(Verbatim from the application): The long term objective of this proposal is to determine if impairment of cardioprotective signal transduction and increased oxidative stress are mechanisms responsible for the exacerbation of myocardial ischemic injury in diabetes and hyperglycemia, using an integrated cellular and physiological approach. Coronary artery disease is the leading cause of death in diabetic patients, and hyperglycemia has been described as one of the strongest predictors of death after acute myocardial infarction in both diabetic and non-diabetic patients. Recent findings from this laboratory have demonstrated that acute hyperglycemia abolishes the protection afforded by the early phase of ischemic preconditioning, an endogenous cardioprotective mechanism mediated by activation of adenosine receptors, protein kinase C (PKC) and adenosine triphosphate-regulated potassium (KATP) channels. Experiments conducted to meet Specific Aim 1 will address the hypotheses that acute hyperglycemia (dosedependently) and acute (3 weeks) and chronic (6 months) diabetes (alloxan/streptozotocin) exacerbate myocardial injury during ischemia and abolish the protection afforded by early and late ischemic preconditioning in canine myocardium.
Specific Aim 2 will address the hypotheses that hyperglycemia and diabetes attenuate cardioprotective signal transduction via inhibition of adenosine receptor (A1 and A3), PKC, and KATP channel activation. In vivo canine experiments measuring the reduction in myocardial infarct size in response to specific agonists will be complemented by in vitro experiments. Sarcolemmal KATP channel activity will be assessed using patch clamp techniques, mitochondrial KATP channel activity measured with flavoprotein fluorescence, interstitial adenosine concentrations determined with HPLC, and PKC isoforms quantified in control, hyperglycemic and diabetic dogs. The hypothesis that oxygen-derived free radicals contribute to enhanced myocardial injury via interactions with adenosine and KATP channels will be further investigated during Specific Aim 3. Experiments wifi be conducted in animals after chronic treatment with the antioxidants, tempol or dimethyithiourea, to reverse the deleterious effects of increased oxidant stress on the extent of ischemia and reperfusion injury, interstitial adenosine concentration and KATP channel activity induced by diabetes and hyperglycemia. The duration and severity of diabetes and hyperglycemia will be specifically examined as determinants of degree of oxidant stress. Thus, this proposal will delineate mechanisms responsible for the adverse consequences of diabetes and hyperglycemia during myocardial ischemia using an integrated approach of in vivo and cellular techniques.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063705-04
Application #
6695294
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Liang, Isabella Y
Project Start
2001-01-01
Project End
2005-12-31
Budget Start
2004-02-01
Budget End
2005-12-31
Support Year
4
Fiscal Year
2004
Total Cost
$299,000
Indirect Cost
Name
Medical College of Wisconsin
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Ge, Zhi-Dong; Li, Yingchuan; Qiao, Shigang et al. (2018) Failure of Isoflurane Cardiac Preconditioning in Obese Type 2 Diabetic Mice Involves Aberrant Regulation of MicroRNA-21, Endothelial Nitric-oxide Synthase, and Mitochondrial Complex I. Anesthesiology 128:117-129
Liu, Yanan; Baumgardt, Shelley L; Fang, Juan et al. (2017) Transgenic overexpression of GTP cyclohydrolase 1 in cardiomyocytes ameliorates post-infarction cardiac remodeling. Sci Rep 7:3093
Wu, Hsiang-En; Baumgardt, Shelley L; Fang, Juan et al. (2016) Cardiomyocyte GTP Cyclohydrolase 1 Protects the Heart Against Diabetic Cardiomyopathy. Sci Rep 6:27925
Baumgardt, Shelley L; Paterson, Mark; Leucker, Thorsten M et al. (2016) Chronic Co-Administration of Sepiapterin and L-Citrulline Ameliorates Diabetic Cardiomyopathy and Myocardial Ischemia/Reperfusion Injury in Obese Type 2 Diabetic Mice. Circ Heart Fail 9:e002424
Leucker, Thorsten M; Ge, Zhi-Dong; Procknow, Jesse et al. (2013) Impairment of endothelial-myocardial interaction increases the susceptibility of cardiomyocytes to ischemia/reperfusion injury. PLoS One 8:e70088
Baotic, Ines; Ge, Zhi-Dong; Sedlic, Filip et al. (2013) Apolipoprotein A-1 mimetic D-4F enhances isoflurane-induced eNOS signaling and cardioprotection during acute hyperglycemia. Am J Physiol Heart Circ Physiol 305:H219-27
Vladic, Nikolina; Ge, Zhi-Dong; Leucker, Thorsten et al. (2011) Decreased tetrahydrobiopterin and disrupted association of Hsp90 with eNOS by hyperglycemia impair myocardial ischemic preconditioning. Am J Physiol Heart Circ Physiol 301:H2130-9
Leucker, Thorsten M; Bienengraeber, Martin; Muravyeva, Maria et al. (2011) Endothelial-cardiomyocyte crosstalk enhances pharmacological cardioprotection. J Mol Cell Cardiol 51:803-11
Ge, Zhi-Dong; Ionova, Irina A; Vladic, Nikolina et al. (2011) Cardiac-specific overexpression of GTP cyclohydrolase 1 restores ischaemic preconditioning during hyperglycaemia. Cardiovasc Res 91:340-9
Ge, Zhi-Dong; Pravdic, Danijel; Bienengraeber, Martin et al. (2010) Isoflurane postconditioning protects against reperfusion injury by preventing mitochondrial permeability transition by an endothelial nitric oxide synthase-dependent mechanism. Anesthesiology 112:73-85

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