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Background and Purpose: The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) posed a serious threat to global public health. Hydroxychloroquine (HCQ), which is a derivative of Chloroquine (CQ), was a WHO-recommended drug to treat COVID-19 with mixed effects. The purpose of the present study is to evaluate the plausible mechanisms of HCQ actions behind its observed mixed effect. Key Results: We demonstrate that CQ-treatment significantly up-regulates mesenchymal markers and SARS-CoV-2 receptor ACE2 in cultured endothelial cells. Conclusions & Implications: The detrimental effect of HCQ in seriously ill COVID-19 patients might be due to CQ-induced increased expression of endothelial ACE2 exacerbating the severity of SARS-CoV-2 infection. Our study warrants further investigation in animal models and humans and caution while prescribing HCQ to patients with an impaired renin-angiotensin-aldosterone system, such as in hypertension, cardiovascular diseases, or chronic kidney disease; particularly with ACE-inhibitors or statin therapy.