Specialized Proresolving Lipid Mediators: A Potential Therapeutic Target for Atherosclerosis Int. J. Mol. Sci. 2022, 23(6), 3133 Received: 3 February 2022 / Revised: 8 March 2022 / Accepted: 9 March 2022 / Published: 15 March 2022 https://www.mdpi.com/1422-0067/23/6/3133/htm
Unresolved inflammation has been proven to play a causal role in the onset of CVD [12]. As such, a clear understanding of these endogenous inflammatory processes is critical to pinpoint the cause behind the continuous nonresolution of cardiovascular inflammation [13]. To this end, CVD research has recently focused on specialized pro resolving lipid mediators (SPMs) as bioactive compounds capable of reducing the characteristic inflammatory state that affects CVD patients [14]. SPMs have been shown to mitigate disease progression in CVD by modulating various molecular pathways which are involved in CVD pathogenesis [15,16,17,18]. This review aims to describe the role of SPMs in the inflammatory response and the molecular pathways they mediate, along with gathering and reporting evidence from cardiovascular experimental studies, specifically in the field of atherosclerosis and intimal hyperplasia.
The E-series resolvins are formed from the metabolism of the omega-3 polyunsaturated fatty eicosapentaenoic acid (EPA)
SPMs appear to be valuable therapeutic alternatives in treating reperfusion injury by having numerous anti-inflammatory and cardio-protective effects and benefits regarding the repair and regeneration of affected tissue. Moreover, the protective effects of SPMs are not limited to the heart, having been described within the setting of ischemia in other tissues such as the brain, kidneys and liver, suggesting their potential use in situations such as myocardial infarction stroke, among others [117].
6. SPMs as Therapeutic Target in Atherosclerosis The essential role that SPMs play in CVD inflammation resolution opens the door for new therapeutic strategies based on SPM positive regulation [118,119]. In this sense, preclinical and in vitro studies have shown how proresolution pharmacology can promote local and systemic anti-inflammation, significantly reducing the consequences of a poorly controlled inflammatory process.
A study named REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) found that an EPA-only formulation lowered a composite of cardiovascular events by 25% in patients with established cardiovascular disease or diabetes mellitus and other cardiovascular risk factors [125]. Several reports have also shown that in mice fed a diet enriched in omega-3 polyunsaturated fatty acids, endogenous arachidonic acid and EPA production through desaturation of the upstream precursor omega-6 and omega-3 fatty acids, respectively, are needed to favor SPM formation [126].
On the other hand, human studies have not shown adequate levels of SPMs after dietary supplementation with fish oil in healthy volunteers [127]. Furthermore, in the study that detected aspirin-triggered SPMs in patients with diabetes and coronary artery disease, the dosage was three times higher than the conventional one. This proves that the exogenous administration of these molecules must not be dependent on their precursors. Otherwise, they would require specific metabolic and release systems [128]. From a molecular perspective, several reports have shown that the inhibition of leukotrienes plays a modulating role in the atherosclerotic process via the decrease of proinflammatory molecules and reactive oxygen species induced by TNF-a [129,130]. In the near future, it will be possible to consider a combined pharmacological approach of leukotriene inhibition and the induction of SPM-producing metabolic pathways as a therapeutic strategy in the management of the low-grade inflammation seen in CVD. This poses an alternative to recent trials that sought to achieve anti-inflammatory control of atherosclerotic cardiovascular disease by modulating or blocking proinflammatory signaling pathways in the final steps [131,132]. Instead, combining PUFAs (especially EPA) with SPM signaling agonists, or GLP-1 agonists with selective activators of specific SPM receptors, could constitute good pharmacological strategies destined not only to control dyslipidemia or obesity as isolated risk factors, but also with an impact on unresolved inflammation. To summarize, lipid mediators have been shown to be a promising alternative in the resolution of inflammation in several clinical scenarios including CVD [133,134]. However, their use in a clinical trials has been delayed by various factors, i.e., biodistribution and bioavailability, pharmokinetics and pharmcodynamics. The quick degradation of the compounds, the complex process required to significantly trigger endogenous SPM synthesis, the lack of synthetic structures that could be administered systemically, and their limited localized use pose significant problems for the use of SPMs compared to other drugs for the management of CVD. Thus, strategies that allow the systemic administration of synthetic analogues with longer half-lives are required. Further research is urgently needed in the field, given that that cardiovascular diseases are still the first cause of death worldwide. 7. Conclusions Due to the increasing morbidity and mortality of CVD, describing and understanding the pathophysiology of this condition and the metabolic pathways involved in it is of the highest importance. SPMs have been identified as a potential therapeutic target in the treatment of CVD. These compounds can promote the resolution of inflammation without resulting in immunosuppression. Preclinical evidence positions SPMs as novel and promising mediators in CVD prevention and management strategies, either by promoting SPMs endogenous synthesis through PUFA supplementation and other molecules that promote its synthesis, or as a result of exogenous synthetic analogue administration, alone or in combination with other cardioprotective drugs. In addition, SPMs improve host defenses, as reported by in vitro and in vivo preclinical studies, unlike current anti-inflammatory treatments; this will likely give rise to the creation of new guidelines on the use of SPMs in CVD management. Several mechanisms are linked to SPMs, e.g., atherosclerosis in murine models and potential metabolic pathways in human diseases. However, large-scale clinical studies are required to further explore SPM analogue compounds, i.e., to test their stability and resistance to degradation, as well as their safety for human use. In addition, guaranteeing systemic bioavailability is key to any positive effects SPMs might have in vascular inflammation resolution. Regardless, the results so far have been promising, and soon SPMs could represent a novel therapeutic alternative for CVD.
