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Ursolic-Acid-Enriched Herba Cynomorii Extract Protects against Oxidant Injury in H9c2 Cells and Rat Myocardium by Increasing Mitochondrial ATP Generation Capacity and Enhancing Cellular Glutathione Redox Cycling, Possibly through Mitochondrial Uncoupling.

ABSTRACT: Mitochondrial decay is considered to be a major contributor to aging-related diseases, including neurodegenerative diseases, cardiovascular disorders, and certain metabolic diseases. Therefore, the maintenance of mitochondrial functional capacity and antioxidant status should play an essential role in preventive health. Herba Cynomorii, which is one of the most potent "Yang-invigorating" Chinese tonic herbs, was found to increase mitochondrial ATP generation capacity (ATP-GC) in rat hearts ex vivo. In the present study, we demonstrated that HCY2, an active fraction of Herba Cynomorii, and its major ingredient ursolic acid (UA) could protect against hypoxia/reoxygenation-induced cell apoptosis in H9c2 cells in vitro and also against ischemia/reperfusion-induced injury in rat hearts ex vivo. The cardioprotection was associated with an increase in ATP-GC and an enhancement of glutathione redox cycling. The results suggest that UA may be one of the active ingredients responsible for the cardioprotection afforded by Herba Cynomorii, and this effect may be mediated, at least in part, by enhancement of mitochondrial functional capacity and antioxidant status, possibly through the induction of mitochondrial uncoupling.

SUBMITTER: Chen J

PROVIDER: S-EPMC3638637 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Ursolic-Acid-Enriched Herba Cynomorii Extract Protects against Oxidant Injury in H9c2 Cells and Rat Myocardium by Increasing Mitochondrial ATP Generation Capacity and Enhancing Cellular Glutathione Redox Cycling, Possibly through Mitochondrial Uncoupling.

Chen Jihang J Ko Kam Ming KM

Evidence-based complementary and alternative medicine : eCAM 20130410

Mitochondrial decay is considered to be a major contributor to aging-related diseases, including neurodegenerative diseases, cardiovascular disorders, and certain metabolic diseases. Therefore, the maintenance of mitochondrial functional capacity and antioxidant status should play an essential role in preventive health. Herba Cynomorii, which is one of the most potent "Yang-invigorating" Chinese tonic herbs, was found to increase mitochondrial ATP generation capacity (ATP-GC) in rat hearts ex vi ...[more]

PMID: 23690863

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Project description:Diabetic complications are the leading cause of morbidity and mortality in diabetic patients. Elevated blood glucose contributes to the development of endothelial and vascular dysfunction, and, consequently, to diabetic micro- and macrovascular complications, because it increases the mitochondrial proton gradient and mitochondrial oxidant production. Therapeutic approaches designed to counteract glucose-induced mitochondrial reactive oxygen species (ROS) production in the vasculature are expected to show efficacy against all diabetic complications, but direct pharmacological targeting (scavenging) of mitochondrial oxidants remains challenging due to the high reactivity of some of these oxidant species. In a recent study, we have conducted a medium-throughput cell-based screening of a focused library of well-annotated pharmacologically active compounds and identified glucocorticoids as inhibitors of mitochondrial superoxide production in microvascular endothelial cells exposed to elevated extracellular glucose. The goal of the current study was to investigate the mechanism of glucocorticoids' action. Our findings show that glucocorticoids induce the expression of the mitochondrial UCP2 protein and decrease the mitochondrial potential. UCP2 silencing prevents the protective effect of the glucocorticoids on ROS production. UCP2 induction also increases the oxygen consumption and the "proton leak" in microvascular endothelial cells. Furthermore, glutamine supplementation augments the effect of glucocorticoids via further enhancing the expression of UCP2 at the translational level. We conclude that UCP2 induction represents a novel experimental therapeutic intervention in diabetic vascular complications. While direct repurposing of glucocorticoids may not be possible for the therapy of diabetic complications due to their significant side effects that develop during chronic administration, the UCP2 pathway may be therapeutically targetable by other, glucocorticoid-independent pharmacological means.

Project description:IntroductionOxidative phosphorylation is an essential feature of Animalian life. Multiple adaptations have developed to protect against hypoxia, including hypoxia-inducible-factors (HIFs). The major role of HIFs may be in protecting against oxidative stress, not the preservation of high-energy phosphates. The precise mechanism(s) of HIF protection is not completely understood.Materials and methodsTo better understand the role of hypoxia-inducible-factor-1, we exposed heart/myocardium cells (H9c2) to both normoxia and hypoxia, as well as cobalt chloride (prolyl hydroxylase inhibitor), echniomycin (HIF inhibitor), A2P (anti-oxidant), and small interfering RNA to beclin-1. We measured cell viability, intracellular calcium and adenosine triphosphate, NADP/NADPH ratios, total intracellular reactive oxidative species levels, and markers of oxidative and antioxidant levels measured.ResultsHypoxia (1%) leads to increased intracellular Ca2+ levels, and this response was inhibited by A2P and echinomycin (ECM). Exposure of H9c2 cells to hypoxia also led to an increase in both mRNA and protein expression for Cav 1.2 and Cav 1.3. Exposure of H9c2 cells to hypoxia led to a decrease in intracellular ATP levels and a sharp reduction in total ROS, SOD, and CAT levels. The impact of hypoxia on ROS was reversed with HIF-1 inhibition through ECM. Exposure of H9c2 cells to hypoxia led to an increase in Hif1a, VEGF and EPO protein expression, as well as a decrease in mitochondrial DNA. Both A2P and ECM attenuated this response to varying degrees.ConclusionHypoxia leads to increased intracellular Ca2+, and inhibition of HIF-1 attenuates the increase in intracellular Ca2+ that occurs with hypoxia. HIF-1 expression leads to decreased adenosine triphosphate levels, but the role of HIF-1 on the production of reactive oxidative species remains uncertain. Anti-oxidants decrease HIF-1 expression in the setting of hypoxia and attenuate the increase in Ca2+ that occurs during hypoxia (with no effect during normoxia). Beclin-1 appears to drive autophagy in the setting of hypoxia (through ATG5) but not in normoxia. Additionally, Beclin-1 is a powerful driver of reactive oxidative species production and plays a role in ATP production. HIF-1 inhibition does not affect autophagy in the setting of hypoxia, suggesting that there are other drivers of autophagy that impact beclin-1.

Dataset Information

Ursolic-Acid-Enriched Herba Cynomorii Extract Protects against Oxidant Injury in H9c2 Cells and Rat Myocardium by Increasing Mitochondrial ATP Generation Capacity and Enhancing Cellular Glutathione Redox Cycling, Possibly through Mitochondrial Uncoupling.

Publications

Ursolic-Acid-Enriched Herba Cynomorii Extract Protects against Oxidant Injury in H9c2 Cells and Rat Myocardium by Increasing Mitochondrial ATP Generation Capacity and Enhancing Cellular Glutathione Redox Cycling, Possibly through Mitochondrial Uncoupling.

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