Ageing Res Rev 2020 Nov 4;64:101201. Does eNOS derived nitric oxide protect the young from severe COVID-19 complications? Shou Ping Guan 1, Raymond Chee Seong Seet 2, Brian K Kennedy 3 Affiliations
1Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
2Division of Neurology, Department of Medicine, National University Hospital, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
3Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Centre for Healthy Longevity, National University Health System, Singapore. Electronic address: firstname.lastname@example.org.
Abstract The COVID-19 pandemic poses an imminent threat to humanity, especially to the elderly. The molecular mechanisms underpinning the age-dependent disparity for disease progression is not clear. COVID-19 is both a respiratory and a vascular disease in severe patients. The damage endothelial system provides a good explanation for the various complications seen in COVID-19 patients. These observations lead us to suspect that endothelial cells are a barrier that must be breached before progression to severe disease. Endothelial intracellular defences are largely dependent of the activation of the interferon (IFN) system. Nevertheless, low type I and III IFNs are generally observed in COVID-19 patients suggesting that other intracellular viral defence systems are also activated to protect the young. Intriguingly, Nitric oxide (NO), which is the main intracellular antiviral defence, has been shown to inhibit a wide array of viruses, including SARS-CoV-1. Additionally, the increased risk of death with diseases that have underlying endothelial dysfunction suggest that endothelial NOS-derived nitric oxide could be the main defence mechanism. NO decreases dramatically in the elderly, the hyperglycaemic and the patients with low levels of vitamin D. However, eNOS derived NO occurs at low levels, unless it is during inflammation and co-stimulated by bradykinin. Regrettably, the bradykinin-induced vasodilation also progressively declines with age, thereby decreasing anti-viral NO production as well. Intriguingly, the inverse correlation between the percentage of WT eNOS haplotype and death per 100K population could potentially explain the disparity of COVID-19 mortality between Asian and non-Asian countries. These changes with age, low bradykinin and NO, may be the fundamental reasons that intracellular innate immunity declines with age leading to more severe COVID-19 complications. Keywords: Bradykinin (BK); COVID-19; Endothelial cells (ECs); Endothelial nitric oxide synthase (eNOS); Nitric oxide (NO).
Fig. 1 Correlation between COVID-19 death per 100 K population and the percent of NOS3 WT haplotype. The death per 100k was based on John Hopkins University Coronavirus Resources Centre and the US data was based on CDC COVID data tracker and U.S. Census Bureau. data (as of Oct 16, 2020). The reference for the percent of WT NOS3 haplotype was based on reference shown below: China (Han Chinese) (Qi et al., 2020), South Korea (Shim et al., 2010), India (Nishank et al., 2013), Saudi Arabia (Alkharfy et al., 2012), Columbian (Average of Black and White) (Serrano et al., 2010), US (White, Black) (Thomas et al., 2013), Brazil (Sandrim et al., 2006), Spain (Amoli et al., 2003).