From DNA Repair to Redox Signaling: The Multifaceted Role of APEX1 (Apurinic/Apyrimidinic Endonuclease 1) in Cardiovascular Health and Disease

Abstract

Apurinic/apyrimidinic endonuclease 1 (APEX1) serves as a potent regulatory factor in innate immunity, exhibiting both redox and endonuclease activities. Its redox function enables the regulation of transcription factors such as NF-κB or STAT3, whereas its endonuclease activity recognizes apurinic/apyrimidinic (AP) sites in damaged DNA lesions during base excision repair (BER) and double-stranded DNA repair, thereby I confirm.anti-inflammatory, antioxidative stress and antiapoptotic effects. APEX1 is expressed in a variety of cell types that constitute the cardiovascular system, including cardiomyocytes, endothelial cells, smooth muscle cells, and immune cells. Emerging genetic and experimental evidence points towards the functional roles of APEX1 in the pathophysiology of cardiovascular diseases, including neointimal formation and atherosclerosis. This review aims to present comprehensive coverage of the up-to-date literature concerning the molecular and cellular functions of APEX1, with a particular focus on how APEX1 contributes to the (dys)functions of different cell types during the pathogenesis of cardiovascular diseases. Furthermore, we underscore the potential of APEX1 as a therapeutic target for the treatment of cardiovascular diseases.

Keywords: APEX1; DNA repair; atherosclerosis; cardiovascular diseases; endonuclease activity; redox activity.

Figure 1

Domain Structure of the Human APEX1 Protein. The above is the structural model diagram of APEX1. The diagram below is the 3D structural model, with the 3D crystal structure obtained from the PDB database. The blue region represents the redox domain of APEX1 (The red region, C63 and C93, are the active sites of the redox domain), while the green region represents the endonuclease domain (The pink regions are active site of the endonuclease domain).

Figure 2

APEX1 repairs DNA damage mechanisms. Oxidative stress, hypoxia, and other factors lead to the production of a large amount of reactive oxygen species (ROS) within cells, resulting in damage to nuclear DNA and mitochondrial DNA. DNA damage in the nucleus exposes AP sites, which are recognized and bound by APEX1. APEX1 cleaves the AP site, and with the involvement of DNA glycosylase, the damaged base is excised, generating a -OH group at the 3′ end of the damage site. DNA repair is then carried out with the participation of DNA polymerase and DNA ligase. In the case of mitochondrial DNA damage, APEX1 is translocated to the mitochondria through a series of signal transduction processes to facilitate DNA repairs. (DSR, double-strand break repair pathway; mtDNA, mitochondrial DNA; SSR, single strand repair. The blue arrow represents APEX1’s involvement in the mitochondrial DNA repair pathway, while the purple arrow represents APEX1’s involvement in the nuclear DNA repair pathway.

Figure 3

DNA damage and systemic diseases of the cardiovascular system. In the cardiovascular system, the accumulation of DNA damage in different cell types can lead to various cardiovascular diseases. For example, DNA damage accumulation in vascular smooth muscle cells and vascular endothelial cells can contribute to hypertension, pulmonary arterial hypertension, and atherosclerosis. Meanwhile, DNA damage accumulation in cardiomyocytes and cardiac fibroblasts can lead to myocardial fibrosis and heart failure.

Figure 4

Regulation of APEX1 Expression Through Different Mechanisms and the Function of APEX1 in cardiovascular pathophysiology. (1) Activation of APEX1 by various factors, resulting in the gene transcription of Apex1; (2) Mechanism of APEX1 antiapoptotic function; (3) Mechanism of APEX1 DNA damage repair; (4) Mechanism by which APEX1 inhibits proliferation; (5) Mechanism by which APEX1 protects vascular endothelial function; (6) Mechanism of APEX1 anti-inflammatory function; (7) Mechanism of APEX1 anticalcification; (8) Mechanism of APEX1 antiautophagy.(↑: Increase the content of this component in the cells; ↓: Decrease the content of this component in the cells).