Cardiac noradrenergic nerve terminal function is abnormal in the failing heart. Both presynaptic and postsynaptic abnormalities have been observed. They include norepinepbrine (NE) depletion, reduced neuronal NE uptake activity, increased interstitial NE, f3-adrenoceptor down-regulation and deterioration of cardiac function. Since the changes are associated with a decrease of nerve growth factor (NGF), and can e prevented by antioxidant vitamins, this application is designed to elucidate the relative roles of oxidative stress and NGF on the adrenergic nerve terminal function and cardiac function in heart failure. We will measure the protein and mRNA expressions of cardiac NGF, NGF receptor TrKA, tissue oxidative stress (oxidized glutathione, hydroxyl free radicals, mitochondria DNA oxidation products) and myocyte apoptosis in pacing-induced cardiomyopathy. The findings will be correlated to the presynaptic myocardial NE uptake site density, NE histofluorescence, tyrosine hydroxylase profiles, as well as the postsynaptic myocardial B-adrenoceptor density and B-adrenergic sensitivity and cardiac function. Superoxide dismutase and selegiline, which have been shown to prevent cardiac sympathetic nerve abnormalities in heart failure, will be used to determine whether their effects are mediated via reductions of cardiac NE release and oxidative stress, and/or preservation of cardiac NGF. Studies also will be performed to determine if the beneficial effects of carvedilol in heart failure are mediated via its blocking actions on the a- or f3-receptors, or related causally to its antioxidant effect. Studies have shown that NE reduces cardiac NGF by an a-receptor action, whereas its apoptotic effects are mediated via the B-receptors Finally, a NGF minigene will be injected directly into the heart to determine if it will produce salutary effects on sympathetic nerve endings and cardiac function. Our research will not only elucidate the mechanisms responsible for noradrenergic nerve ending dysfunction, but also provide a potentially useful new modality for the treatment of heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068151-04
Application #
6758642
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Lathrop, David A
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2006-06-30
Support Year
4
Fiscal Year
2004
Total Cost
$379,241
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Mao, Weike; Iwai, Chikao; Liu, Jiahao et al. (2008) Darbepoetin alfa exerts a cardioprotective effect in autoimmune cardiomyopathy via reduction of ER stress and activation of the PI3K/Akt and STAT3 pathways. J Mol Cell Cardiol 45:250-60
Liang, Chang-Seng; Mao, Weike; Liu, Jiahao (2008) Pro-apoptotic effects of anti-beta1-adrenergic receptor antibodies in cultured rat cardiomyocytes: actions on endoplasmic reticulum and the prosurvival PI3K-Akt pathway. Autoimmunity 41:434-41
Liu, Jiahao; Mao, Weike; Ding, Bo et al. (2008) ERKs/p53 signal transduction pathway is involved in doxorubicin-induced apoptosis in H9c2 cells and cardiomyocytes. Am J Physiol Heart Circ Physiol 295:H1956-65
Liu, Jiahao; Mao, Weike; Iwai, Chikao et al. (2008) Adoptive passive transfer of rabbit beta1-adrenoceptor peptide immune cardiomyopathy into the Rag2-/- mouse: participation of the ER stress. J Mol Cell Cardiol 44:304-14
Liang, Chang-seng (2007) Cardiac sympathetic nerve terminal function in congestive heart failure. Acta Pharmacol Sin 28:921-7
Mao, Weike; Fukuoka, Shuji; Iwai, Chikao et al. (2007) Cardiomyocyte apoptosis in autoimmune cardiomyopathy: mediated via endoplasmic reticulum stress and exaggerated by norepinephrine. Am J Physiol Heart Circ Physiol 293:H1636-45
Liang, Chang-Seng; Mao, Weike; Iwai, Chikao et al. (2006) Cardiac sympathetic neuroprotective effect of desipramine in tachycardia-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 290:H995-1003
Mao, Weike; Iwai, Chikao; Keng, Peter C et al. (2006) Norepinephrine-induced oxidative stress causes PC-12 cell apoptosis by both endoplasmic reticulum stress and mitochondrial intrinsic pathway: inhibition of phosphatidylinositol 3-kinase survival pathway. Am J Physiol Cell Physiol 290:C1373-84
Qin, Fuzhong; Liang, Michelle C; Liang, Chang-Seng (2005) Progressive left ventricular remodeling, myocyte apoptosis, and protein signaling cascades after myocardial infarction in rabbits. Biochim Biophys Acta 1740:499-513
Mao, Weike; Iwai, Chikao; Qin, Fuzhong et al. (2005) Norepinephrine induces endoplasmic reticulum stress and downregulation of norepinephrine transporter density in PC12 cells via oxidative stress. Am J Physiol Heart Circ Physiol 288:H2381-9

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