Co-expression of POU4F2/Brn-3b with p53 may be important for controlling expression of pro-apoptotic genes in cardiomyocytes following ischaemic/hypoxic insults

Abstract

Cardiomyocyte death following ischaemic/hypoxic injury causes irreversible damage to cardiac function and contributes to chronic diseases such as heart failure. Understanding the mechanisms associated with myocyte loss under these conditions can help to identify strategies to minimise/abrogate such detrimental effects. The p53 protein can induce apoptosis or cell cycle arrest, but effects on cell fate depend on interactions with other regulators such as POU4F2/Brn-3b (Brn-3b), which co-operates with p53 to increase the expression of pro-apoptotic genes. In contrast, the related POU4F1/Brn-3a (Brn-3a) blocks p53-mediated apoptosis but co-operates with p53 to enhance cell cycle arrest. In this study, we showed that permanent coronary artery ligation in mouse hearts, which induced apoptotic markers, activated caspase-3 and -8 and necroptosis markers; RIP-1 and -3 also increased Brn-3b and Brn-3a expression. However, Brn-3a was only detected in uninjured myocardium but not at the site of injury, whereas Brn-3b showed generalised increase, including within the infarct zone. Conversely, p53 was detected in the infarct zone and in some cells adjacent to the site of injury but not in uninjured myocardium. Co-localisation studies showed Brn-3a co-expression with p53 in cardiomyocytes adjacent to the infarct zone, whereas Brn-3b was co-localised with p53 in the infarct zone only. Increased Brn-3b and p53 correlated with elevated expression of pro-apoptotic target genes, Bax, Noxa and PUMA, whereas cleaved caspase-3 confirmed the presence of apoptotic cells within this region of the injured heart. Similarly, simulated ischaemia/reoxygenation (sI/R) injury in neonatal rat ventricular cardiomyocytes (NRVM) and heart derived H9c2 myoblasts increased Brn-3b, p53 as well as apoptotic genes, and this was associated with enhanced apoptosis. Furthermore, targeted reduction of Brn-3b using shRNA caused reduction in pro-apoptotic Bax and Noxa proteins, even though p53 expression remained intact, suggesting that Brn-3b is important for controlling the fate of the myocardium in the injured heart.

High-density lipoprotein protects cardiomyocytes against necrosis induced by oxygen and glucose deprivation through SR-B1, PI3K, and AKT1 and 2

“…Cells subjected to OGD exhibited only very low levels of apoptosis, as measured by TUNEL or AxV staining, and these very low levels were unaffected by HDL treatment ( Figure 1B–D ). The lack of cardiomyocyte apoptosis following 4 h of OGD in our experiment is consistent with a recent report that 4 h of OGD induced significant cell death with little detectable apoptosis in neonatal rat ventricular cardiomyocytes [ 24 ]. Despite the low levels of apoptosis, exposure of HIVCM to 4 h of OGD caused membrane permeabilization (a marker of necrotic or necroptotic cell death) as evidenced by increased nuclear staining with PI compared with corresponding normoxic controls (82.6 ± 1.7 vs. 0 ± 0% PI-positive cardiomyocytes, Figure 1E,G ), and treatment with HDL attenuated PI uptake (49.2 ± 12.1 vs. 82.6 ± 1.7% PI-positive cardiomyocytes, Figure 1E,G ).…”

“…We sought to determine if HDL could protect cardiomyocytes against cell death induced by OGD as a model of induced ischemia and to evaluate if SR-B1, PI3K, and AKT are involved in the protective signaling elicited by HDL. Others have shown that following 4 h of hypoxic stress, neonatal rat ventricular cardiomyocyte cell death was a result of necrosis, though reoxygenating cells for increasing lengths of time resulted in a shift of cell death from necrosis to apoptosis [ 24 ]. Similarly, we found that in HIVCM and NMCM exposed to OGD for 4 h, necrosis (detected by PI staining) was the primary driver of cell death, and that there was little to no induction of apoptosis (as evidenced by a lack of TUNEL or AxV staining), or necroptosis (as evidenced by resistance to the necroptosis inhibitor, Nec-1s).…”

TRANSCRIPTION FACTOR BRN-3α AND PROSTATE CANCER, RELATION WITH HORMONE RECEPTORS AND AKT/M-TOR SIGNALING PATHWAY ACTIVATION

“…В развитии гормонозависимых опухолей чело-века большое значение имеют транскрипционные факторы POU4F1, также известные как нейроген-ные факторы Brn-3α [1]. Они представляют собой важные ядерные белки, регулирующие процессы пролиферации и дифференцировки клетки.…”

Nucleostemin exerts anti-apoptotic function via p53 signaling pathway in cardiomyocytes

“…Cardiomyocytes death occurs following coronary artery occlusion can cause irreversible damage to the heart because these terminally differentiated cells have poor regenerative capacity and are not readily replaced (Budhram-Mahadeo et al 2014). It is important to understand the mechanisms associated with cardiomyocyte loss under these conditions.…”