Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia
Authors
Seung Hyun Lee ; Nayoung Kim ; Minkyu Kim ; Sang-Ho Woo ; Inhee Han ; Jisu 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
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 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.