Propofol-Anesthesia, Diabetes and Myocardial Signal Transduction: Role of Protein Kinase C and Nitric Oxide
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Kent State University / OhioLINK
2008
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ndltd-OhioLink-oai-etd.ohiolink.edu-kent12065544122021-08-03T05:36:32Z Propofol-Anesthesia, Diabetes and Myocardial Signal Transduction: Role of Protein Kinase C and Nitric Oxide Wickley, Peter J. Biomedical Research anesthesia diabetes cardiac protein kinase C nitric oxide <p>Induction and maintenance of anesthesia typically causes myocardial depression in healthy patients presenting for cardiac surgery. Moreover, the diabetic patient presents the anesthesiologist with an even greater risk for adverse clinical outcomes during the pre-, peri- and post-operative periods due to pre-existing myocardial dysfunction associated with the disease. Intracellular free Ca2+ concentration ([Ca2+]i) and myofilament Ca2+ sensitivity are the two key factors regulating cardiomyocyte function. We previously demonstrated that the intravenous anesthetic, propofol, modifies cardiomyocyte contractile function via interactions with multiple signaling pathways. Several potential mediators may be involved including protein kinase C (PKC) and nitric oxide synthase (NOS). The overall working hypothesis of this investigation is that activation of individual PKC and/or NOS isoforms in myocardial cells mediate the cardiac contractile dysfunction observed in response to propofol and experimental diabetes. </p><p>I first tested the hypothesis that propofol stimulates PKC activation and translocation to distinct intracellular sites in cardiomyocytes where they can potentially alter [Ca2+]i and/or myofilament Ca2+ sensitivity. I then tested the hypothesis that PKC and/or NOS isoform expression was up-regulated in diabetic cardiomyocytes and whether an increase in their activity is responsible for the propofol-induced alterations in cellular signaling pathways regulating [Ca2+]i and/or myofilament Ca2+ sensitivity. Finally, I assessed the role of superoxide in regulating nitric oxide (NO) bioavailability, as well as cellular mechanisms leading to NOS activation in diabetic cardiomyocytes. </p><p>I observed that propofol stimulates translocation of PKC alpha, PKC delta, PKC epsilon and PKC zeta to distinct intracellular locations in cardiomyocytes. I also observed that [Ca2+]i and myofilament Ca2+ sensitivity is reduced in diabetic cardiomyocytes and that propofol causes a PKC- and NOS-dependent reduction in [Ca2+]i and myofilament Ca2+ sensitivity. Propofol also prolongs cytosolic Ca2+ removal in diabetic cardiomyocytes via a PKC-dependent inhibition of the Na+/Ca2+ exchanger. Finally, NO bioavailability, eNOS phosphorylation and expression of heat shock protein 90 are decreased, while Akt phosphorylation is increased in diabetic cardiomyocytes. In diabetic rats, the decrease in cardiomyocyte NO bioavailability is rescued by intraperitoneal injection of superoxide dismutase. I suggest that increases in PKC and/or NO are important mediators of myocardial dysfunction observed in response to propofol and/or experimental diabetes.</p> 2008-03-27 English text Kent State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=kent1206554412 http://rave.ohiolink.edu/etdc/view?acc_num=kent1206554412 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biomedical Research anesthesia diabetes cardiac protein kinase C nitric oxide |
| spellingShingle |
Biomedical Research anesthesia diabetes cardiac protein kinase C nitric oxide Wickley, Peter J. Propofol-Anesthesia, Diabetes and Myocardial Signal Transduction: Role of Protein Kinase C and Nitric Oxide |
| author |
Wickley, Peter J. |
| author_facet |
Wickley, Peter J. |
| author_sort |
Wickley, Peter J. |
| title |
Propofol-Anesthesia, Diabetes and Myocardial Signal Transduction: Role of Protein Kinase C and Nitric Oxide |
| title_short |
Propofol-Anesthesia, Diabetes and Myocardial Signal Transduction: Role of Protein Kinase C and Nitric Oxide |
| title_full |
Propofol-Anesthesia, Diabetes and Myocardial Signal Transduction: Role of Protein Kinase C and Nitric Oxide |
| title_fullStr |
Propofol-Anesthesia, Diabetes and Myocardial Signal Transduction: Role of Protein Kinase C and Nitric Oxide |
| title_full_unstemmed |
Propofol-Anesthesia, Diabetes and Myocardial Signal Transduction: Role of Protein Kinase C and Nitric Oxide |
| title_sort |
propofol-anesthesia, diabetes and myocardial signal transduction: role of protein kinase c and nitric oxide |
| publisher |
Kent State University / OhioLINK |
| publishDate |
2008 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=kent1206554412 |
| work_keys_str_mv |
AT wickleypeterj propofolanesthesiadiabetesandmyocardialsignaltransductionroleofproteinkinasecandnitricoxide |
| _version_ |
1719422420604944384 |