The involvement of angiogenesis in disease and its potential as a therapeutic target have been firmly established over recent decades. Endothelial cells (ECs) are central elements in vessel homeostasis and regulate the passage of material and cells into and out of the bloodstream. EC proliferation and migration are modified by alterations to mitochondrial biogenesis and dynamics resulting from several signals and environmental cues, such as oxygen, hemodynamics, and nutrients. As intermediary signals, mitochondrial ROS are released as important downstream modulators of the expression of angiogenesis-related genes. In this review, we discuss the physiological actions of these signals and aberrant responses during vascular disorders.

Mitochondria in endothelial cells: Sensors and integrators of environmental cues.

Oxidative stress is a great challenge to neurons following cerebral ischemia. PGC-1α has been shown to act as a potent modulator of oxidative metabolism. In this study, the effects of ZLN005, a small molecule that activate PGC-1α, against oxygen–glucose deprivation (OGD)- or ischemia-induced neuronal injury in vitro and in vivo were investigated. Transient middle cerebral artery occlusion (tMCAO) was performed in rats and ZLN005 was administered intravenously at 2 h, 4 h, or 6 h after ischemia onset. Infarct volume and neurological deficit score were detected to evaluate the neuroprotective effects of ZLN005. Well-differentiated PC12 cells, which were subjected to OGD for 2 h followed by reoxygenation for 22 h, were used as an in vitro ischemic model. Changes in expression of PGC-1α, its related genes, and antioxidant genes were determined by real-time quantitative PCR. The results showed that ZLN005 reduced cerebral infarct volume and improved the neurological deficit in rat with tMCAO, and significantly protected OGD-induced neuronal injury in PC12 cells. Furthermore, ZLN005 enhanced expression of PGC-1α in PC12 cells and in the ipsilateral hemisphere of rats with tMCAO. Additionally, ZLN005 increased antioxidant genes, including SOD1 and HO-1, and significantly prevented the ischemia-induced decrease in SOD activity. Taking together, the PGC-1α activator ZLN005 exhibits neuroprotective effects under ischemic conditions and molecular mechanisms possibly involve activation of PGC-1α signaling pathway and cellular antioxidant systems.

The PGC-1α Activator ZLN005 Ameliorates Ischemia-Induced Neuronal Injury In Vitro and In Vivo

During goat follicular development, abnormal expression of peroxisome proliferator- activated receptor gamma coactivator-1 alpha (PGC-1α) in granulosa cells (GCs) may contribute to follicular atresia with unknown regulatory mechanisms. In this study, we investigate the effect of ectopic expression or interference of PGC-1α on cell apoptosis of goat first passage granulosa cells (FGCs) in vitro. The results indicate that PGC-1α silencing by short hairpin RNA (shRNA) in goat FGCs significantly reduced mitochondrial DNA (mtDNA) copy number (P < 0.05), changed mitochondria ultrastructure, and induced cell apoptosis (P < 0.05). The transcription and translation levels of the apoptosis-related genes BCL-2-associated X protein (BAX), caspase 3, and caspase 9 were significantly up-regulated (P < 0.05, respectively). Moreover, the ratio of BAX/B-cell lymphoma 2 (BCL-2) was reduced (P < 0.05), and the release of cytochrome c (cyt c) and lactate dehydrogenase (LDH) was significantly enhanced (P < 0.05, respectively) in PGC-1α interference goat FGCs. Furthermore, the expression of anti-oxidative related genes superoxide dismutase 2 (SOD2), glutathione peroxidase (GPx) and catalase (CAT) was down-regulated (P < 0.05, respectively) and the activity of glutathione/glutathione disulfide (GSH/GSSG) was inhibited (P < 0.05). While enforced expression of PGC-1α increased the levels of genes involved in the regulation of mitochondrial function and biogenesis, and enhanced the anti-oxidative and anti-apoptosis capacity. Taken together, our results reveal that lack of PGC-1α may lead to mitochondrial dysfunction and disrupt the cellular redox balance, thus resulting in goat GCs apoptosis through the mitochondria-dependent apoptotic pathway.

