key: cord-0841661-1oi97w3e authors: Ilias, Ioannis; Kaltsas, Gregory; Barkas, Konstantinos; Chrousos, George P. title: Inherited/Genetically-Associated Pheochromocytoma/ Paraganglioma Syndromes and COVID-19 date: 2021-09-28 journal: Medicina (Kaunas) DOI: 10.3390/medicina57101033 sha: 7b5d331a6d2e23edc15de33cc9f43ab25dd23568 doc_id: 841661 cord_uid: 1oi97w3e In some subjects with inherited pheochromocytoma/paraganglioma (PPG) syndromes, hypoxia-inducible factor 1 alpha (HIF1α) stabilization/activation could lead to an increase in angiotensin converting enzymes (ACE). This would result in the stimulation of angiotensin (AT) II production and, hence, reduce the availability of ACE 2. The latter would provide decreased numbers of binding sites for the spike protein of SARS-CoV-2 and, therefore, result in less points of viral entry into cells. Thus, subjects with HIF1α-associated PPG syndromes may benefit from an inherent protective effect against COVID-19. Such an implication of HIF1α vis-à-vis COVID-19 could open ways of therapeutic interventions. The diagnosis and treatment of pheochromocytomas/paragangliomas (PPG) can be challenging [1] ; concomitant COVID-19 can render these tasks more difficult [2] . Inherited/genetically associated PPG syndromes, particularly those caused by mutations in the succinate dehydrogenase (SDH) B or D genes or the von Hippel-Lindau (VHL) gene, are associated with the stabilization/activation of the hypoxia-inducible factor 1 alpha (HIF1α). This factor is implicated in promoting angiogenesis and tumour growth [3, 4] . High-altitude dwelling with hypoxia may lead to physiological adaptations that include morphological and functional alterations in the carotid bodies, HIF1α stabilization/activation and upregulation of angiotensin-converting enzyme (ACE) expression [5] [6] [7] [8] [9] [10] . Recent reports indicate that living in high altitudes entails some degree of protection from SARS-CoV-2 infection/COVID-19, possibly by intermittent activation of HIF1α [11] [12] [13] . The latter also suppresses the expression of angiotensin-converting enzyme 2 (ACE2), which is the receptor that permits the cellular entry of SARS-CoV-2 [14] [15] [16] . Bearing all the above in mind, in some subjects with inherited PPG syndromes, HIF1α stabilization/activation could lead to an increase in ACE. This would result in stimulation of angiotensin (AT) II production and, hence, reduced availability of ACE 2. The latter would provide decreased numbers of binding sites for the spike protein of SARS-CoV-2 and, therefore, less points of viral entry into cells. Thus, subjects with HIF1α-associated PPG syndromes may benefit from an inherent protective effect against COVID-19. A study of PPG patients that are followed in specialized centres worldwide would be informative; Addressing delays in the diagnosis of pheochromocytoma/paraganglioma Catecholamine physiology and its implications in patients with COVID-19 Mutation of SDHB is a cause of hypoxia-related high-altitude paraganglioma What Have We Learned from Molecular Biology of Paragangliomas and Pheochromocytomas? Physiological Effects of Chronic Hypoxia Hypoxia Inducible Factor Pathway and Physiological Adaptation: A Cell Survival Pathway? Human high-altitude adaptation: Forward genetics meets the HIF pathway Adapting to high altitude by mutating EPAS-1, the gene encoding HIF-2α The molecular response Role of HIF-1alpha in the regulation ACE and ACE2 expression in hypoxic human pulmonary artery smooth muscle cells Impact of altitude on COVID-19 infection and death in the United States: A modeling and observational study Lower Incidence of COVID-19 at High Altitude: Facts and Confounders Does the pathogenesis of SARS-CoV-2 virus decrease at high-altitude? Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate HIF-1α, and COVID-19: From pathogenic factors to potential therapeutic targets Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor