Expression of SARS‐CoV‐2 Viroporins Triggers Cardiac Arrhythmia

Autor: Yugene Guo, Jin O-Uchi, Bong Sook Jhun, Elena Tolkacheva, Iuliia Polina
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: The FASEB Journal
ISSN: 1530-6860
0892-6638
Popis: Introduction COVID‐19 caused by SARS‐CoV‐2 is an ongoing global health emergency. Pre‐existing cardiovascular diseases (CVD) including hypertension have a higher risk for severe illness, cardiac damage, and death. Therefore, strategies for cardiovascular protection in COVID‐19 are urgently needed, in addition to the development of vaccines against COVID‐19. Previously, it has been reported that several SARS‐CoV‐1 genes including encoded Envelope (E) protein, open reading frame (ORF) 3a, are capable of forming viral channels in mammalian cells and damaging the cells via activation of apoptotic or endoplasmic reticulum (ER) stress signaling. In addition, SARS‐CoV‐1 patients are found to possess antibodies against ORF3a, indicating that this protein was expressed at the surface of the host cells. Moreover, a recent clinical report confirmed that SARS‐CoV‐2 can directly infect cardiomyocytes. However, the specific molecular mechanisms underlying the linkage between SARS‐CoV‐2 infection and cardiac risk are unclear. Hypothesis SARS‐CoV‐2 genes including ORF3a can be expressed in cardiomyocytes after virus infection, and subsequently dysregulate cardiac functions. Methods HEK293T cells and H9c2 cardiac myoblasts were transfected with ORF3a and utilized for biochemical, cell biological, and electrophysiological assays. Numerical model of rabbit ventricular action potential was used to evaluate the role of ORF3a on cardiac electrophysiology and arrhythmia. Results Although ORF3a sequences from SARS‐CoV‐1 and ‐CoV‐2 have 72% similarity, ORF3a from SARS‐CoV‐2 maintains high homology with SARS‐CoV‐1 in the protein sequences of the transmembrane domains and the pore, which are critical for forming ion channels. We found that SARS‐CoV‐2‐ORF3a is expressed at plasma membrane and outer mitochondrial membrane as assessed by protein fractionation, mitochondrial digestion, and live‐cell imaging. Whole cell patch clamp revealed that ORF3a can form K+‐permeable channels at the plasma membrane with similar channel properties as the endogenous transient outward K+ current (Ito). Moreover, numerical simulations suggest that increased Ito amplitude (mimicking increase of ORF3a expression) may dysregulate Ca2+ transient and increase the risk for early afterdepolarization in response to increased heart rate. Lastly, we found that ORF3a promotes apoptotic signaling activation, but not ER stress signaling, assessed by caspase activity and the expression of major ER chaperones, respectively. Conclusion ORF3a from SARS‐CoV‐2 forms K+‐permeable channels at the plasma membrane and dysregulates cardiac Ca2+ handling and electrophysiology. ORF3a can also be expressed at the mitochondria and activate oxidative stress signaling, which exacerbates the risk of arrhythmia. Targeting SARS‐CoV‐2 viroporins including ORF3a may reduce the risk of sudden cardiac death and cardiac damage in COVID‐19 patients with pre‐existing CVDs.
Databáze: OpenAIRE
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