GATA4 and Cellular Senescence
Researchers have in the past connected GATA4 expression to various age-related conditions, such as scarring in heart tissue. Here, they link GATA4 to cellular senescence, which is also implicated in many of the same conditions. Senescent cells accumulate with age, and their pro-growth, pro-inflammatory signals are disruptive to tissue function throughout the body. In recent years the evidence for clearance of senescent cells via senolytic therapies to be beneficial in older individuals has prompted greater research to connect cellular senescence to many other lines of research in the context of aging and age-related disease.
DNA damage can activate Ataxia telangiectasia-mutated serine/threonine kinase (ATM) and Rad3-related serine/threonine kinase (ATR), after which p53 activates p21, stopping the cell cycle and inducing cell senescence. GATA4 is a transcription factor that regulates signal response processes in many organs, such as cardiac precursor cell differentiation, cardiac development, cardiac hypertrophy, and resistance to apoptosis, as well as mediating the effects of genetic mutations caused by congenital heart disease.
GATA4 regulates proteins in a context-dependent manner, thereby performing multiple functions. It has been reported that GATA4 is regulated upstream by the DNA damage response (DDR) pathway co-opting ATM and ATR, and downstream in a manner different from the conventional DDR pathway, leading to senescence. GATA4 is regulated by ATM and ATR, which inhibit the binding of p62 and GATA4 to inhibit selective lineage autophagy of GATA4, thereby activating NF-κB, leading to cellular senescence. In addition, alterations in the GATA4 signaling pathway have been frequently observed in various age-related diseases, including atherosclerosis and heart failure.
This paper reviews the mechanisms through which the DDR signaling pathway leads to cellular senescence, the involvement of the GATA4 factor in these processes, as well as the link to atherosclerosis and heart failure. This provides many possibilities to invent a drug to inhibit GATA4 activity and thereby prevent cell senescence, but there are still many problems to be solved.