Hua Y.,Center for Cardiovascular Research and Alternative Medicine |
Kandadi M.R.,Center for Cardiovascular Research and Alternative Medicine |
Zhu M.,University of Wyoming |
Ren J.,Center for Cardiovascular Research and Alternative Medicine |
Sreejayan N.,Center for Cardiovascular Research and Alternative Medicine
Journal of Cardiovascular Pharmacology | Year: 2010
BACKGROUND/AIM:: Recent evidence suggests that endoplasmic reticulum (ER) stress provoked under diabetic conditions augments the expression of scavenger receptors on macrophages, promoting the uptake of oxidized low-density lipoprotein uptake and atherogenesis. The aim of the present study was to test the hypothesis that the chemical chaperone tauroursodeoxycholic acid (TUDCA) attenuates lipid accumulation in macrophages subjected to ER stress. METHODS:: Cultured human macrophages were subjected to ER stress by treating them with tunicamycin. Lipid uptake by macrophages subjected to ER stress in the presence or absence of TUDCA was assessed by oil red O staining and by assessing the cellular uptake of Dil-oxidized low-density lipoprotein by fluorescence measurement. Protein levels and phosphorylation status of ER stress markers, insulin-signaling molecules, and scavenger receptor were assessed by Western blotting. RESULTS:: Treatment of cultured human macrophages with the ER stressor tunicamycin caused an increase in the protein levels of cluster of differentiation 36 (CD-36) and augmentation of lipid uptake both of which were inhibited by TUDCA. TUDCA treatment inhibited tunicamycin-induced ER stress as evidenced by the attenuation of phosphorylation of eukaryotic translation initiation factor-2a and glucose reactive protein-78. In addition, TUDCA improved insulin signaling in macrophages by augmenting Akt phosphorylation and blunting c-Jun N-terminal kinase activity. CONCLUSIONS:: Inhibition of macrophage ER stress may represent a potential strategy in preventing atherogenesis under diabetic conditions. Copyright © 2010 by Lippincott Williams & Wilkins.
Ge W.,PLA Fourth Military Medical University |
Ge W.,Center for Cardiovascular Research and Alternative Medicine |
Hu N.,Center for Cardiovascular Research and Alternative Medicine |
George L.A.,University of Wyoming |
And 7 more authors.
Journal of Nutritional Biochemistry | Year: 2013
Maternal nutrient restriction during pregnancy is associated with the development of a "thrifty phenotype" in offspring, conferring increased prevalence of metabolic diseases in adulthood. To explore the possible mechanisms behind heart diseases in adulthood following maternal nutrient restriction, dams were fed a nutrient-restricted (NR: 50%) or control (100%) diet from 28 to 78 days of gestation. Both groups were then fed 100% of requirements to lambing. At 6 years of age, female offspring of NR and control ewes of similar weight and body condition were subjected to ad libitum feeding of a highly palatable diet for 12 weeks. Cardiac geometry, post-insulin receptor signaling, autophagy and proinflammatory cytokines were evaluated in hearts from adult offspring. Our results indicated that maternal nutrient restriction overtly increased body weight gain and triggered cardiac remodeling in offspring following the 12-week ad libitum feeding. Phosphorylation of insulin receptor substrate-1 (IRS1) was increased in left but not right ventricles from NR offspring. Levels of signal transducer and activator of transcription-3 were up-regulated in left ventricles, whereas expression of tumor necrosis factor-α and toll-like receptor-4 was enhanced in right ventricles, in adult offspring of maternal nutrition-restricted ewes. No significant differences were found in pan-IRS1, pan-AMP-dependent protein kinase (AMPK), pan-Akt, phosphorylated AMPK, phosphorylated Akt, glucose transporter 4, phosphorylated mammalian target of rapamycin, Beclin-1 and microtubule-associated protein 1 light-chain 3 II proteins in left and right ventricles between the control and NR offspring. These data revealed that maternal nutrient restriction during early to mid gestation may predispose adult offspring to cardiac remodeling possibly associated with phosphorylation of IRS1 as well as proinflammatory cytokines but not autophagy. © 2013 Elsevier Inc.
Ma H.,Center for Cardiovascular Research and Alternative Medicine |
Ma H.,PLA Fourth Military Medical University |
Jones K.R.,Center for Cardiovascular Research and Alternative Medicine |
Guo R.,Center for Cardiovascular Research and Alternative Medicine |
And 4 more authors.
Clinical and Experimental Pharmacology and Physiology | Year: 2010
Summary 1. Cisplatin is a potent chemotherapeutic agent with broad-spectrum antineoplastic activity against various types of tumours. However, a major factor limiting treatment with cisplatin is its acute and cumulative cardiotoxicity. The aim of the present study was to explore the effect of cisplatin on myocardial contractile function and the possible underlying cellular mechanisms. 2. C57 mice were treated with cisplatin (10 mg/kg per day, i.v.) or vehicle (0.9% NaCl) for 1 week and myocardial function was assessed using the Langendorff and cardiomyocyte edge-detection systems. Transmission electron microscopy, mitochondrial membrane potential, indices of endoplasmic reticulum (ER) stress and caspase 3 activity were evaluated. 3. Cisplatin-treated mice developed myocardial contractile dysfunction, as evidenced by a reduction in left ventricular developed pressure (LVDP) and the first derivative of LVDP (+/-dP/dt). Cisplatin treatment significantly prolonged time to 90% relengthening, depressed peak shortening, maximal velocity of shortening/relengthening (+/-dL/dt) and augmented the frequency-elicited depression in peak shortening. The JC-1 fluorescent assay demonstrated that cispatin-induced cardiac dysfunction was associated with mitochondrial membrane depolarization. Transmission electron microscopy revealed that cisplatin induces ultrastructural abnormalities of the mitochondria. Following cisplatin treatment, cardiomyocytes show activation of the ER stress response, increased caspase 3 activity and increased terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) staining. 4. The data indicate that cisplatin is cardiotoxic and may lead to left ventricular dysfunction and depressed cardiomyocyte contraction associated with mitochondrial abnormalities, enhanced ER stress and apoptosis. This work should shed some light on the management of cisplatin-induced cardiac injury. © 2010 Blackwell Publishing Asia Pty Ltd.