17(R)-Resolvin D1: a novel approach for SCD cardiomyopathy

In this issue of Blood, Federti et al¹ show that, in a humanized mouse model of sickle cell disease (SCD), cardiomyocyte dysfunction is driven by unresolved inflammation due to hypoxia/reoxygenation (H/R) stress, which can be mitigated by 17(R)-resolvin D1 (17R-RvD1).

SCD is associated with a unique cardiomyopathy characterized by cardiomyocyte hypertrophy, myocardial fibrosis, and inflammation, leading to ventricular dilation, restrictive filling (diastolic dysfunction), and increased propensity for ventricular arrhythmia.² The possible role of subclinical acute transient myocardial ischemia during acute sickle cell–related vaso-occlusive crises has been suggested, but the mechanisms leading from this ischemia to SCD cardiomyopathy are not fully understood. In their study, Federti et al probed SCD cardiomyopathy by integrated omics using a humanized SCD mouse model exposed to H/R, mimicking acute vaso-occlusive crises. In mice exposed to H/R, a neutrophil-driven cardiac hypertrophic response is initiated by cardiac proinflammatory pathways. The study shows that unresolved inflammation is crucial in pathologic heart remodeling in SCD mice exposed to H/R stress.

The model was subsequently used to examine the effect of 17R-RvD1. The compound is an equipotent epimer of resolvin D1 (RvD1); however, unlike RvD1, 17R-RvD1 is not inactivated by eicosanoid oxidoreductase.³ The use of this compound allows reliable activating RvD1 signaling mediated by 2 G-protein–coupled receptors, ALX/FPR2 and GPR32, which regulate multiple target genes via specific microRNAs.⁴ Previous research by the same authors demonstrated the potential of resolvins in addressing SCD-associated inflammation, showing that 17R-RvD1 reduced systemic and local inflammation and vascular dysfunction in the lungs and kidneys of SCD mice exposed to H/R.⁵ Their current study shows that 17R-RvD1 mitigates NF-κB activation, suppresses fibrosis via platelet-derived growth factor subunit B receptor (PDGFB-R) and transforming growth factor (TGF)-β1/Smad2-3 pathways, modulates hypoxia-inducible factor (HIF)-dependent angiogenesis, and alleviates H/R-induced proapoptotic signatures, highlighting its multifaceted cardioprotective effects.

The finding that 17R-RvD1 inhibits the activation of NF-κB p65, an essential transcription factor in inflammation, is vital. NF-κB activation is linked to cardiac inflammation and remodeling. Continuous activation of NF-κB, especially the p65 subunit, worsens cardiac remodeling by inducing proinflammatory, profibrotic, and proapoptotic effects in cardiomyocytes. Such activation results in higher levels of inflammatory cytokines, contributing to detrimental cardiac remodeling and dysfunction (see figure). Suppressing NF-κB activation has been shown to enhance cardiac function, decrease ventricular dilation and hypertrophy, and improve survival rates in animal heart failure models.⁶ Furthermore, NF-κB activation plays a role in shifting the endoplasmic reticulum stress response from adaptive to proapoptotic, leading to cardiomyocyte death.⁶ Inhibiting NF-κB activation can reduce the expression and activity of matrix metalloproteinases like MMP-9, contributing to pathologic cardiac remodeling.⁷ By preventing NF-κBp65 activation, 17R-RvD1 may alleviate these adverse effects, potentially lowering inflammation, fibrosis, and cardiomyocyte apoptosis associated with SCD-related cardiomyopathy.

