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Specialized pro-resolving mediators in vascular inflammation and atherosclerotic cardiovascular disease

Nature Reviews Cardiology (2024)Cite this article

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Abstract

Timely resolution of the acute inflammatory response (or inflammation resolution) is an active, highly coordinated process that is essential to optimal health. Inflammation resolution is regulated by specific endogenous signalling molecules that function as ‘stop signals’ to terminate the inflammatory response when it is no longer needed; to actively promote healing, regeneration and tissue repair; and to limit pain. Specialized pro-resolving mediators are a superfamily of signalling molecules that initiate anti-inflammatory and pro-resolving actions. Without an effective and timely resolution response, inflammation can become chronic, a pathological state that is associated with many widely occurring human diseases, including atherosclerotic cardiovascular disease. Uncovering the mechanisms of inflammation resolution failure in cardiovascular diseases and identifying useful biomarkers for non-resolving inflammation are unmet needs. In this Review, we discuss the accumulating evidence that supports the role of non-resolving inflammation in atherosclerosis and the use of specialized pro-resolving mediators as therapeutic tools for the treatment of atherosclerotic cardiovascular disease. We highlight open questions about therapeutic strategies and mechanisms of disease to provide a framework for future studies on the prevention and treatment of atherosclerosis.

Key points

  • The resolution of inflammation is an active biosynthetic process that is regulated, in part, by specialized pro-resolving mediators (SPMs).

  • SPMs are not immunosuppressive in animal models and act to stimulate phagocyte function, promote tissue repair pathways and limit pain.

  • SPMs are protective in animal models of cardiovascular disease including atherosclerosis, myocardial infarction and heart failure.

  • Clinical trials are needed to rigorously test whether increasing SPMs in humans can prevent atherosclerosis progression, reduce cardiovascular risk and promote cardioprotection.

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Fig. 1: Specialized pro-resolving mediator synthesis, receptors and cell targets.
Fig. 2: Role of the activated vascular endothelium in the production of resolvins via transcellular biosynthesis with neutrophils.
Fig. 3: Non-resolving inflammation underpins atherosclerosis.
Fig. 4: Specialized pro-resolving mediators protect against atherosclerosis in experimental models.

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Acknowledgements

We dedicate this Review in memory of Hildur Arnardottir, who was promoted to permanent faculty at the Karolinska Institute in Stockholm, Sweden. Arnardottir opened new avenues in resolution of inflammation research with specialized pro-resolving mediators with her findings in ageing, human breast milk and specialized pro-resolving mediator receptors in atherosclerotic cardiovascular disease. We shall always remember Arnardottir’s bright smile, scientific curiosity, rigour, passion for science, insightful discussions and very devoted hard work to contribute to medical sciences. G.F. is supported by NIH/NHLBI R01HL170249 and R01HL153019. C.N.S. is supported by NIH/NIHGMS R35GM139430.

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  1. Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA

    Gabrielle Fredman

  2. Center for Experimental Therapeutics and Reperfusion Injury, Department of Anaesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Charles N. Serhan

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G.F. is a member of a scientific advisory board for Esperion Therapeutics. C.N.S. is a co-founder of Nocendra and an inventor on patents on specialized pro-resolving mediators assigned to Brigham and Women’s Hospital that were reviewed by Mass General Brigham.

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Fredman, G., Serhan, C.N. Specialized pro-resolving mediators in vascular inflammation and atherosclerotic cardiovascular disease. Nat Rev Cardiol (2024). https://doi.org/10.1038/s41569-023-00984-x

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