17(R)-RESOLVIN D1 PROTECTS AGAINST SICKLE CELL-RELATED INFLAMMATORY CARDIOMYOPATHY IN HUMANIZED MICE

• In SCD mice, the unresolved inflammation initiates a cardiac hypertrophic neutrophil-driven response responsible for myocardial fibrosis.

• Treatment with 17R-RvD1-resolvin prevents the H/R induced pathways involved in maladaptive heart remodeling in SS mice.

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.