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1.
Ann Thorac Surg ; 104(6): 1909-1914, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29100648

ABSTRACT

BACKGROUND: Paraplegia from spinal cord ischemia-reperfusion (SCIR) remains an elusive and devastating complication of complex aortic operations. Erythropoietin (EPO) attenuates this injury in models of SCIR. Upregulation of the EPO beta common receptor (ßcR) is associated with reduced damage in models of neural injury. The purpose of this study was to examine whether EPO-mediated neuroprotection was dependent on ßcR expression. We hypothesized that spinal cord neurons subjected to oxygen-glucose deprivation would mimic SCIR injury in aortic surgery and EPO treatment attenuates this injury in a ßcR-dependent fashion. METHODS: Lentiviral vectors with ßcR knockdown sequences were tested on neuron cell cultures. The virus with greatest ßcR knockdown was selected. Spinal cord neurons from perinatal wild-type mice were harvested and cultured to maturity. They were treated with knockdown or nonsense virus and transduced cells were selected. Three groups (ßcR knockdown virus, nonsense control virus, no virus control; n = 8 each) were subjected to 1 hour of oxygen-glucose deprivation. Viability was assessed. ßcR expression was quantified by immunoblot. RESULTS: EPO preserved neuronal viability after oxygen-glucose deprivation (0.82 ± 0.04 versus 0.61 ± 0.01; p < 0.01). Additionally, EPO-mediated neuron preservation was similar in the nonsense virus and control mice (0.82 ± 0.04 versus 0.80 ± 0.05; p = 0.77). EPO neuron preservation was lost in ßcR knockdown mice compared with nonsense control mice (0.46 ± 0.03 versus 0.80 ± 0.05; p < 0.01). CONCLUSIONS: EPO attenuates neuronal loss after oxygen-glucose deprivation in a ßcR-dependent fashion. This receptor holds immense clinical promise as a target for pharmacotherapies treating spinal cord ischemic injury.


Subject(s)
Erythropoietin/pharmacology , Neurons/drug effects , Neurons/metabolism , Neuroprotection/physiology , Receptors, Erythropoietin/metabolism , Spinal Cord/pathology , Cell Culture Techniques , Cell Survival , Humans , Spinal Cord/metabolism
2.
Horm Metab Res ; 49(5): 400-406, 2017 May.
Article in English | MEDLINE | ID: mdl-28395380

ABSTRACT

The pharmacological effects of type 2 diabetes (T2DM) medications on lipoprotein metabolism are difficult to assess in preclinical models because those created failure to replicate the human condition in which insulin deficiency is superimposed on obesity-related insulin resistance. To create a better model, we fed mice with high fat (HF) diet and treated the animals with low dose streptozotocin (STZ) to mimic T2DM. We used this model to evaluate the effects of canagliflozin (CANA), a drug that reduces plasma glucose by inhibiting the sodium-glucose transporter 2 (SGLT2), which mediates ~90% of renal glucose reabsorption] on lipid and lipoprotein metabolism. After 6 weeks of CANA (30 mg/kg/day) treatment, the increase in total plasma cholesterol in HF-STZ diabetic mice was reversed, but plasma triglycerides were not affected. Lipoprotein fractionation and cholesterol distribution analysis showed that CANA kept HDL-Cholesterol, LDL-Cholesterol, and IDL-Cholesterol levels steady while these lipoprotein species were increased in placebo- and insulin-treated control groups. CANA treatment of HF-STZ mice reduced post-heparin plasma lipoprotein lipase (LPL) activity at 2 (-40%) and 5 (-30%) weeks compared to placebo. Tissue-specific LPL activity following CANA treatment showed similar reduction. In summary, CANA prevented the total cholesterol increase in HF-STZ mice without effects on plasma lipids or lipoproteins, but did decrease LPL, implying a potential role of LPL-dependent lipoprotein metabolism in CANA action. These effects did not recapitulate the effect of SGLT2 inhibitors on lipids and lipoproteins in human, suggesting that a better murine T2DM model (such as the ApoB100 humanized CETP-overexpressing mouse) is needed next.


