Smooth muscle cell modulation by the MaR1-LGR6 duo: novel role in the resolution of human cardiovascular inflammation.

ongoing

Atherosclerotic cardiovascular disease (ASCVD) is a progressive disease characterized by aberrant immune activation and chronic vascular inflammation as a result from a failure in the resolution phase. However, the mechanisms responsible for this dysregulation are not well understood. Little is known about the role of smooth muscle cells (SMCs) in regulating resolution of inflammation, an active process orchestrated by endogenous specialized proresolving lipid mediators (SPMs). These include the maresin family, and in particular maresin 1 (MaR1), which was recently shown to be a specific activator of LGR6. Despite the potent anti-inflammatory and proresolving actions of MaR1 in murine models and human cells, its role in ASCVD remains uncovered. Hence, this proposal aims to elucidate the role of SMC-derived resolution of inflammation in ASCVD, and the impact of MaR1-LGR6 in stimulating resolution. Specifically, I will focus on the molecular mechanisms of MaR1-LGR6 signaling, mainly on the phagocytic capacity of SMCs. I will employ mechanistic and functional assays in human SMCs, as a proxy for its potential in plaque “clearing” and plaque stabilization. I will characterize the expression of LGR6, by mass spectrometry imaging, and the biosynthesis of MaR1 in human atherosclerotic tissue (local) and identify indicators in blood samples (systemic) by LC-MS/MS-derived lipidomic profiling of human samples, in to obtain a profile of systemic lipid biomarker(s) that reflects the local abundance of SPMs or their receptors. This could be used to design personalized proresolving prevention in prone-to-CVD individuals. Lastly, I will investigate the SMC phenotypic modulation by MaR1-LGR6 in a LGR6-specific SMC-deletion ASCVD mouse model. Deciphering the SMC-mediated resolution programs in inflammation (a novel concept in ASCVD), and the involvement of MaR1-LGR6 in this process, will be a major advance in understanding chronic cardiovascular inflammation and its mechanisms.