title: Impaired redox signaling and mitochondrial uncoupling contributes vascular inflammation and cardiac dysfunction in type 1 diabetes: Protective role of arjunolic acid.
abstract: Vascular inflammation and cardiac dysfunction are the leading causes of mortality and morbidity among the diabetic patients. Type 1 diabetic mellitus (T1DM) is associated with increased cardiovascular complications at an early stage of the disease. The purpose of the present study was to explore whether arjunolic acid (AA) plays any protective role against cardiovascular complications in T1DM and if so, what molecular pathways it utilizes for the mechanism of its protective action. Streptozotocin (STZ) was used to induce T1DM in experimental rats. Alteration in plasma lipid profile and release of membrane bound enzymes like LDH (lactate dehydrogenase) and CK (creatine kinase) established the association of hyperlipidemia and cell membrane disintegration with hyperglycemia. Hyperglycemia altered the levels of oxidative stress related biomarkers, decreased the intracellular NAD and ATP concentrations. Hyperglycemia-induced enhanced levels of VEGF, ICAM-1, MCP-1 and IL-6 in the plasma of STZ treated animals indicate vascular inflammation in T1DM. Histological studies and FACS analysis revealed that hyperglycemia caused cell death mostly via the apoptotic pathway. Investigating molecular mechanism, we observed NF-κB and MAPKs (p38 and ERK1/2) activations, mitochondrial membrane depolarization, cytochrome C release, caspase 3 activation and PARP cleavage in apoptotic cell death in the diabetic cardiac tissue. Treatment with AA (20 mg/kg body weight) reduced hyperglycemia, membrane disintegration, oxidative stress, vascular inflammation and prevented the activation of oxidative stress induced signaling cascades leading to cell death. Results suggest that AA possesses the potential to be a beneficial therapeutic agent in diabetes and its associated cardiac complications.
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, West Bengal, India.
authors.forename: Prasenjit
authors.initials: P
authors.lastname: Manna
authors.forename: Parames C
authors.initials: PC
authors.lastname: Sil
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D018932:Chemokine CCL2 / Q000097:blood; D045304:Cytochromes c / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D005434:Flow Cytometry; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D051336:Mitochondrial Membranes / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D000975:Antioxidants; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D007004:Hypoglycemic Agents; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D014315:Triterpenes; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; C061640:arjunolic acid; D045304:Cytochromes c