17R-RvD1 has demonstrated protection against myocardial fibrosis by suppressing the PDGFB-R and TGF-β1/Smad2-3 pathways induced by H/R. These pathways play a critical role in the fibrotic processes of the heart, and their inhibition may help prevent maladaptive cardiac remodeling. TGF-β1 activates Smad2 and Smad3 via phosphorylation (see figure). Once activated, Smad2/3 facilitates myofibroblast proliferation, migration, and extracellular matrix (ECM) production. Smad3 is a crucial mediator for ECM production and tissue fibrosis; inhibiting this pathway can decrease collagen deposition and cardiac fibrosis.⁸ In addition, PDGF signaling intersects with TGF-β pathways to modulate fibroblast activation, where PDGF encourages fibroblast proliferation and ECM production.⁸ The protective effects of 17R-RvD1 arise from its ability to inhibit these pathways, potentially leading to reduced myofibroblast activation and proliferation, ECM protein production, and collagen deposition. Such inhibition may prevent the transition of cardiac fibroblasts into myofibroblasts, ultimately contributing to decreased cardiac fibrosis and enhanced heart function. By targeting PDGFB-R and TGF-β1/Smad2-3 pathways, 17R-RvD1 effectively tackles various facets of the fibrotic process, potentially providing more comprehensive protection against maladaptive cardiac remodeling.

17R-RvD1's ability to reduce HIF-dependent proangiogenic signaling is crucial in preventing harmful cardiac remodeling through various mechanisms. HIF-1, a key regulator of angiogenesis, oversees multiple proangiogenic pathways. By suppressing HIF-dependent signaling, 17R-RvD1 may block excessive or uncontrolled angiogenesis. HIF-1 also enhances the expression of vascular endothelial growth factor, a vital element in the angiogenesis process. Lowering HIF signaling can diminish levels of vascular endothelial growth factor, which may restrict abnormal blood vessel formation. HIF-1 activation increases vascular permeability, as well as the proliferation and migration of endothelial cells. By moderating these activities, 17R-RvD1 may avert the development of immature or leaky vessels. Prolonged activation of HIF-1α can cause cardiomyopathy and a decline in myocardial contractile function. Thus, by modulating HIF signaling, 17R-RvD1 may help balance essential and harmful angiogenesis. HIF-1 also controls several genes related to vascular remodeling. By diminishing HIF-dependent signaling, 17R-RvD1 could support maintaining standard vascular structure and function. Ultimately, by regulating these HIF-dependent processes, 17R-RvD1 may prevent the excessive or disorganized angiogenesis that leads to adverse cardiac remodeling associated with SCD-related cardiomyopathy.

17R-RvD1 alleviates H/R-induced proapoptotic signatures in cardiomyocytes through multiple mechanisms: NF-κB inhibition, which prevents NF-κB p65 activation and suppresses proapoptotic gene expression; mitochondrial protection, likely preserving mitochondrial integrity to reduce cytochrome c release and subsequent caspase activation; anti-inflammatory effects (see figure), which lower inflammatory cytokine production and decrease activation of the extrinsic apoptotic pathway⁹; oxidative stress reduction, potentially lowering reactive oxygen species levels that trigger apoptosis; activation of survival pathways, enhancing prosurvival signaling pathways like phosphatidylinositol 3-kinase/Akt; and caspase inhibition, as 17R-RvD1 suppresses the expression of caspases, crucial enzymes in executing apoptosis. By curtailing cardiomyocyte apoptosis, 17R-RvD1 plays a role in preserving cardiac muscle mass and function, potentially slowing the progression of SCD-related cardiomyopathy.

Federti and colleagues have comprehensively examined the cardiac-specific molecular pathways affected by RvD1 in SCD, in contrast to earlier studies that focused on systemic effects or other organs. The study incorporates miRNA analysis, showing that 17R-RvD1 impacts the miRNAome, offering a fresh perspective on its mechanism of action. Although earlier research has addressed anti-inflammatory properties, the current study underscores the role 17R-RvD1 in promoting inflammation resolution, a crucial factor in preventing chronic cardiac injury. Finally, the authors have explicitly addressed the effects of 17R-RvD1 on perivascular fibrosis, a key element in cardiac remodeling related to SCD. The ability of 17R-RvD1 to modulate multiple pathways involved in maladaptive cardiac remodeling suggests its potential as a multifaceted treatment strategy. Further studies are needed to translate these findings to clinical applications, but the results provide a promising foundation for developing novel therapies to improve cardiovascular outcomes in SCD patients.

Conflict-of-interest disclosure: The authors declare no competing financial interests.