Inhibition of protein kinase C βII isoform ameliorates methylglyoxal advanced glycation endproduct-induced cardiomyocyte contractile dysfunction
| Autor: | Bingyang Chen, Dong Shen, Dangsheng Huang, Sara A. Babcock, Liwei Zhang, Jun Ren, Yongjiang Ma, Chunhong Zhang |
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| Rok vydání: | 2014 |
| Předmět: |
Glycation End Products
Advanced Male medicine.medical_specialty Programmed cell death Indoles Blotting Western Apoptosis medicine.disease_cause General Biochemistry Genetics and Molecular Biology Maleimides Rats Sprague-Dawley chemistry.chemical_compound Glycation Internal medicine Diabetic cardiomyopathy Protein Kinase C beta medicine Animals Myocytes Cardiac General Pharmacology Toxicology and Pharmaceutics Protein kinase C Aconitate Hydratase NADPH oxidase biology Methylglyoxal General Medicine Pyruvaldehyde medicine.disease Myocardial Contraction Mitochondria Rats Oxidative Stress Endocrinology chemistry Apocynin biology.protein Calcium Oxidative stress |
| Zdroj: | Life Sciences. 94:83-91 |
| ISSN: | 0024-3205 |
| DOI: | 10.1016/j.lfs.2013.11.011 |
| Popis: | Aims Accumulation of advanced glycation endproduct (AGE) contributes to diabetic complication including diabetic cardiomyopathy although the precise underlying mechanism still remains elusive. Recent evidence depicted a pivotal role of protein kinase C (PKC) in diabetic complications. To this end, this study was designed to examine if PKCβII contributes to AGE-induced cardiomyocyte contractile and intracellular Ca 2 + aberrations. Main methods Adult rat cardiomyocytes were incubated with methylglyoxal-AGE (MG-AGE) in the absence or presence of the PKCβII inhibitor LY333531 for 12 h. Contractile and intracellular Ca 2 + properties were assessed using an IonOptix system including peak shortening (PS), maximal velocity of shortening/relengthening (± dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR 90 ), rise in intracellular Ca 2 + Fura-2 fluorescence intensity and intracellular Ca 2 + decay. Oxidative stress, O 2 − production and mitochondrial integrity were examined using TBARS, fluorescence imaging, aconitase activity and Western blotting. Key findings MG-AGE compromised contractile and intracellular Ca 2 + properties including reduced PS, ± dL/dt, prolonged TPS and TR 90 , decreased electrically stimulated rise in intracellular Ca 2 + and delayed intracellular Ca 2 + clearance, the effects of which were ablated by the PKCβII inhibitor LY333531. Inhibition of PKCβII rescued MG-AGE-induced oxidative stress, O 2 − generation, cell death, apoptosis and mitochondrial injury (reduced aconitase activity, UCP-2 and PGC-1α). In vitro studies revealed that PKCβII inhibition-induced beneficial effects were replicated by the NADPH oxidase inhibitor apocynin and were mitigated by the mitochondrial uncoupler FCCP. Significance These findings implicated the therapeutic potential of specific inhibition of PKCβII isoform in the management of AGE accumulation-induced myopathic anomalies. |
| Databáze: | OpenAIRE |
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