Subject(s)
Canagliflozin/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Lipids/blood , Lipoproteins/blood , Animals , Blood Glucose/metabolism , Body Weight , Cholesterol/blood , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Type 2/blood , Diet, High-Fat , Heparin/pharmacology , Insulin/blood , Lipoprotein Lipase/metabolism , Male , Mice, Inbred C57BL , Myocardium/enzymology , Organ Specificity/drug effects , Streptozocin , Triglycerides/blood
3.
Eur J Pharm Sci ; 100: 163-175, 2017 Mar 30.
Article in English | MEDLINE | ID: mdl-28104473

ABSTRACT

The association of lipophilic statins with plasma lipoproteins in the presence of disturbed acid-base balance can modify the pharmacokinetics and tissue distribution of these drugs, resulting in alteration in their efficacy and toxicity profiles. The purpose of this study is to elucidate the role of hyperlipidaemia alone or in combination with acidosis/alkalosis in the development and potentiation of statin-induced myotoxicity. Statins association with plasma lipoproteins was examined under conditions of physiological and altered pH levels. The effect of this association on cellular uptake and myotoxicity of statins was also assessed at different pH levels using C2C12 cells that overexpress lipoprotein lipase. Lipophilic simvastatin displayed considerable association with the non-polar lipoprotein fractions (triglyceride-rich lipoproteins and low-density lipoprotein). This association contributed to increased cellular uptake of simvastatin by C2C12 cells through lipoprotein lipase-mediated process, resulting in enhanced muscle toxicity in hyperlipidaemic conditions. Furthermore, a combination of low pH environment (representing acidosis) and hyperlipidaemia increased the association of simvastatin with plasma lipoproteins causing potentiation of cellular uptake and myotoxicity of this drug. Comorbidities such as hyperlipidaemia, especially when coincident with acidosis, can enhance statin-associated muscle toxicity, and therefore require extra caution by prescribing clinicians. Hydrophilic rather than lipophilic statins could be a preferable choice in this patient population.


Subject(s)
Acidosis/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hyperlipidemias/metabolism , Muscular Diseases/chemically induced , Pravastatin/adverse effects , Simvastatin/adverse effects , Adult , Animals , Cell Line , Chylomicron Remnants/metabolism , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Lipoproteins/metabolism , Male , Mice , Models, Biological , Muscular Diseases/metabolism , Pravastatin/pharmacology , Simvastatin/pharmacology
4.
Biochem Biophys Res Commun ; 465(2): 287-92, 2015 Sep 18.
Article in English | MEDLINE | ID: mdl-26265042

ABSTRACT

LPL is the rate-limiting enzyme for uptake of TG-derived FFA in peripheral tissues, and the enzyme is expressed in the brain and CNS. We previously created a mouse which lacks neuronal LPL. This animal becomes obese on a standard chow, and we observed reduced lipid uptake in the hypothalamus at 3 months preceding obesity. In our present study, we replicated the animal phenotype in an immortalized mouse hypothalamic cell line (N41) to examine how LPL affects expression of AgRP as well as entry and storage of lipids into neurons. We show that LPL is able to modulate levels of the orexigenic peptide AgRP. LPL also exerts effects on lipid uptake into culture neurons, and that uptake of neutral lipid can be enhanced even by mutant LPL lacking catalytic activity. N41 cells also accumulate neutral lipid in droplets, and this is at least in part regulated by LPL. These data in addition to those published in mice with neuron-specific deletion of LPL suggest that neuronal LPL is an important regulator of lipid homeostasis in neurons and that alterations in LPL levels may have important effects on systemic metabolism and neuronal lipid biology.


Subject(s)
Apolipoproteins/metabolism , Hypothalamus/metabolism , Lipoprotein Lipase/metabolism , Neurons/metabolism , Triglycerides/metabolism , Agouti-Related Protein/genetics , Agouti-Related Protein/metabolism , Animals , Biological Transport , Cell Line, Transformed , Gene Expression , Genetic Vectors , Homeostasis/genetics , Humans , Hypothalamus/cytology , Lipid Droplets/metabolism , Lipid Metabolism , Lipoprotein Lipase/genetics , Mice , Neurons/cytology , Retroviridae/genetics , Retroviridae/metabolism , Signal Transduction
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