Highlights d Osteolectin interacts with Fap and inhibits its protease activity d Genetic deletion of Fap ameliorates bone loss in aged mice d Pharmacological inhibition of Fap attenuates ovariectomyinduced osteoporosis d Osteolectin inhibits Fap to promote mineralization during zebrafish development

33Background: COVID-19 patients with comorbidities such as hypertension or heart failure (HF) are 34 associated with poor clinical outcomes. Angiotensin-converting enzyme 2 (ACE2), the critical enzyme 35 for SARS-CoV-2 infection, is broadly expressed in many organs including heart. However, the cellular 36 distribution of ACE2 in the human heart, particularly the failing heart is unknown. 37Methods: We analyzed single-cell RNA sequencing (scRNA-seq) data in both normal and failing hearts, 38 and characterized the ACE2 gene expression profile in various cell subsets, especially in cardiomyocyte : medRxiv preprint 3 subsets, as well as its interaction with gene networks relating to various defense and immune responses 40 at the single cell level. 41Results: The results demonstrated that ACE2 is present in cardiomyocytes (CMs), endothelial cells, 42 fibroblasts and smooth muscle cells in the heart, while the number of ACE2-postive (ACE2+) CMs and 43 ACE2 gene expression in these CMs are significantly increased in the failing hearts. Interestingly, both 44 brain natriuretic peptides (BNP) and atrial natriuretic peptide (ANP) are significantly up-regulated in 45 the ACE2+ CMs. Further analysis shows that ANP, BNP and ACE2 may form a negative feedback loop 46 with a group of genes associated with the development of heart failure. To our surprise, we found that 47