Single-Cell Transcriptome Analysis Decipher New Potential Regulation Mechanism of ACE2 and NPs Signaling Among Heart Failure Patients Infected With SARS-CoV-2

Abstract

Aims: COVID-19 patients with comorbidities such as hypertension or heart failure (HF) are associated with poor clinical outcomes. The cellular distribution of Angiotensin-converting enzyme 2 (ACE2), the critical enzyme for SARS-CoV-2 infection, in the human heart is unknown. We explore the underlying mechanism that leads to increased susceptibility to SARS-CoV-2 in patients with cardiovascular diseases and patients of cardiac dysfunction have increased risk of multi-organ injury compared with patients of normal cardiac function.Methods and Results: We analyzed single-cell RNA sequencing (scRNA-seq) data in both normal and failing hearts. The results demonstrated that ACE2 is present in cardiomyocytes (CMs) and non-CMs, while the number of ACE2-postive (ACE2+) CMs and ACE2 gene expression in these CMs are significantly increased in the failing hearts. Interestingly, both brain natriuretic peptides (BNP) and atrial natriuretic peptide (ANP) are significantly up-regulated in the ACE2+ CMs, which is consistent with other studies that ACE2, ANP, and BNP increased in HF patients. We found that genes related to virus entry, virus replication and suppression of interferon-gamma signaling are all up-regulated in failing CMs, and the increase was significantly higher in ACE2+ CMs, suggesting that these CMs may be more vulnerable to virus infection. As the level of expression of both ACE2 and BNP in CMs were up-regulated, we further performed retrospective analysis of the plasma BNP levels and clinical outcomes of 91 COVID-19 patients from a single-center. Patients with higher plasma BNP were associated with significantly higher mortality and expression levels of inflammatory and infective markers.Conclusion: In the failing heart, the upregulation of ACE2 and virus infection associated genes could potentially facilitate SARS-CoV-2 virus entry and replication in these vulnerable cardiomyocyte subsets. COVID-19 patients with higher plasma BNP levels had poorer clinical outcomes. These observations may allude to a potential regulatory association between ACE2 and BNP in mediating myocarditis associated with COVID-19.

A Contemporary View of Natriuretic Peptides in the SARS-CoV-2 Era

“…Herein, ACE2 was found to be expressed in cardiomyocytes, vascular endothelial cells, fibroblasts, smooth muscle cells and immune cells in normal hearts, and its expression further increased in several cell subsets of the failing hearts (Ma et al, 2021). Importantly, BNP and ANP expression was upregulated in the more vulnerable ACE2-positive cardiomyocytes of failing hearts, along with a subset of genes favoring the viral infection (Ma et al, 2021). Although the latter evidence did not establish the exact type of relationship between ACE2 and NPs expression toward the virus entry and infection of the heart, it further suggested that NPs and ACE2 are tightly linked and may play an important role in the SARS-CoV-2 disease of HF patients.…”

“…The precise role of NPs at the heart level in the context of SARS-CoV-2 infection remains to be established. The only study investigating a potential link of NPs with SARS-CoV-2 within the heart was conducted by performing a single-cell RNA sequencing (scRNA-seq) in both normal and failing hearts (Ma et al, 2021). Herein, ACE2 was found to be expressed in cardiomyocytes, vascular endothelial cells, fibroblasts, smooth muscle cells and immune cells in normal hearts, and its expression further increased in several cell subsets of the failing hearts (Ma et al, 2021).…”

“…The only study investigating a potential link of NPs with SARS-CoV-2 within the heart was conducted by performing a single-cell RNA sequencing (scRNA-seq) in both normal and failing hearts (Ma et al, 2021). Herein, ACE2 was found to be expressed in cardiomyocytes, vascular endothelial cells, fibroblasts, smooth muscle cells and immune cells in normal hearts, and its expression further increased in several cell subsets of the failing hearts (Ma et al, 2021). Importantly, BNP and ANP expression was upregulated in the more vulnerable ACE2-positive cardiomyocytes of failing hearts, along with a subset of genes favoring the viral infection (Ma et al, 2021).…”

COVID-19 and myocarditis: a review of literature

“…Furthermore, it has been demonstrated that failing hearts show greater expression of ACE2 proteins than normal [ 45 – 47 ]. The higher concentrations of ACE2 in these hearts may allow for easier uptake of the SARS-CoV-2 virus [ 46 ]. As the heart is the first organ encountered by pulmonary outflow, the SARS-CoV-2 virus is likely to encounter ACE2 expressing cardiomyocytes in patients with cardiovascular disease [ 45 ].…”

Uptake of severe acute respiratory syndrome coronavirus 2 spike protein mediated by angiotensin converting enzyme 2 and ganglioside in human cerebrovascular cells

“…The spike protein (SP) of SARS-CoV-2 is a structural protein, which is assemble as a trimer of the heterodimer (S1-S2), that protrudes from the viral surface to give it the crown-like appearance ( Gordon et al, 2020 ; Li et al, 2020 ). The S1 unit contains a receptor binding domain (RBD), which promotes attachment to host cells via facilitators, such as to the extracellular peptidase domain on angiotensin converting enzyme 2 receptor (ACE2), the main receptor for SARS-CoV-2 ( Hamming et al, 2004 ; Doobay et al, 2007 ; Hoffmann et al, 2020 ; Perrotta et al, 2020 ; Ma et al, 2021 ). TMPRESS 2 (transmembrane protease, serine 2) on the host cells cleaves the SP to promote viral entry into cells ( Matsuyama et al, 2020 ).…”