Arjunolic acid ameliorates reactive oxygen species via inhibition of p47 phox -serine phosphorylation and mitochondrial dysfunction

Abstract

Impaired cardiovascular function during acute myocardial infarction (MI) is partly associated with recruitment of activated polymorphonuclear neutrophils. The protective role of arjunolic acid (AA; 2:3:23-Trihydroxy olean-12-en-28-oic acid) is studied in the modulation of neutrophil functions in vitro by measuring the reactive oxygen species (ROS) generation. Neutrophils were isolated from normal and acute MI mice to find out the efficacy of AA in reducing oxidative stress. Stimulation of neutrophils with phorbol-12-myristate-13-acetate (PMA) resulted in an oxidative burst of superoxide anion (O2•−) and enhanced release of lysosomal enzymes. The treatment of neutrophils with PMA induced phosphorylation of Ser345 on p47phox, a cytosolic component of NADPH oxidase. Furthermore, we observed activated ERK induced phosphorylation of Ser345 in MI neutrophils. Treatment with AA significantly inhibited the phosphorylation of P47phox and ERK in the stimulated controls and MI neutrophils. Oxidative phosphorylation activities in MI cells were lower than in control, while the glycolysis rates were elevated in MI cells compared to the control. In addition, we observed AA decreased intracellular oxidative stress and reduced the levels of O2•− in neutrophils. This study therefore identifies targets for AA in activated neutrophils mediated by the MAPK pathway on p47phox involved in ROS generation.

Energy metabolism disorders and potential therapeutic drugs in heart failure

“…Ginsenoside Rb3 protects the heart by regulating PPAR α receptors to regulate fatty acid oxidation, protect the integrity of the mitochondrial membrane, and exert antiapoptotic effects 178 . Arjunolic acid, a naturally occurring chiral triterpenoid saponin, significantly inhibits the phosphorylation of P47 phox and ERK in neutrophils from myocardial infarction, and reduces oxidative phosphorylation activity, reactive oxygen levels and oxidative stress in cardiomyocytes to reduce mitochondrial dysfunction and increase glycolysis rate 179 . Furthermore, it upregulates PPAR α , reduces the phosphorylation level of TAK1, decreases p38 MAPK and NF- κ B P65 activation, reduces excessive collagen synthesis and cardiac hypertrophy, and protects the heart 180 .…”

Recent Progress in Environmental Toxins-Induced Cardiotoxicity and Protective Potential of Natural Products

“…The overall preventive effect of arjunolic acid may be due to its scavenging free radicals and metal chelating properties, thereby reducing the arsenic load in the cells ( Manna et al, 2008 ). Another research revealed that arjunolic acid could regulate oxidative phosphorylation in the mitochondria and subsequently inhibit ROS generation through abrogated p47phox-Ser345 phos phorylation in stimulated and myocardial infarction neutrophils, which is the first report showing the protective effect of arjunolic acid on p47phox phosphorylation and mitochondrial bioenergetics ( Miriyala et al, 2015 ). Moreover, arjunolic acid as a Peroxisome Proliferator-Activated Receptorα (PPARα) agonist up-regulates PPARα, leading to repression of TGF-β signaling, especially by inhibiting TGF-β activated kinase1phosphorylation, which reduces the activity of p38MAPK and NFκBp65, ultimately reversing hypertrophy-related myocardial fibrosis.…”

Cardioprotective Effects of Arjunolic Acid in LPS-Stimulated H9C2 and C2C12 Myotubes via My88-Dependent TLR4 Signaling Pathway

“…AA has been reported to possess a cardioprotective effect through different mechanisms. According to Miriyala et al (2015), arjunolic acid improved myocardial infarction (MI) by inhibiting reactive oxygen species (ROS) generation.…”