Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPAR gamma during hyperlipidemia

Abstract

Identifying the mechanisms underlying the early inflammatory phase of aortic valve disease is crucial for disease prevention. Here the authors perform single-cell RNA sequencing to show the immunomodulatory role of PPAR gamma in valvular endothelial cells during hyperlipidemia. Valvular inflammation triggered by hyperlipidemia has been considered as an important initial process of aortic valve disease; however, cellular and molecular evidence remains unclear. Here, we assess the relationship between plasma lipids and valvular inflammation, and identify association of low-density lipoprotein with increased valvular lipid and macrophage accumulation. Single-cell RNA sequencing analysis reveals the cellular heterogeneity of leukocytes, valvular interstitial cells, and valvular endothelial cells, and their phenotypic changes during hyperlipidemia leading to recruitment of monocyte-derived MHC-IIhi macrophages. Interestingly, we find activated PPAR gamma pathway in Cd36(+) valvular endothelial cells increased in hyperlipidemic mice, and the conservation of PPAR gamma activation in non-calcified human aortic valves. While the PPAR gamma inhibition promotes inflammation, PPAR gamma activation using pioglitazone reduces valvular inflammation in hyperlipidemic mice. These results show that low-density lipoprotein is the main lipoprotein accumulated in the aortic valve during hyperlipidemia, leading to early-stage aortic valve disease, and PPAR gamma activation protects the aortic valve against inflammation.