Single-Cell Analysis Identify Transcription Factor BACH1 as a Master Regulator Gene in Vascular Cells During Aging

Abstract

Vascular aging is a potent driver of cardiovascular and cerebrovascular diseases. Vascular aging features cellular and functional changes, while its molecular mechanisms and the cell heterogeneity are poorly understood. This study aims to 1) explore the cellular and molecular properties of aged cardiac vasculature in monkey and mouse and 2) demonstrate the role of transcription factor BACH1 in the regulation of endothelial cell (EC) senescence and its mechanisms. Here we analyzed published single-cell RNA sequencing (scRNA-seq) data from monkey coronary arteries and aortic arches and mouse hearts. We revealed that the gene expression of YAP1, insulin receptor, and VEGF receptor 2 was downregulated in both aged ECs of coronary arteries’ of monkey and aged cardiac capillary ECs of mouse, and proliferation-related cardiac capillary ECs were significantly decreased in aged mouse. Increased interaction of ECs and immunocytes was observed in aged vasculature of both monkey and mouse. Gene regulatory network analysis identified BACH1 as a master regulator of aging-related genes in both coronary and aorta ECs of monkey and cardiac ECs of mouse. The expression of BACH1 was upregulated in aged cardiac ECs and aortas of mouse. BACH1 aggravated endothelial cell senescence under oxidative stress. Mechanistically, BACH1 occupied at regions of open chromatin and bound to CDKN1A (encoding for P21) gene enhancers, activating its transcription in senescent human umbilical vein endothelial cells (HUVECs). Thus, these findings demonstrate that BACH1 plays an important role in endothelial cell senescence and vascular aging.

Regulation of BACH1 by hemin improves cardiac function in a mouse model of myocardial infarction

“…This is in keeping with previous data showing BACH1 levels remain elevated during the first 48h post MI in the murine left ventricular myocardium 24 and microarray data from human circulating endothelial cells demonstrating elevated BACH1 expression after MI 25 . Furthermore, other cardiovascular risk factors such as elevated glucose 26 and aging 27 have also been associated with increased BACH1 expression in the mouse aorta and heart respectively. For aging, this was further linked to increased endothelial cell senescence when under oxidative stress 27 .…”

“…Furthermore, other cardiovascular risk factors such as elevated glucose 26 and aging 27 have also been associated with increased BACH1 expression in the mouse aorta and heart respectively. For aging, this was further linked to increased endothelial cell senescence when under oxidative stress 27 . Likewise, BACH1 expression was also found to be elevated in human atherosclerotic plaques 28 .…”

A new "single" era of biomedicine and implications in disease research

“…[74–98] To date, with the rapid development of SC technologies, great progress has been made in their applications in CVDs as well as cardiovascular biology and research, such as targeted endothelial cell–related diseases (AMI, pulmonary arterial hypertension, and vascular aging), molecular markers, and new mechanisms and therapeutics. [75,99–101]…”

“…To date, with the rapid development of SC technologies, great progress has been made in their applications in CVDs as well as cardiovascular biology and research, such as targeted endothelial cell-related diseases (AMI, pulmonary arterial hypertension, and vascular aging), molecular markers, and new mechanisms and therapeutics. [75,[99][100][101] scRNA-seq for SARS-CoV-2 discovery As a hot topic in biomedicine, there are more than 200 studies on SC technologies published in Science Advances, which covers basic to clinical research and provides new insights into the effects of SARS-CoV-2 on human tissues including the heart. For example, there are several studies on COVID-19 based on SC technologies.…”

Single-Cell Analysis Reveals Transcriptomic Reprogramming in Aging Cardiovascular Endothelial Cells

“…It is well known that cardiovascular ECs are involved in the pathologies of age-related cardiovascular diseases (CVDs) ( 3 , 4 ) and cardiovascular EC senescence has been identified as a major risk factor for the onset and progression of CVDs ( 5 ). Despite the importance of cardiovascular EC senescence in aging-related diseases, very limited studies have been focusing on the molecular dynamics of the aging cardiovascular ECs ( 6 , 7 ). Accordingly, a comprehensive study across multiple time points may better illustrate the transcriptomic reprogramming in cardiovascular EC aging process.…”