Graphic abstract of the research
Abdominal aortic aneurysm (AAA) is a life-threatening disease in which the main blood vessel in the abdomen becomes weakened and expands abnormally. This condition can lead to catastrophic events like rupture and sudden death. Currently, there are no proven pharmaceutical treatments available to prevent AAA progression, due to the limited understanding of the mechanisms that cause AAA to develop and progress. A type of protein called activating transcription factor 3 (ATF3) has been increasingly recognised as a key regulator of cardiovascular diseases. However, the role of ATF3 in the development and progression of AAA has not yet been studied.
Prof. Jack Tang, Head of Health Sciences and Professor in the School of Nursing and Health Studies at Hong Kong Metropolitan University, together with a team of researchers from several medical universities, hospitals, and research institutes in mainland China and Australia, conducted a research to investigate the underlying mechanism by which ATF3 contributes to the development and progression of AAA.
The research team conducted experiments using mice that were induced to develop AAA by injecting them with a substance called angiotensin II (Ang II). They isolated the aortas (the main blood vessels) from these mice and performed a special analysis called genome-wide RNA sequencing. This analysis allowed them to examine the activity of all the genes present in the aorta.
Through their analysis, they found that ATF3 could be an important gene related to AAA development. To further investigate its role, they manipulated the levels of ATF3 in specific cells called vascular smooth muscle cells (VSMC), which are responsible for maintaining the structure and function of blood vessels. They used special viruses to either decrease or increase the amount of ATF3 in these cells in the AAA-induced mice. They also conducted similar experiments using human and mouse VSMC in the laboratory. Since one key feature of AAA is the reduction in the number of VSMC in the media layer of blood vessel, understanding how ATF3 affects the growth and death of VSMC could provide insights into the development and progression of AAA.
A representative image of ATF3/BCL2/DAPI expression by immunofluorescence staining in lesion (non-aneurysm) section at the early stage of AAA
Their research outcomes suggest that a lack of ATF3 in VSMC of the blood vessel would increase the risk of AAA formation and blood vessel rupture. In addition, ATF3 influenced the function of VSMC at different stages of the disease. At the early stage of AAA, ATF3 enhanced the proliferation of VSMC. While at the advanced stage of AAA, the absence of ATF3 resulted in the cell death of VSMC. The spatiotemporal (space and time) pattern of ATF3 expression ultimately determines whether VSMC will proliferate or undergo cell death that impact the development and progression of AAA.
This study demonstrates the previously unrecognised role of ATF3 in AAA development and progression. ATF3 has the potential to be used as a new target for developing new therapies to treat AAA, and as a marker to predict the progression and outcomes of AAA.
The research findings were published in Circulation Research with the paper title 'Spatiotemporal ATF3 Expression Determines VSMC Fate in Abdominal Aortic Aneurysm'.
