Pigment Epithelium-Derived Factor Mediates Autophagy and Apoptosis in Myocardial Hypoxia/Reoxygenation Injury.
Hsuan-Fu KuoPo-Len LiuInn-Wen ChongYu-Peng LiuYung-Hsiang ChenPo-Ming KuChia-Yang LiHsiu-Hua ChenHui-Ching ChiangChiao-Lin WangHuang-Jen ChenYen-Chieh ChenChong-Chao HsiehPublished in: PloS one (2016)
Pigment epithelium-derived factor (PEDF) is a multifunctional protein that exhibits anti-angiogenic, antitumor, anti-inflammatory, antioxidative, anti-atherogenic, and cardioprotective properties. While it was recently shown that PEDF expression is inhibited under low oxygen conditions, the functional role of PEDF in response to hypoxia/reoxygenation (H/R) remains unclear. The goal of this study was to therefore investigate the influence of PEDF on myocardial H/R injury. For these analyses, PEDF-specific small interfering RNA-expressing and PEDF-expressing lentivirus (PEDF-LV) vectors were utilized to knockdown or stably overexpress PEDF, respectively, within human cardiomyocytes (HCM) in vitro. We noted that reactive oxygen species (ROS) play important roles in the induction of cell death pathways, including apoptosis and autophagy in ischemic hearts. Our findings demonstrate that overexpression of PEDF resulted in a significant reduction in ROS production and attenuation of mitochondrial membrane potential depletion under H/R conditions. Furthermore, PEDF inhibited the activation of a two-step apoptotic pathway in which caspase-dependent (caspase-9 and caspase-3) and caspase-independent (apoptosis inducing factor and endonuclease G), which in turn cleaves several crucial substrates including the DNA repair enzyme poly (ADP-ribose) polymerase. Meanwhile, overexpression of PEDF also promoted autophagy, a process that is typically activated in response to H/R. Therefore, these findings suggest that PEDF plays a critical role in preventing H/R injury by modulating anti-oxidant and anti-apoptotic factors and promoting autophagy.
Keyphrases
- cell death
- cell cycle arrest
- endoplasmic reticulum stress
- dna repair
- induced apoptosis
- oxidative stress
- reactive oxygen species
- endothelial cells
- signaling pathway
- cell proliferation
- drug delivery
- left ventricular
- transcription factor
- poor prognosis
- climate change
- small molecule
- protein protein
- dna damage response
- blood brain barrier
- long non coding rna
- atrial fibrillation
- cancer therapy