Biology subjects

Shyy, J. Y.- J.

Publications and source records attributed to Shyy, J. Y.- J..

3 recordsLinked to original sources

bioRxiv2026

Endothelial MRG15 Is a Mechanosensitive Suppressor of Atherosclerosis

Disturbed blood flow induces early endothelial inflammation in atherosclerosis, yet the precise mechanisms of endothelial sensing of disturbed flow remain incompletely understood. In this study, we integrated proteomic profiling of human endothelial cells (ECs) subjected to disturbed flow with coronary artery disease risk related genes from large-scale genome-wide association studies (GWAS). We identified mortality factor 4-like protein 1 (MORF4L1, also called MRG15) as a critical modulator in the pathogenesis of atherosclerosis induced by disturbed flow. We show that the expression of MRG15 is markedly reduced in ECs of human aortic atherosclerotic plaques, as well as in ECs exposed to disturbed flow in mouse carotid artery and in cultured human umbilical vein endothelial cells (HUVECs). Endothelial-specific deletion of Mrg15 significantly worsened, while its overexpression attenuated endothelial inflammation and atherosclerotic lesions in turbulent blood flow- or Western diet-induced mouse atherosclerosis model. Single-cell transcriptomics showed that Mrg15 deficiency increased endothelial inflammation and intercellular adhesion molecule 1 (Icam1) expression, and enhanced integrin-mediated adhesion pathways. Mechanistically, MRG15 facilitated the recruitment of enhancer of zeste homolog 2 (EZH2) to maintain repressive histone H3 lysine 27 trimethylation (H3K27me3) marks on the promoters of ICAM1 and integrin subunit alpha 5 (ITGA5). Disturbed blood flow rapidly led to an elevation of protein neddylation, which subsequently induced neddylation-dependent degradation of MRG15 within endothelial cells. This degradation of MRG15 alleviated the transcriptional repression of ICAM1 and ITGA5, thereby enhancing monocyte adhesion to ECs. These findings highlight endothelial MRG15 as a mechanosensitive suppressor of atherosclerosis induced by disturbed flow. Consequently, MRG15 emerges as a promising novel therapeutic target for atherosclerosis.

molecular biology↗

bioRxiv2024

Store-operated Ca2+ entry is involved in endothelium-to-mesenchymal transition in lung vascular endothelial cells

Endothelial-to-mesenchymal transition (EndMT) is a biological process that converts endothelial cells to mesenchymal cells with increased proliferative and migrative abilities. EndMT has been implicated in the development of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH), a fatal and progressive lung vascular disease. Transforming growth factor {beta}1 (TGF-{beta}1), an inflammatory cytokine, is known to induce EndMT in many types of endothelial cells including lung vascular endothelial cells (LVEC). An increase in cytosolic free Ca2+ concentration ([Ca2+]cyt) is a major stimulus for cellular proliferation and phenotypic transition, but it is unknown whether Ca2+ signaling is involved in EndMT. In this study we tested the hypothesis that TGF-{beta}1-induced EndMT in human LVEC is Ca2+-dependent. Treatment of LVEC with TGF-{beta}1 for 5-7 days resulted in increase in SNAI1/2 expression, induction of EndMT, upregulation of STIM/Orai1 and enhancement of store-operated Ca2+ entry (SOCE). Removal (or chelation) of extracellular or intracellular Ca2+ with EGTA or BAPTA-AM respectively abolished EndMT in response to TGF-{beta}1. Moreover, EGTA diminished TGF-{beta}1-induced increase in SNAI in a dose-dependent manner. Knockdown of either STIM1 or Orai1 was sufficient to prevent TGF-{beta}-mediated increase in SNAI1/2 and EndMT, but did not rescue the continuous adherent junctions. Blockade of Orai1 channels by AnCoA4 inhibited TGF-{beta}-mediated EndMT and restored PECAM1-positive continuous adherent junctions. In conclusion, intracellular Ca2+ signaling plays a critical role in TGF-{beta}-associated EndMT through enhanced SOCE and STIM1-Orai1 interaction. Thus, targeting Ca2+ signaling pathways regulating EndMT may be a novel therapeutic approach to treat PAH and other forms of pre-capillary pulmonary hypertension. New & NoteworthyEndMT has been reported to contribute to the pathogenesis of PH. In this study we aimed to determine the role of Ca2+ signaling in the development of EndMT in human lung vascular endothelial cells. Our data suggest that TGF-{beta}1 requires store-operated Ca2+ entry through STIM1/Orai channels to induce SNAI-mediated EndMT. For the first time we demonstrated that TGF-{beta}1-induced EndMT is Ca2+-dependent event while inhibition of STIM1/Orai interaction attenuated EndMT in response to TGF-{beta}1.

cell biology↗

bioRxiv2024

Smooth muscle Cxcl12 activation is associated with vascular remodeling in flow-induced pulmonary hypertension

Patients with congenital heart disease (CHD) resulting in significant left-to-right shunting of blood are at risk for the development of pulmonary arterial hypertension (PAH). The underlying mechanism by which pulmonary overcirculation and shear stress lead to vascular remodeling remains unclear. Our study established a new "two-hit" murine model of severe pulmonary hypertension (PH) by combining left pneumonectomy and exposure to hypoxia (LP/Hx). Utilizing transgenic reporter lines, immunofluorescence staining, and advanced microscopy, we conducted cell-lineage tracing experiments for endothelial cells (ECs), smooth muscle cells (SMCs), and pericytes. We identified that SMCs is a primary contributor to distal arteriolar remodeling after LP/Hx. Subsequent qPCR analysis on isolated cells demonstrated that Cxcl12 was upregulated in both ECs and SMCs from LP/Hx animals. Likewise, CXCL12 was overexpressed in the SMC layer of arterioles in patients with acyanotic PAH-CHD. These findings provide novel insights into the contribution of SMCs and Cxcl12 to pulmonary flow-induced vascular remodeling. This newly established murine model of PH will serve as a new tool for research and targeted therapeutics for patients with PAH.

molecular biology↗