The SARS-CoV-2 Spike protein induces long-term transcriptional perturbations of mitochondrial metabolic genes, causes cardiac fibrosis, and reduces myocardial contractile in obese mice

Abstract

Background: As the pandemic evolves, post-acute sequelae of CoV-2 (PACS) including cardiovascular manifestations have emerged as a new health threat. This study aims to study whether the Spike protein plus obesity can exacerbate PACS-related cardiomyopathy. Methods: A Spike protein-pseudotyped (Spp) virus with the proper surface tropism of SARS-CoV-2 was developed for viral entry assay in vitro and administration into high fat diet (HFD)-fed mice. The systemic viral loads and cardiac transcriptomes were analyzed at 2 and 24 hrs, 3, 6, and 24 weeks post introducing (wpi) Spp using RNA-seq or real time RT-PCR. Echocardiography was used to monitor cardiac functions. Results: Low-density lipoprotein cholesterol enhanced viral uptake in endothelial cells, macrophages, and cardiomyocyte-like H9C2 cells. Selective cardiac and adipose viral depositions were observed in HFD mice but not in normal-chow-fed mice. The cardiac transcriptional signatures in HFD mice at 3, 6, and 24 wpi showed systemic suppression of mitochondria respiratory chain genes including ATP synthases and nicotinamide adenine dinucleotide:ubiquinone oxidoreductase gene members, upregulation of stress pathway-related crucial factors such as nuclear factor-erythroid 2-related factor 1 and signal transducer and activator of transcription 5A, and increases in expression of glucose metabolism-associated genes. As compared with the age-matched HFD control mice, cardiac ejection fraction and fractional shortening were significantly decreased, while left ventricular end-systolic diameter and volume were significantly elevated, and cardiac fibrosis was increased in HFD mice at 24 wpi. Conclusion: Our data demonstrated that the Spike protein could induce long-term transcriptional suppression of mitochondria metabolic genes and cause cardiac fibrosis and myocardial contractile impairment, providing mechanistic insights to PACS-related cardiomyopathy.

Possible Pathogenesis and Prevention of Long COVID: SARS-CoV-2-Induced Mitochondrial Disorder

“…The mechanism underlying the persistence of long COVID has not yet been identified [72], but it has been speculated that it may be related to abnormal immune responses, virus-specific pathophysiology, inflammatory damage in response to acute infection [73], persistence of the virus in certain tissues [74,75] or exosomes and hypertrophy cells [76,77], SARS-CoV-2 interactions with the host microbiome/virome community, coagulation/coagulation problems, and dysfunctional brainstem/vagal signaling [78]. In addition, the role of SARS-CoV-2 in relation to mitochondrial damage and the subsequent immune response has been recently considered [79][80][81]. For example, the spike protein of SARS-CoV-2 can inhibit the transcription of mitochondrial metabolic genes in the long term, resulting in myocardial fibrosis and myocardial contractile dysfunction [79].…”

“…In addition, the role of SARS-CoV-2 in relation to mitochondrial damage and the subsequent immune response has been recently considered [79][80][81]. For example, the spike protein of SARS-CoV-2 can inhibit the transcription of mitochondrial metabolic genes in the long term, resulting in myocardial fibrosis and myocardial contractile dysfunction [79]. Long COVID neurological symptoms are associated with SARS-CoV-2 proteins and abnormalities in mitochondrial proteins in nerve cells [81].…”

2023 Chinese expert consensus on the impact of COVID-19 on the management of cardiovascular diseases

“…There is a positive correlation between the severity of cardiac involvement and the amount of SARS-Cov-2 in the lungs [ 15 ] , indicating that myocardial injury caused by SARS-Cov-2 correlates with the severity of pulmonary invasion. A recent study showed that SARS-Cov-2 can cause myocardial fibrosis and myocardial contractile dysfunction via prolonged inhibition of mitochondrial metabolism [ 16 ] . In a recent study by Nchioua et al .…”

“…There is a positive correlation between the severity of cardiac involvement and the amount of SARS-Cov-2 in the lungs [15] , indicating that myocardial injury caused by SARS-Cov-2 correlates with the severity of pulmonary invasion. A recent study showed that SARS-Cov-2 can cause myocardial fibrosis and myocardial contractile dysfunction via prolonged inhibition of mitochondrial metabolism [16] . In a recent study by Nchioua et al in cardiomyocytes differentiated from human induced pluripotent stem cells (iPSC) [17] , human cardiomyocytes could be infected by a variety of SARS-Cov-2 subvariants, including the early variant NL-02-2020, delta and omicron (BA.1, BA.2 and BA.5); viral replication generally achieved Precise prevalence of myocarditis caused by COVID-19 is unknown due to a lack of specific diagnostic measures for assessing myocarditis.…”

Induction of the inflammasome by the SARS-CoV-2 accessory protein ORF9b, abrogated by small-molecule ORF9b homodimerization inhibitors

“…Host-virus interactome analyses have uncovered human proteins that physically associate with SARS-CoV-2 proteins and that may participate in the virus life cycle, infection, replication, and budding (4)(5)(6)(7)(8)(9). Among these, interactions with mitochondrial proteins are particularly abundant.…”