Abstract
Type 2 diabetes (T2D) patients with SARS-CoV-2 infection hospitalized develop an acute cardiovascular syndrome. It is urgent to elucidate underlying mechanisms associated with the acute cardiac injury in T2D hearts. We performed bioinformatic analysis on the expression profiles of public datasets to identify the pathogenic and prognostic genes in T2D hearts. Cardiac RNA-sequencing datasets from db/db or BKS mice (GSE161931) were updated to NCBI-Gene Expression Omnibus (NCBI-GEO), and used for the transcriptomics analyses with public datasets from NCBI-GEO of autopsy heart specimens with COVID-19 (5/6 with T2D, GSE150316), or dead healthy persons (GSE133054). Differentially expressed genes (DEGs) and overlapping homologous DEGs among the three datasets were identified using DESeq2. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses were conducted for event enrichment through clusterProfile. The protein-protein interaction (PPI) network of DEGs was established and visualized by Cytoscape. The transcriptions and functions of crucial genes were further validated in db/db hearts. In total, 542 up-regulated and 485 down-regulated DEGs in mice, and 811 up-regulated and 1399 down-regulated DEGs in human were identified, respectively. There were 74 overlapping homologous DEGs among all datasets. Mitochondria inner membrane and serine-type endopeptidase activity were further identified as the top-10 GO events for overlapping DEGs. Cardiac CAPNS1 (calpain small subunit 1) was the unique crucial gene shared by both enriched events. Its transcriptional level significantly increased in T2D mice, but surprisingly decreased in T2D patients with SARS-CoV-2 infection. PPI network was constructed with 30 interactions in overlapping DEGs, including CAPNS1. The substrates Junctophilin2 (Jp2), Tnni3, and Mybpc3 in cardiac calpain/CAPNS1 pathway showed less transcriptional change, although Capns1 increased in transcription in db/db mice. Instead, cytoplasmic JP2 significantly reduced and its hydrolyzed product JP2NT exhibited nuclear translocation in myocardium. This study suggests CAPNS1 is a crucial gene in T2D hearts. Its transcriptional upregulation leads to calpain/CAPNS1-associated JP2 hydrolysis and JP2NT nuclear translocation. Therefore, attenuated cardiac CAPNS1 transcription in T2D patients with SARS-CoV-2 infection highlights a novel target in adverse prognostics and comprehensive therapy. CAPNS1 can also be explored for the molecular signaling involving the onset, progression and prognostic in T2D patients with SARS-CoV-2 infection.
Highlights
Type 2 diabetes (T2D) as a chronic medical condition is one of the most important risk factors for adverse outcomes of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1–4]
Our results reveal that attenuated cardiac CAPNS1 transcription in T2D patients who succumbed to SARS-CoV-2 infection highlights a novel event in adverse prognostics, and provide for a more detailed molecular mechanism underlying the acute cardiac injury of occurrence and progression in T2D patients with SARS-CoV-2 infection
The gene expression profiles in public datasets from NCBI-GEO were analyzed to identify differentially expressed genes (DEGs) in the heart tissues between T2D mice and control, as well as T2D patients who succumbed to SARS-CoV-2 infection [18] and control (Figure 1A)
Summary
Type 2 diabetes (T2D) as a chronic medical condition is one of the most important risk factors for adverse outcomes of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1–4]. SARS-CoV-2 directly infects cardiomyocytes in vitro or in T2D patients in an ACE2-dependent manner [6, 11]. SARS-CoV-2 may cause pleiotropic alterations of glucose metabolism that could complicate the pathophysiology of preexisting diabetes or lead to new mechanisms of disease [10]. That means the increased susceptibility of hearts themselves in T2D patients is directly involved in the adverse outcomes of COVID-19, SARS-CoV-2 infection alone could cause clotting issues in the coronaries. Acute cardiac injury in T2D appears as one of the leading causes of severe disease and death in patients with COVID-19 [4, 9]. The significance of important mediating mechanism for the acute COVID-19 cardiovascular syndrome in T2D patients has not been fully illuminated
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