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

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 () and Jae-Hoon Choi ()
Additional contact information
Seung Hyun Lee: Hanyang University
Nayoung Kim: The Catholic University of Korea
Minkyu Kim: Hanyang University
Sang-Ho Woo: Seoul National University
Inhee Han: Hanyang University
Jisu Park: Hanyang University
Kyeongdae Kim: Hanyang University
Kyu Seong Park: Hanyang University
Kibyeong Kim: Hanyang University
Dahee Shim: Hanyang University
Sang-eun Park: Hanyang University
Jing Yu Zhang: Hanyang University
Du-Min Go: Seoul National University
Dae-Yong Kim: Seoul National University
Won Kee Yoon: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Seung-Pyo Lee: Seoul National University Hospital, Seoul National University College of Medicine
Jongsuk Chung: Samsung Medical Center
Ki-Wook Kim: The University of Illinois College of Medicine
Jung Hwan Park: Hanyang University College of Medicine
Seung Hyun Lee: Yonsei University College of Medicine
Sak Lee: Yonsei University College of Medicine
Soo-jin Ann: Yonsei University College of Medicine
Sang-Hak Lee: Yonsei University College of Medicine
Hyo-Suk Ahn: The Catholic University of Korea
Seong Cheol Jeong: The Catholic University of Korea
Tae Kyeong Kim: Ewha Womans University
Goo Taeg Oh: Ewha Womans University
Woong-Yang Park: Samsung Medical Center
Hae-Ock Lee: The Catholic University of Korea
Jae-Hoon Choi: Hanyang University

Nature Communications, 2022, vol. 13, issue 1, 1-22

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-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.

Date: 2022
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DOI: 10.1038/s41467-022-33202-2

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