AKR1C3 protects cardiomyocytes against hypoxia-induced cell apoptosis through the Nrf-2/NF-κB pathway

Abstract

Hypoxia-induced apoptosis plays a critical role in the progression of various cardiac diseases, such as heart failure and acute myocardial infarction (AMI). Aldosterone reductase 1C3 (AKR1C3), a member of the aldo-keto reductase superfamily, participates in the metabolism of steroid hormones and redox reactions in vivo. Imbalances in prostaglandin levels have been linked to coronary events. However, the function and molecular mechanism by which AKR1C3 influences AMI are not yet fully understood. This study aims to investigate the role of AKR1C3 in hypoxia-induced myocardial cell damage and elucidate its mechanism. Our findings reveal that a hypoxic microenvironment triggers cardiomyocyte apoptosis and elevates AKR1C3 expression in H9C2 and AC16 cells, as well as in cardiac tissue from rats and mice with AMI. The overexpression of AKR1C3 promotes cardiomyocyte proliferation and cell vitality, whereas the silencing of AKR1C3 exerts the opposite effects in vitro. AKR1C3 protects cardiomyocytes against hypoxia-induced cell apoptosis by reducing ROS levels, preventing mitochondrial damage, and maintaining the oxygen consumption rate (OCR) and ATP production; conversely, AKR1C3 knockdown leads to adverse outcomes. Moreover, the application of a ROS inhibitor (MitoQ10) mitigates the increase in mitochondrial ROS in cardiomyocytes induced by AKR1C3 knockdown under hypoxic conditions. Mechanically, AKR1C3 increases Nrf-2 expression through the ubiquitin-proteasome pathway in cardiomyocytes and subsequently inhibits the NF-κB signaling pathway, thereby inhibiting Bax/caspase-3 signaling. Collectively, these results suggest that AKR1C3 prevents hypoxia-induced cardiomyocyte injury by modulating the Nrf-2/NF-κB axis, suggesting new insights into the mechanisms underlying myocardial protection.

1. Introduction

Heart failure is the main cause of disability and death after myocardial infarction [1]. During the early stages of acute myocardial infarction (AMI), apoptosis is recognized as a key contributor to myocardial cell loss after AMI, serving as a pivotal factor in the initiation of ventricular remodeling and the progression of heart failure [2]. Our previous study demonstrated that integrin β3 exerts a protective effect on cardiomyocytes during hypoxia-induced apoptosis [3]. The heart is an organ with a high demand for energy, and mitochondria serve as the principal source of adenosine triphosphate (ATP) and reactive oxygen species (ROS) in cardiomyocytes. Disruption of oxidative phosphorylation and excessive production of ROS increase cardiomyocyte apoptosis [4]. Therefore, exploring the mechanism of hypoxia-induced cardiomyocyte apoptosis is crucial.

Mitochondrial ROS has always been a therapeutic target for preventing hypoxic injury. Under physiological conditions, ROS serves as the second messenger in signal transduction pathways, participating in the regulation of oxidative balance and various biological activities. However, excessive ROS production can lead to oxidative stress and damage [5]. Pathological stimuli, such as hypoxia, can trigger a “burst” release of mitochondrial ROS, disrupting the endogenous antioxidant balance, ultimately resulting in mitochondrial depolarization and mitochondrial outer membrane permeabilization (MOMP) and ultimately leading to apoptosis [6]. Aldosterone reductase 1C3 (AKR1C3) belongs to the aldosterone reductase (AKR) superfamily and has a strong affinity for NADPH, primarily facilitating redox reactions [7]. AKR1C3 is predominantly expressed in endocrine organs such as the prostate, adrenal gland, mammary gland, and uterus. AKR1C3 also participates in the de novo synthesis of steroids in the adrenal gland and tumors [8]. Many studies have revealed the role of AKR1C3 in tumor progression [9–12]. In addition, AKR1C3 was found to induce chemoresistance by regulating redox balance and ROS production in malignant tumor cells [13]. AKR1C3 functions as a prostaglandin (PG)F2 synthase, modulating vasodilation and vasoconstriction [14]. Imbalances in prostaglandins have been associated with coronary events [15,16]. Despite previous studies reporting no significant difference in AKR1C3 expression between AMI patients and controls on the basis of the GSE48060 dataset, these findings may be limited by small sample sizes [17]. Thus, further investigations are needed to understand the relationship between AKR1C3 and AMI comprehensively.

In the present study, we investigated the precise mechanisms by which AKR1C3 influences cardiomyocyte proliferation and protects against hypoxia-induced apoptosis.