide and angiotensin II have inhibitory effects on HERG protein expression: Evidence for the role of PML SUMOylation

Abstract

The human ether-a-go-go-related gene (HERG) channel is a novel target for the treatment of drug-induced long QT syndrome, which causes lethal cardiotoxicity. This study is designed to explore the possible role of PML SUMOylation and its associated nuclear bodies (NBs) in the regulation of HERG protein expression. Both arsenic trioxide (ATO) and angiotensin II (Ang II) were able to significantly reduce HERG protein expression, while also increasing PML SUMOylation and accelerating the formation of PML-NBs. Pre-exposure of cardiomyocytes to a SUMOylation chemical inhibitor, ginkgolic acid, or the silencing of UBC9 suppressed PML SUMOylation, subsequently preventing the downregulation of HERG induced by ATO or Ang II. Conversely, knockdown of RNF4 led to a remarkable increase in PML SUMOylation and the function of PML-NBs, further promoting ATO- or Ang II-induced HERG protein downregulation. Mechanistically, an increase in PML SUMOylation by ATO or Ang II dramatically enhanced the formation of PML and Pin1 complexes in PML-NBs, leading to the upregulation of TGF-β1 protein, eventually inhibiting HERG expression through activation of protein kinase A. The present work uncovered a novel molecular mechanism underlying HERG protein expression and indicated that PML SUMOylation is a critical step in the development of drug-acquired arrhythmia.

In silico mechanisms of arsenic trioxide-induced cardiotoxicity

“…This study revealed that long-term ATO suppressed the I Kr current in HEK293 cells, and the dosage of ATO directly determined the reduction degree of I Kr ( Ficker et al, 2004 ). The same phenomenon can also be observed in other HEK293 experiments ( Zhao et al, 2015 ; Yan et al, 2017 ), and the inhibiting effect of ATO on the hERG channel has also appeared in rodent animals, such as guinea pig VMs ( Ficker et al, 2004 ; Zhao et al, 2014 ), neonatal rat VMs (NRVMs) ( Zhao et al, 2015 ), and neonatal mouse cardiomyocytes ( Liu et al, 2017 ). In addition, the underlying RNA regulation mechanisms of ATO-impaired hERG were revealed ( Shan et al, 2013 ; Zhao et al, 2015 ).…”

“…Moreover, lead compound optimization was also reported to be a strategy that alleviated ATO toxicity ( Zhou et al, 2016 ). In addition, the regulatory mechanism of TGF-β1 under ATO treatment ( Chu et al, 2012 ; Liu et al, 2017 ) provided new methods for preventing hERG and Kir2.1 protein damage by treatment with the protein kinase A (PKA) antagonist H89 and the TβR-I inhibitor LY364947 ( Chu et al, 2012 ).…”

TGF‐β1‐PML SUMOylation‐peptidyl‐prolyl cis–trans isomerase NIMA‐interacting 1 (Pin1) form a positive feedback loop to regulate cardiac fibrosis

“…Various factors, such as arsenic trioxide (ATO), angiotensin‐II (Ang II), and FBS, are reported to trigger the PML SUMOylation (Y. Liu, Li et al, ; Xu, Liu, Wu, Qiao, & Yan, ). In the current study, we found that TGF‐β1 dramatically triggered PML SUMOylation (Figure a,b) in a dose‐ and time‐dependent manner, which was well consistent with TGF‐β1‐mediated and increased its own expression (Figure a,b).…”

“…In the formation and degradation of PML‐NB, several factors play key roles in localization of proteins, for instance, SUMOylation, a process of posttranslational modification of proteins by the SUMO family of proteins, is known to be involved in yeast and mammalian somatic cell‐cycle regulation, including signal transduction, protein trafficking, chromosome segregation, and DNA repair (Feitosa & Morris, ). The PML SUMOylation can be enhanced by a variety of stimuli, including interferon (IFN), FBS, CdCl 2 , Ang II, heat shock, DNA damage, and ATO (Y. Liu, Li et al, ; Y. Liu, Zhao, ; Sahin et al, ); and the PML‐NBs can be formed immediately after PML is recruited into the nucleus. Here, we found that PML SUMOylation can be enhanced by TGF‐β1 as a new stimulus.…”

Risk Compounds, Preclinical Toxicity Evaluation, and Potential Mechanisms of Chinese Materia Medica–Induced Cardiotoxicity

“…The delayed rectifying potassium current ( I kr ) channel protein on human cardiomyocytes is encoded by human hERG. Studies demonstrated that the loss of hERG function and the inhibition of I kr caused by drugs prolonged QT interval and possibly induced TdP, thus leading to fatal arrhythmias ( Liu et al, 2017 ). Some toxic CMM induce cardiotoxicity by directly inhibiting the expression of hERG channel protein or coding gene to suppress potassium channels.…”