cytochrome-c-t and Vascular-Diseases

Vascular calcification is prevalent in patients with chronic kidney disease and leads to increased cardiovascular morbidity and mortality. Although several reports have implicated mitochondrial dysfunction in cardiovascular disease and chronic kidney disease, little is known about the potential role of mitochondrial dysfunction in the process of vascular calcification. This study investigated the effect of α-lipoic acid (ALA), a naturally occurring antioxidant that improves mitochondrial function, on vascular calcification in vitro and in vivo. Calcifying vascular smooth muscle cells (VSMCs) treated with inorganic phosphate (Pi) exhibited mitochondrial dysfunction, as demonstrated by decreased mitochondrial membrane potential and ATP production, the disruption of mitochondrial structural integrity and concurrently increased production of reactive oxygen species. These Pi-induced functional and structural mitochondrial defects were accompanied by mitochondria-dependent apoptotic events, including release of cytochrome c from the mitochondria into the cytosol, subsequent activation of caspase-9 and -3, and chromosomal DNA fragmentation. Intriguingly, ALA blocked the Pi-induced VSMC apoptosis and calcification by recovery of mitochondrial function and intracellular redox status. Moreover, ALA inhibited Pi-induced down-regulation of cell survival signals through the binding of growth arrest-specific gene 6 (Gas6) to its cognate receptor Axl and subsequent Akt activation, resulting in increased survival and decreased apoptosis. Finally, ALA significantly ameliorated vitamin D(3) -induced aortic calcification and mitochondrial damage in mice. Collectively, the findings suggest ALA attenuates vascular calcification by inhibiting VSMC apoptosis through two distinct mechanisms; preservation of mitochondrial function via its antioxidant potential and restoration of the Gas6/Axl/Akt survival pathway.

Topics: Animals; Apoptosis; Axl Receptor Tyrosine Kinase; Calcium; Caspase 3; Caspase 9; Cells, Cultured; Cholecalciferol; Cytochromes c; DNA Fragmentation; Humans; Intercellular Signaling Peptides and Proteins; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Mitochondria; Muscle, Smooth, Vascular; Phosphates; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Receptor Protein-Tyrosine Kinases; Thioctic Acid; Vascular Calcification; Vascular Diseases

Vascular disease is the leading cause of morbidity and mortality. Oxidative stress can cause endothelial cell apoptosis. Low insulin like growth factor-1 (IGF-1) has been linked to adverse risk profile and increased vascular disease incidence. Since IGF-1 acts as an important survival factor for multiple cell types, we undertook this study to investigate whether IGF-1 favorably affects oxidative-stress mediated apoptosis of vascular endothelial cells. Exposure to hydrogen peroxide induced apoptotic changes (e.g. DNA fragmentation, altered mitochondrial membrane potential and caspase-3 activity) in human umbilical vein endothelial cells (HUVECs) in a time dependent manner. Addition of IGF-1 blocked the oxidative-stress effect parallel to IGF-1 receptor (IGF-1R) expression, and silencing the IGF-1R with small interference RNA attenuated the IGF-1 influence. Our findings show that enhanced IGF-1 signaling inhibits oxidative-stress induced apoptosis in HUVECs by reducing mitochondrial dysfunction. Specifically the protective mechanism of IGF-1 involves preserving the mitochondrial membrane potential, maintaining the mitochondrial retention of cytochrome-c, and reducing caspase-3 activity. These results may have therapeutic implications in preventing/reducing vascular disease associated endothelial dysfunction.

Topics: Apoptosis; Caspase 3; Caspase Inhibitors; Cells, Cultured; Cytochromes c; DNA Fragmentation; Gene Silencing; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen Peroxide; Insulin-Like Growth Factor I; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Stress; Receptor, IGF Type 1; RNA, Small Interfering; Signal Transduction; Vascular Diseases

Topics: Catabolite Repression; Cytochromes; Cytochromes c; Glucose; Glutarates; Ketoglutaric Acids; Liver Diseases; Pyruvates; Pyruvic Acid; Vascular Diseases