Potential Treatments for PAH Patients With COVID-19 Identified
Spotted via computer analyses of biological processes common to both diseases
Dozens of medicines with the potential to treat pulmonary arterial hypertension (PAH) patients ill with COVID-19 were identified through computer analyses of the biological processes shared by both conditions, a pilot study reported.
Disease-related features common to COVID-19 and PAH included inflammation, fibrosis (tissue scarring), hypoxia (low oxygen), immune responses, blood clotting, and oxidative stress, or tissue damage caused by highly reactive molecules that contain oxygen.
The pilot study, “Uncovering Common Pathobiological Processes between COVID-19 and Pulmonary Arterial Hypertension by Integrating Omics Data,” was published in the journal Pulmonary Circulation.
Study into gene activity, protein interactions shared by PAH and COVID-19
PAH is a progressive disorder marked by high blood pressure caused by the narrowing of pulmonary arteries, the blood vessels that supply the lungs.
Coronavirus disease 2019 (COVID-19) is caused by a SARS-CoV-2 viral infection, with severity ranging from asymptomatic to critical. A higher risk of severe disease and mortality exists among people with high blood pressure, diabetes, and certain lung conditions. In addition, COVID-19 can cause long-term lung complications, including pulmonary fibrosis (lung tissue scarring) and PAH.
Although several studies have addressed comorbidities (co-existing conditions) underlying COVID-19 and its complications affecting the heart and lungs, the common molecular mechanisms driving these processes have yet to be thoroughly examined.
Investigators at Harvard Medical School, in Massachusetts, set out to identify pathways common to COVID-19 and PAH by using computers to analyze large datasets containing information on gene activity and protein interactions.
The team first collected data on 332 proteins that bind to 26 proteins from the SARS-CoV-2 virus. Among these, 326 mapped onto the human interactome — the set of all protein-to-protein interactions in human cells.
Mapping a set of 357 PAH-related genes to the human interactome identified eight proteins with overlap between COVID-19 and PAH. Some common functional features among these proteins were related to a response to oxygen levels and oxidative stress.
Consistently, “a few studies have shown that COVID-19 patients have severely increased levels of oxidative stress and oxidant damage,” the investigators noted.
Similarities between the interaction data for COVID-19 and PAH prompted the researchers to explore changes in gene expression (activity) in immune cells and lung tissue induced by both conditions. Genes with altered activity levels are known as differentially expressed genes (DEGs).
Immune cells affected by both diseases shared 451 DEGs, many of which are involved in immune responses. Likewise, lung tissue samples showed 728 overlapping DEGs between COVID-19 and PAH, also involved in immune responses as well as metabolism.
Mapping the common DEGs in immune cells identified 128 proteins and 126 interactions, called networks, representing impaired biological processes in immune cells induced by both COVID-19 and PAH. Similarly, lung tissue DEGs generated a network of 209 proteins and 197 interactions, reflecting common lung tissue alterations in both conditions.
Common characteristics of DEGs shared by the two diseases included inflammation, fibrosis, hypoxia, oxidative stress, immune responses, and blood clots.
“We found that … SARS-CoV-2 infection-induced gene expression overlaps significantly with PAH-induced gene expression in both PBMCs [peripheral blood mononuclear cells or immune cells] and lung tissue,” the researchers wrote.
42 medicines show potential to treat PAH patients with COVID-19
Proteins that regulate gene expression, which are themselves altered by COVID-19 and PAH, also were discovered. These proteins include RUNX1, HIF1A, and STAT1 in immune cells and HIF1A, JUN, STAT3, RFX5, NFKB1 in lung tissue.
Finally, the researchers searched for existing or investigational medicines that might be repurposed to treat COVID-19 in PAH patients. More than 700 medicines with measured efficacy against COVID-19 were screened to determine whether their protein targets fell within the shared COVID-19 and PAH networks.
With immune cells, 30 medicines showed common COVID-19 and PAH networks, while in lung tissue, 21 matching medications were identified, with nine common to both sample types.
Overall, 42 medicines show a potential to be “particularly useful” in treating COVID-19 patients with PAH, the researchers noted.
“The identified common molecular alterations and pathways could potentially accelerate drug development and shed light on the design of tailored treatment for COVID-19 patients with PAH as a comorbidity,” the researchers wrote.
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