Single-cell Transcriptome Analysis Indicates New Potential Regulation Mechanism of ACE2 and NPs signaling among heart failure patients infected with SARS-CoV-2

Abstract

AbstractThe coronavirus disease 2019 (COVID-19) has resulted in high morbidity and mortality worldwide since December 2019. Recent studies showed that patients with previous heart disease, especially heart failure (HF), whose plasma Natriuretic Peptides (NPs) concentrations are higher, were more susceptible to SARS-CoV-2 infection. In this study, we retrospectively analyzed single-center case series of 91 patients with COVID-19 in China. 46 (50.5%) patients exhibited cardiac dysfunction as indicated by elevated Natriuretic Peptides B (BNP) levels. Moreover, the results indicate that patients with cardiac dysfunction had higher mortality than those without cardiac dysfunction. Nonetheless, it remains unclear as to how the virus infects the heart, especially in HF patients and why a higher level of BNP in the heart dampen inflammation. Angiotensin-converting enzyme 2 (ACE2), the critical host cellular receptor of SARS-CoV-2, expresses in different organs. Still, its cellular distribution in the human heart, especially in patients with HF remains unclear. Thus, we investigated ACE2 gene expression pattern in single-cell RNA sequence (scRNA-seq) data of hearts from normal adults versus patients with HF. Our results indicate that ACE2 is predominantly enriched in cardiomyocytes (CMs), endothelial cells, fibroblasts and smooth muscle cells in normal heart. Not only ACE2+ CMs, but also expression of ACE2 are significantly boosted in CMs of patients with HF. Also, genes related to virus entry, virus replication and suppression of IFN-γ signaling besides ACE2 were up-regulated in HF patient, mainly in CMs, indicating the higher susceptibility to SARS-CoV-2 infection. Interestingly, NPs are significantly up-regulated in ACE2-postive (ACE2+) ventricular myocytes and share the upstream transcription factor. ACE2 and NPs can form a negative feedback loop with protective effects. But it maybe turns into a positive feedback loop by virus and ineffective NPs, which lead to severe prognosis. In summary, the increased expression of ACE2, NPs during HF predisposes to SARS-CoV-2 infection. Modulating the levels of ACE2, NPs therefore may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection.