Bos, J. Martijn and Hebl, Virginia B. and Oberg, Ann L. and Sun, Zhifu and Herman, Daniel S. and Teekakirikul, Polakit and Seidman, Jonathan G. and Seidman, Christine E. and dos Remedios, Cristobal G. and Maleszewski, Joseph J. and Schaff, Hartzell V. and Dearani, Joseph A. and Noseworthy, Peter A. and Friedman, Paul A. and Ommen, Steve R. and Brozovich, Frank V. and Ackerman, Michael J. (2020) Marked Up-Regulation of ACE2 in Hearts of Patients With Obstructive Hypertrophic Cardiomyopathy: Implications for SARS-CoV-2–Mediated COVID-19. Mayo Clinic Proceedings, 95. p. 7. ISSN 00256196
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Abstract
Objective: To explore the transcriptomic differences between patients with hypertrophic cardiomyopathy (HCM) and controls.
Patients and methods: RNA was extracted from cardiac tissue flash frozen at therapeutic surgical septal myectomy for 106 patients with HCM and 39 healthy donor hearts. Expression profiling of 37,846 genes was performed using the Illumina Human HT-12v3 Expression BeadChip. All patients with HCM were genotyped for pathogenic variants causing HCM. Technical validation was performed using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. This study was started on January 1, 1999, and final analysis was completed on April 20, 2020.
Results: Overall, 22% of the transcriptome (8443 of 37,846 genes) was expressed differentially between HCM and control tissues. Analysis by genotype revealed that gene expression changes were similar among genotypic subgroups of HCM, with only 4% (1502 of 37,846) to 6% (2336 of 37,846) of the transcriptome exhibiting differential expression between genotypic subgroups. The qRT-PCR confirmed differential expression in 92% (11 of 12 genes) of tested transcripts. Notably, in the context of coronavirus disease 2019 (COVID-19), the transcript for angiotensin I converting enzyme 2 (ACE2), a negative regulator of the angiotensin system, was the single most up-regulated gene in HCM (fold-change, 3.53; q-value =1.30×10-23), which was confirmed by qRT-PCR in triplicate (fold change, 3.78; P=5.22×10-4), and Western blot confirmed greater than 5-fold overexpression of ACE2 protein (fold change, 5.34; P=1.66×10-6).
Conclusion: More than 20% of the transcriptome is expressed differentially between HCM and control tissues. Importantly, ACE2 was the most up-regulated gene in HCM, indicating perhaps the heart's compensatory effort to mount an antihypertrophic, antifibrotic response. However, given that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 for viral entry, this 5-fold increase in ACE2 protein may confer increased risk for COVID-19 manifestations and outcomes in patients with increased ACE2 transcript expression and protein levels in the heart.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 02 Jun 2020 03:51 |
| Last Modified: | 29 Jan 2021 03:54 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/981 |
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