Intracellular Mechanism of Rosuvastatin-Induced Decrease in Mature hERG Protein Expression on Membrane

Abstract

The hERG potassium channel (IKr) encoded by human ether-a-go-go-related gene plays an important role in cardiac repolarization. Decreased IKr may lead to long QT syndrome, which subsequently causes torsade de pointes and sudden cardiac death. Previous studies have shown that statins inhibit IKr and are more potent in inhibiting hERG currents when combined with other drugs. Since chemical structure of rosuvastatin is similar to that of several IKr blockers (ibutilide and E-4031), the present study aimed to reveal the mechanism that underlies rosuvastatin-induced hERG current reduction and to evaluate the possibility of cardiac toxicity. The results showed that rosuvastatin reduced hERG currents by accelerating the inactivation and prolonged action potential duration (APD) in hiPSC-CMs. Meanwhile, it was observed that rosuvastatin reduced the expression of the mature hERG. Transcription factor Sp1 was involved in hERG protein downregulation induced by rosuvastatin, and the result was verified by Sp1 siRNA and Sp1 agonist epicatechin. These results indicated that rosuvastatin could potentially inhibit transcription and reduce hERG mRNA expression. The interaction between hERG and heat shock protein was evaluated to study the mechanism of trafficking inhibition through co-immunoprecipitation. We found that rosuvastatin reduces the interaction of heat shock protein 70 (Hsp70) with the hERG protein, thereby affecting the folding of the hERG channel. Additionally, rosuvastatin significantly activates ATF6, which plays a key role in the activation of the unfolded protein response (UPR) pathway. Increased expression of the molecular chaperone calnexin and calreticulin, which are activated by ATF6 to help channel folding, further confirmed UPR activation. Meanwhile, the degradation of the hERG channel was mediated by lysosomes and proteasomes. In conclusion, Rosuvastatin reduced the expression of hERG plasma membrane by two pathways, the first is to disrupt the transport of immature hERG channels to the membrane, and the second is to increase the degradation of mature hERG channels. In addition, Rosuvastatin potently blocked hERG current, delayed cardiac repolarization, and thereby prolonged APDs and QTc intervals. Therefore, caution should be taken when rosuvastatin is used in the treatment of hyperlipidemia, especially when combined with drugs that can prolong the QT interval.

Modulation of Phospholipid Bilayer Properties by Simvastatin

“…90 These changes can also affect the structures of integral membrane proteins which deform to maximize hydrophobic interactions with the surrounding lipid bilayer, 91 and other processes such as protein aggregation, 91 helix−helix interactions, 91 and the dimerization of membrane proteins. 92 We also note that statins can influence the structure and function of these proteins via other pathways (for example, statins can affect the folding of the human ether-a-go-go related genes (hERG) potassium channel by binding directly to the heat shock protein), 93 although this study is focused on simvastatin− membrane interactions, and the impact on the physical properties of the model bilayer.…”

Small ubiquitin-related modifier (SUMO)ylation of SIRT1 mediates (-)-epicatechin inhibited- differentiation of cardiac fibroblasts into myofibroblasts

“…EPI was known to regulate activity of transcription factor SP1 (Feng et al. 2019 ). As indicated in Figure 6(A–D) , EPI could increase protein level of SP1 in both H9C2, CMs and CFs.…”

Potential therapeutic drugs for COVID-19 risk prolonging QT interval targeting hERG channel

“…It has been confirmed that HIV protease inhibitors induce ERS in intestinal epithelial cells(Wuet al 2010) and ERS can down-regulate cardiac ion channel expression (Liu et al 2018). Referring to the effect of rosuvastatin on hERG (Feng et al 2019), ERS may play an important role in diLQTS. Whether hERG is affected by ERS requires further verification.…”

“…Many different structurally drug groups cause QT prolongation targeting hERG through disrupting the trafficking of protein (Dennis et al 2007, Nogawa and Kawai 2014. These drugs include arsenic (Ficker et al 2004), pentamidine (Kuryshev et al 2005), fluconazole (Han et al2011) and ketoconazole (Takemasa et al 2008), fluoxetine (Hancox and Mitcheson 2006), cardiac glycosides (Wang et al 2007), rosuvastatin (Feng et al 2019), thioridazine (Liu et al2020) and so on. Arsenic trioxide (As 2 O 3 ) is the first example of a drug that produces hERG liability by inhibition of channel protein trafficking through disrupting hERG-chaperone complexes (Ficker et al 2004).…”