Laminar shear stress inhibits endothelial-mesenchymal transition and mitigates atherosclerosis through SRXN1

Atherosclerosis (AS), a critical inflammatory condition of the arteries that leads to cardiovascular diseases, has a complex pathophysiological mechanism involving multifactorial interactions. Endothelial-mesenchymal transition (EndMT) is considered an important factor promoting AS. Laminar shear stress (LSS) has a pivotal function in regulating AS and EndMT processes; however, its specific mechanisms remain unknown.

We analyzed the transcriptomic and proteomic data of human aortic endothelial cells (HAECs) in static culture and subjected to LSS treatment and identified a key gene, namely sulfiredoxin-1 (SRXN1), closely associated with AS progression. To understand how SRXN1 influences EndMT and AS and the potential underlying mechanisms, we conducted an in vitro flow chamber study with HAECs and an in vivo study with AS model mice.

Our results indicated that LSS alleviated oxidized low-density lipoprotein (ox-LDL)-induced EndMT in HAECs. Transcriptome and proteome sequencing analyses showed that SRXN1 functions as a key gene in LSS-treated endothelial cells; moreover, in HAECs, LSS remarkably suppressed ox-LDL-induced inflammation, oxidative stress, and EndMT, and this protective effect was substantially attenuated by SRXN1 knockdown. Additionally, SRXN1 overexpression reversed ox-LDL-induced inflammation and oxidative stress as well as EndMT. In vivo studies revealed that endothelial-specific adeno-associated virus overexpressing SRXN1 (AAV9-SRXN1) administered through the tail vein significantly suppressed aortic plaque development and EndMT in high-fat diet-induced ApoE^-/- mice.

Our data demonstrate that LSS through SRXN1 upregulation inhibits oxidative stress and prevents EndMT progression, thereby maintaining endothelial homeostasis and suppressing atherosclerotic progression.