Cardiovascular disease has been recognized as the main cause of death in adults with sickle cell disease (SCD). Although the exact mechanism linking SCD to cardiomyopathy remains elusive, a possible role of subclinical acute transient myocardial ischemia during acute sickle-cell-related vaso-occlusive-crisis (VOCs) has been suggested. We approached SCD cardiomyopathy by integrated omics using humanized SS mice exposed to hypoxia/reoxygenation stress (10 hours hypoxia followed by 3 hours reoxygenation, H//R), mimicking acute-VOCs. In SS mice exposed to H/R, a neutrophil-driven cardiac hypertrophic response is initiated by cardiac pro-inflammatory pathways, intersecting proteins and miRNA involved in pro-fibrotic signaling. This response may be facilitated by locally unresolved inflammation. We then examined the effect of 17R-Resolvin-D1 (17R-RvD1), a member of the specialized pro-resolving-lipid mediator superfamily, administration on H/R activated pro-fibrotic and pro-angiogenic pathways. In SS mice, we found that 17R-RvD1 (i) modulates miRNAome
(ii) prevents the activation of NF-kBp65
(iii) protects against the H/R induced activation of both PDGFB-R and TGF-b1/Smad2-3 canonical pathways
(iv) reduces the expression of HIF-dependent pro-angiogenic signaling
(v) decreases the H/R induced pro-apoptotic cell signature. The protective role of 17R-RvD1 against H/R induced maladaptive heart remodeling was supported by the reduction of Gal-3, pro-collagen-C-proteinase-enhancer-1, endothelin-1 expression and perivascular fibrosis in SS mice at 3 days after H/R stress when compared to vehicle-treated SS animals. Collectively our data support the novel role of unresolved inflammation in pathologic heart remodeling in SCD mice in response to H/R stress. Our study provides new evidence for protective effects of 17R-RvD1 against SCD-related cardiovascular disease.