Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia
Seung Hyun Lee, Nayoung Kim, Min‐Kyu Kim, Sang‐Ho Woo, In-Hee Han, Ji‐Su Park, Kyeongdae Kim, Kyu Seong Park, Kibyeong Kim, Dahee Shim, Sang-Eun Park, Jing Yu Zhang, Du‐Min Go, Dae-Yong Kim, Won Kee Yoon, Seung‐Pyo Lee, Jongsuk Chung, Ki-Wook Kim, Jung Hwan Park, Seung Hyun Lee, Sak Lee, Soo-jin Ann, Sang‐Hak Lee, Hyo–Suk Ahn, Seong Cheol Jeong, Tae Kyeong Kim, Goo Taeg Oh, Woong‐Yang Park, Hae‐Ock Lee, Jae‐Hoon Choi
Abstract
Abstract 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-II hi macrophages. Interestingly, we find activated PPARγ pathway in Cd36 + valvular endothelial cells increased in hyperlipidemic mice, and the conservation of PPARγ activation in non-calcified human aortic valves. While the PPARγ inhibition promotes inflammation, PPARγ 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 PPARγ activation protects the aortic valve against inflammation.