Pro-resolving lipid mediators in the resolution of neointimal hyperplasia pathogenesis in atherosclerotic diseases

ABSTRACT

Introduction: Despite advances in drug eluting technologies, neointimal hyperplasia (NIH) and restenosis still plagues endovascular therapy in atherosclerotic diseases. By appreciating atherosclerosis and NIH as complex inflammatory processes, specialized pro-resolving mediators (SPMs) are a superfamily of endogenous unsaturated fatty-acid derived lipids with the potential for inflammatory resolution.

Areas covered: Inquiry into SPMs in this context is a novel approach and is the focus of this review, with emphasis on our understanding with NIH. Prior mechanistic understandings of SPM deficiency with atherosclerosis has offered insight, as well as the complexity and diversity of the SPM superfamily. Therapeutic investigation using SPMs to combat NIH is also evaluated here.

Expert commentary: Endogenous deficiency of SPMs synthesis by 12/15-lipoxygenase underlies resolution deficits in atherosclerosis and NIH. Upstream PDGF inhibition by SPMs, most notably RvD1 and LXA4, confers a multifactorial attenuation of NIH that involves interconnected anti-inflammatory efforts, most notably switch pro-resolving smooth muscle cells (vSMCs) and macrophages. The ALX/FPR2 is one receptor system identified on vSMCs that interacts with these SPMs to promote NIH resolution. Therapeutically, while shown to be promising with less stent burden or cytotoxicity, SPMs must be balanced by necessary mechanistic, pharmacokinetic and anatomical considerations.

KEYWORDS:

• Atherosclerosis
• inflammation
• neointimal hyperplasia
• pro-resolving mediators
• resolvins
• lipoxins
• protectins

Acknowledgments

The content of this review article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed they are an inventor on patents related to this area held by UCSF and Partners Healthcare/Brigham and Women’s Hospital, and they are a co-founder of VasaRx, a biotechnology start up focused in this area. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

The research work of D K Agrawal is supported by research grants R01HL112597, R01HL116042, R01HL120659, and R01HL144125 from the National Institutes of Health, USA.