Effect of PGC-1α overexpression or silencing on mitochondrial apoptosis of goat luteinized granulosa cells.

Resveratrol, a natural phytochemical found in grapes and red wine, has been found to possess protective effects against endothelial cell apoptosis and oxidative damage. Oxidized‑low density lipoprotein (ox‑LDL) can induce apoptosis of endothelial cells, which is an important initial event in several cardiovascular diseases. However, the effect of resveratrol on ox‑LDL‑induced apoptosis and oxidative damage, and the possible associated mechanisms remain to be elucidated. In the present study, following exposure to ox‑LDL, human umbilical vein endothelial cells (HUVECs) were treated with or without resveratrol. Cell viability was examined using Cell Counting Kit‑8 and 5‑bromo‑2'‑deoxyuridine uptake assays, respectively. Cell apoptosis was determined by flow cytometry. Apoptosis‑associated markers were detected using western blot analysis. Oxidative stress was analyzed using molecular and biochemical approaches. Resveratrol restored ox‑LDL‑induced HUVEC injury and apoptosis in a dose‑dependent manner. In addition, compared with the control group, ox‑LDL treatment decreased the B cell lymphoma‑2 (Bcl‑2)/Bcl‑2‑associated X protein ratio, mitochondrial membrane potential and activation of superoxide dismutase, and enhanced the release of mitochondrial cytochrome c into the cytoplasm, the activation of caspase and lipid peroxidation. All these alterations were significantly inhibited following treatment with resveratrol. The results demonstrated that resveratrol prevented HUVEC apoptosis through inhibiting mitochondria‑derived oxidative damage. These findings may provide a novel mechanism by which resveratrol prevents against endothelial cell apoptosis.

/pdf/resveratrol-protects-against-oxidized-low-density-4wl33o6lcc.pdf

Resveratrol protects against oxidized low‑density lipoprotein‑induced human umbilical vein endothelial cell apoptosis via inhibition of mitochondrial‑derived oxidative stress

PGC-1α ameliorates AngiotensinII-induced eNOS dysfunction in human aortic endothelial cells.

Endothelial cells (ECs) apoptosis induced by hyperglycemia is intimately involved in the pathophysiology of diabetes and its complication Although PGC-1α is known for its role in glucose metabolism, its role in ECs injury caused by high glucose milieu is still unclear Therefore, this study aims to investigate whether PGC-1α participates in ECs apoptosis under high glucose condition Human umbilical vein endothelial cells (HUVECs) were down-regulated PGC-1α expression by adenovirus-mediated PGC-1α specific siRNA (Ad-shPGC-1α) and exposed to high glucose Cell viability, apoptosis, mitochondrial membrane permeability, apoptotic marker, reactive oxygen species (ROS), and expression of PGC-1α and VDAC isoforms were studied Our results showed that high glucose-induced cell apoptosis was associated with an obvious decrease in PGC-1α expression Lack of PGC-1α exacerbated high glucose-induced cell apoptosis, inner mitochondrial membrane permeabilization, mitochondrial cytochrome c release into cytoplasm and caspases activation; while further decreased cell viability and mitochondrial membrane potential Analysis of apoptotic markers (Bcl-2, Bax), intracellular ROS and endoplasmic reticulum stress revealed that these mechanisms were not accounted for the effects of Ad-shPGC-1α on apoptosis However, we found silencing PGC-1α further increased high glucose-induced VDAC1 expression The pharmacological inhibition of VDAC1 with 4,4’-diisothiocyanostilbene-2,2’-disulfonic acid (DIDS) inhibited the increased apoptosis in high glucose-treated PGC-1α knockdown cells These findings strongly suggest that PGC-1α defect is one of the major mechanisms for ECs apoptosis under high glucose condition, and provide a novel strategy to prevent endothelial dysfunction in diabetes

Lack of PGC-1α exacerbates high glucose-induced apoptosis in human umbilical vein endothelial cells through activation of VADC1.

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Lack of PGC-1α exacerbates high glucose-induced apoptosis in human umbilical vein endothelial cells through activation of VADC1.