Specialized Pro-Resolving Mediators as Emerging Players in Cardioprotection: From Inflammation Resolution to Therapeutic Potential

Abstract

Aim: Timely myocardial reperfusion is essential for restoring blood flow to post-ischemic tissue, thereby reducing cardiac injury and limiting infarct size. However, this process can paradoxically result in additional, irreversible myocardial damage, known as myocardial ischemia-reperfusion injury (MIRI). The goal of this review is to explore the role of specialized pro-resolving mediators (SPMs) in atherosclerosis and MIRI, and to assess the therapeutic potential of targeting inflammation resolution in these cardiovascular conditions.

Methods: This review summarizes current preclinical and clinical evidence on the involvement of SPMs in the pathogenesis of atherosclerosis and MIRI, acknowledging that several cellular and molecular aspects of their mechanisms of action remain to be fully elucidated.

Results: MIRI is a complex phenomenon in which inflammation, initially triggered during ischemia and further amplified upon reperfusion, plays a central role in its pathogenesis. Various cellular and molecular players mediate the initial pro-inflammatory response and the subsequent anti-inflammatory reparative phase following acute myocardial infarction (AMI), contributing both to ischemia- and reperfusion-induced damage as well as to the healing process. SPMs have emerged as key endogenous immunoresolvents with potent anti-inflammatory, antioxidant, and pro-resolving properties that contribute to limit excessive acute inflammation and promote tissue repair. While dysregulated SPM-related signaling has been linked to various cardiovascular diseases (CVD), their precise role in AMI and MIRI remains incompletely understood.

Conclusion: Targeting inflammation resolution may represent a promising therapeutic strategy for mitigating atheroprogression and addressing a complex condition such as MIRI.

Keywords: cardioprotection; inflammation; myocardial ischemia/reperfusion; pro‐resolving mediators; signal transduction cardiac function.

FIGURE 1

Mechanisms underlying myocardial ischemia/reperfusion injury (MIRI). The figure illustrates the key events associated with MIRI. During acute myocardial ischemia, oxygen deprivation forces cells to rely on anaerobic respiration, leading to lactate accumulation and a decrease in intracellular pH. Acidosis‐induced activation of the Na⁺/H⁺ exchanger results in Na⁺ overload, which in turn triggers the Na⁺/Ca²⁺ exchanger, causing an increase in intracellular Ca²⁺ levels. These alterations ultimately impair myocardial contractility. Upon reperfusion, oxygen availability is restored, normalizing intracellular pH and reestablishing the Na⁺/H⁺ and Na⁺/Ca²⁺ exchangers. However, excessive reactive oxygen species (ROS) production disrupts sarcoplasmic reticulum (SR) function, leading to hypercontracture, endoplasmic reticulum (ER) stress, and mitochondrial permeability transition pore (MPTP) opening, which induces cardiomyocyte apoptosis. Oxidative stress further amplifies inflammatory and thrombogenic responses, exacerbating myocardial injury.

FIGURE 2

Overview of pro‐inflammatory and anti‐inflammatory responses in myocardial ischemia/reperfusion injury (MIRI). In the acute phase following myocardial infarction (MI), activation of the complement cascade, reactive oxygen species (ROS), and damage‐associated molecular patterns (DAMPs) stimulate toll‐like receptors (TLRs) and inflammasomes, leading to an increased release of cytokines and chemokines. This promotes the recruitment of immune cells to facilitate the clearance of necrotic cell debris. Following reperfusion, balloon and stent dilation, along with distal microembolization, further enhance the local release of inflammatory mediators. This process intensifies immune cell activation, amplifying oxidative stress and inflammatory responses. The initial pro‐inflammatory phase is subsequently followed by an anti‐inflammatory response, during which neutrophils polarize to a reparative phenotype and produce anti‐inflammatory cytokines that contribute to cardiac repair. Specialized pro‐resolving mediators (SPMs) also play a crucial role in this phase by promoting efferocytosis and reducing pro‐inflammatory signaling, supporting tissue healing and inflammation resolution.

FIGURE 3

Implications of Lipoxin A4 (LXA4) in mitigating myocardial ischemia/reperfusion injury (MIRI): Translational evidence. The figure illustrates the cardioprotective effects of LXA4 demonstrated in both in vitro and in vivo studies. LXA4 is synthesized from arachidonic acid and exerts potent anti‐inflammatory and antioxidant effects by binding to the G‐protein–coupled receptor ALX/FPR2, thereby inhibiting free radical generation and the synthesis of pro‐inflammatory mediators. In vitro, LXA4 protects cardiomyocytes from hypoxia/reoxygenation (H/R) injury by upregulating heme oxygenase‐1 (HO‐1), activating the p38/MAPK pathway, modulating K⁺ channels, and promoting the nuclear translocation of Nrf2. In vivo, LXA4 confers cardioprotection in rat models of left anterior descending (LAD) coronary artery ligation‐induced ischemia followed by reperfusion, reducing myocardial inflammation and preventing arrhythmogenesis. Additionally, LXA4 has been shown to preserve myocardial ultrastructure by activating Na⁺‐K⁺ ATPase and Connexin 43 while inhibiting GRP78 and caspase‐12. In rabbit models of myocardial ischemia–reperfusion injury (MIRI), LXA4 suppresses NF‐κB activation, thereby mitigating intramyocardial inflammatory cell infiltration and apoptosis.

FIGURE 4

Potential cardioprotective effects of Resolvin D1 (RvD1) against myocardial ischemia/reperfusion injury (MIRI). This schematic representation outlines the potential mechanisms through which RvD1, a lipid mediator derived from docosahexaenoic acid (DHA), exerts cardioprotection. Early administration of RvD1, but not late administration, has been shown to reduce infarct size and improve left ventricular (LV) function. On the other hand, RvD1 promotes inflammation resolution by enhancing the synthesis of other specialized pro‐resolving mediators (SPMs) and downregulating high‐mobility group box‐1 (HMGB1) and its downstream signaling pathways, including TLR4 and NF‐κB. Moreover, RvD1 activates the pro‐survival PI3K/Akt pathway, which helps restore macrophage‐mediated clearance, reduces neutrophil accumulation in infarcted areas, and limits cell death, thereby contributing to improved cardiac recovery.

FIGURE 5

Specialized pro‐resolving mediators (SPMs) as key emerging players of the inflammatory resolution process in myocardial ischemia/reperfusion injury (MIRI). The figure highlights the potential cardioprotective role of SPMs, including Lipoxin A4 (LXA4), Resolvin D1 (RvD1), Resolvin E1 (RvE1), Maresin 1 (MaR1), and Protectin D1 (PD1), in modulating inflammation and facilitating cardiac repair following acute myocardial infarction (AMI). By reducing pro‐inflammatory mediator production and enhancing the clearance of cellular debris, SPMs contribute to the resolution of inflammation, ultimately conferring protection against MI and MIRI. Furthermore, the figure emphasizes the complex and dynamic spleen–heart cross‐talk, which orchestrates leukocyte trafficking and SPM biosynthesis in both the infarcted myocardium and the spleen after MI, ultimately shaping the delicate balance between inflammatory and pro‐resolving responses.