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SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells.
Han, Yuling; Zhu, Jiajun; Yang, Liuliu; Nilsson-Payant, Benjamin E; Hurtado, Romulo; Lacko, Lauretta A; Sun, Xiaolu; Gade, Aravind R; Higgins, Christina A; Sisso, Whitney J; Dong, Xue; Wang, Maple; Chen, Zhengming; Ho, David D; Pitt, Geoffrey S; Schwartz, Robert E; tenOever, Benjamin R; Evans, Todd; Chen, Shuibing.
  • Han Y; Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY.
  • Zhu J; Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY.
  • Yang L; Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY.
  • Nilsson-Payant BE; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY (B.E.N.-P., B.R.T.).
  • Hurtado R; Department of Microbiology, New York University (B.E.N.-P., C.A.H., B.R.T.).
  • Lacko LA; Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY.
  • Sun X; Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY.
  • Gade AR; Cardiovascular Research Institute (X.S., A.R.G., G.S.P.), Weill Cornell Medicine, New York, NY.
  • Higgins CA; Cardiovascular Research Institute (X.S., A.R.G., G.S.P.), Weill Cornell Medicine, New York, NY.
  • Sisso WJ; Department of Microbiology, New York University (B.E.N.-P., C.A.H., B.R.T.).
  • Dong X; Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY.
  • Wang M; Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY.
  • Chen Z; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY (M.W., D.D.H.).
  • Ho DD; Department of Population Health Sciences (Z.C.), Weill Cornell Medicine, New York, NY.
  • Pitt GS; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY (M.W., D.D.H.).
  • Schwartz RE; Cardiovascular Research Institute (X.S., A.R.G., G.S.P.), Weill Cornell Medicine, New York, NY.
  • tenOever BR; Division of Gastroenterology and Hepatology, Department of Medicine (R.E.S.), Weill Cornell Medicine, New York, NY.
  • Evans T; Department of Physiology, Biophysics and Systems Biology (R.E.S.), Weill Cornell Medicine, New York, NY.
  • Chen S; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY (B.E.N.-P., B.R.T.).
Circ Res ; 130(7): 963-977, 2022 04.
Article in English | MEDLINE | ID: covidwho-1731376
ABSTRACT

BACKGROUND:

Increasing evidence suggests that cardiac arrhythmias are frequent clinical features of coronavirus disease 2019 (COVID-19). Sinus node damage may lead to bradycardia. However, it is challenging to explore human sinoatrial node (SAN) pathophysiology due to difficulty in isolating and culturing human SAN cells. Embryonic stem cells (ESCs) can be a source to derive human SAN-like pacemaker cells for disease modeling.

METHODS:

We used both a hamster model and human ESC (hESC)-derived SAN-like pacemaker cells to explore the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pacemaker cells of the heart. In the hamster model, quantitative real-time polymerase chain reaction and immunostaining were used to detect viral RNA and protein, respectively. We then created a dual knock-in SHOX2GFP;MYH6mCherry hESC reporter line to establish a highly efficient strategy to derive functional human SAN-like pacemaker cells, which was further characterized by single-cell RNA sequencing. Following exposure to SARS-CoV-2, quantitative real-time polymerase chain reaction, immunostaining, and RNA sequencing were used to confirm infection and determine the host response of hESC-SAN-like pacemaker cells. Finally, a high content chemical screen was performed to identify drugs that can inhibit SARS-CoV-2 infection, and block SARS-CoV-2-induced ferroptosis.

RESULTS:

Viral RNA and spike protein were detected in SAN cells in the hearts of infected hamsters. We established an efficient strategy to derive from hESCs functional human SAN-like pacemaker cells, which express pacemaker markers and display SAN-like action potentials. Furthermore, SARS-CoV-2 infection causes dysfunction of human SAN-like pacemaker cells and induces ferroptosis. Two drug candidates, deferoxamine and imatinib, were identified from the high content screen, able to block SARS-CoV-2 infection and infection-associated ferroptosis.

CONCLUSIONS:

Using a hamster model, we showed that primary pacemaker cells in the heart can be infected by SARS-CoV-2. Infection of hESC-derived functional SAN-like pacemaker cells demonstrates ferroptosis as a potential mechanism for causing cardiac arrhythmias in patients with COVID-19. Finally, we identified candidate drugs that can protect the SAN cells from SARS-CoV-2 infection.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Ferroptosis / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Journal: Circ Res Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Ferroptosis / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Journal: Circ Res Year: 2022 Document Type: Article