It is now established that ions function as intracellular messengers. It has also become clear that ion transport and ion homeostasis are very important aspects of signal transduction. The goal of this research is the development of an understanding of how these pathways are altered under pathologic conditions, i.e., how ion homeostasis and ion transport are altered and thereby lead to altered cell function and disease. Previously, we have shown that an increase in cytosolic free calcium is associated with cell injury. To understand mechanisms responsible, we have investigated interventions which reduce injury. It has been shown that brief intermittent exposure to stress (preconditioning) reduces injury resulting from a subsequent, more severe stress - less necrosis, better preservation of ion homeostasis, slower ATP turnover. We have been investigating various potential mediators of preconditioning adenosine antagonists do not block the protective effect of preconditioning in rat heart. Activation of the glybenclamide sensitive potassium channel was also suggested to be involved in preconditioning, however we found that glybenclamide did not block the protective effects of preconditioning on reducing the rise in Cai during ischemia or improving contractility during reflow. We have also recently begun investigating the role of phosphatases in preconditioning. We find that the phosphatase inhibitor microcystin blocks proconditioning; in the presence of microcystin the rise in Cai during ischemia and recovery of function on reflow are not improved by preconditioning. Our working hypothesis is that preconditioning may stimulate a phosphatase which results in the beneficial effects observed. We are currently investigating whether an arachidonic acid metabolite could activate a phosphatase and mediate preconditioning. We find that blocking the lipoxygenase pathway with nordihydroguaiaretic acid (NDGA) blocks the beneficial effects of preconditioning on the rise in Cai during ischemia and improved recovery of function on reflow. In addition, we find that inhibiting the cyclooxygenase pathway with indomethacin does not block the beneficial effects of preconditioning.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES010004-14
Application #
3777439
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
1993
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Shiva, Sruti; Huang, Zhi; Grubina, Rozalina et al. (2007) Deoxymyoglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial respiration. Circ Res 100:654-61
Huss, Janice M; Imahashi, Ken-ichi; Dufour, Catherine R et al. (2007) The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload. Cell Metab 6:25-37
Delozier, Tracy C; Kissling, Grace E; Coulter, Sherry J et al. (2007) Detection of human CYP2C8, CYP2C9, and CYP2J2 in cardiovascular tissues. Drug Metab Dispos 35:682-8
Murphy, Elizabeth; Steenbergen, Charles (2007) Cardioprotection in females: a role for nitric oxide and altered gene expression. Heart Fail Rev 12:293-300
Murphy, Elizabeth; Steenbergen, Charles (2007) Gender-based differences in mechanisms of protection in myocardial ischemia-reperfusion injury. Cardiovasc Res 75:478-86
Murphy, Elizabeth; Steenbergen, Charles (2007) Preconditioning: the mitochondrial connection. Annu Rev Physiol 69:51-67
Nikolic, Ivana; Liu, Dianxin; Bell, Jamie A et al. (2007) Treatment with an estrogen receptor-beta-selective agonist is cardioprotective. J Mol Cell Cardiol 42:769-80
Seubert, John M; Sinal, Christopher J; Graves, Joan et al. (2006) Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function. Circ Res 99:442-50
Sun, Junhui; Picht, Eckard; Ginsburg, Kenneth S et al. (2006) Hypercontractile female hearts exhibit increased S-nitrosylation of the L-type Ca2+ channel alpha1 subunit and reduced ischemia/reperfusion injury. Circ Res 98:403-11
Sun, Junhui; Steenbergen, Charles; Murphy, Elizabeth (2006) S-nitrosylation: NO-related redox signaling to protect against oxidative stress. Antioxid Redox Signal 8:1693-705

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