Chronic alcoholism remains one of the major risk factors in the pathogenesis of cardiovascular diseases. Dose related bimodal effects of alcohol on cardiovascular system may reflect contrasting influences of light versus heavy alcohol consumption on the vascular endothelium. TNF expressed at the sites of arterial injury following balloon angioplasty suppresses endothelial cell (EC) proliferation and contributes to the development of restenosis. We have shown that in vitro exposure of EC to ethanol not only upregulates TNF transcription and expression but also synergistically exacerbates inhibitory effects of TNF on ECs. Our preliminary data indicates that chronic ethanol feeding in mice delays endothelial recovery and enhances intimal hyperplasia in denuded carotid arteries. At least, part of ethanol responses are mediated via TNF since TNFRI null mice are protected from ethanol-mediated effects on vascular endothelium. Our preliminary ? data also shows that ethanol feeding impairs neo-vascularization in the surgically induced ischemic hind limbs. Endothelial progenitor cells (EPC) have repeatedly been shown to mediate the processes of reendothelialization and neo-vascularization. Interestingly, our preliminary data indicates that kinetics and function of circulating EPCs from mice fed on alcohol is severely compromised. Considering the therapeutic potential for exploiting bone marrow derived progenitors/stem cells for cardiac repair as evident by recent surge in the number of high impact studies reported in the literature, it becomes additionally imperative to assess the effect of chronic alcohol either alone or synergistically with TNF, on the behavior and function of these progenitor cells, in vivo, especially in terms of their participation in the repair of ischemic tissue via neo-vascularization. Its our hypothesis that chronic ethanol impairs the function of EPCs and thereby negatively affect vasculogenesis and that part of ethanol effect on EPCs are mediated via the augmentation of TNF receptor l-mediated augmentation in apoptotic signaling. Using mice model of chronic ethanol feeding followed by surgically induce hind limb ischemia, we propose to verify these hypotheses under following specific aims:
Specific Aim 1 : Determine the effect of chronic alcohol on post-injury neovascularization and EPC kinetics and function in a mouse model of hind limb ischemia.
Specific aim 2 : Evaluate the contribution of TNFRI in alcohol-mediated EPC dysfunction. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21AA014575-02
Application #
7476694
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Brown, Ricardo A
Project Start
2006-08-15
Project End
2008-07-31
Budget Start
2007-03-01
Budget End
2007-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$129,795
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Joladarashi, Darukeshwara; Garikipati, Venkata Naga Srikanth; Thandavarayan, Rajarajan A et al. (2015) Enhanced Cardiac Regenerative Ability of Stem Cells After Ischemia-Reperfusion Injury: Role of Human CD34+ Cells Deficient in MicroRNA-377. J Am Coll Cardiol 66:2214-2226
Krishnamurthy, Prasanna; Lambers, Erin; Verma, Suresh et al. (2010) Myocardial knockdown of mRNA-stabilizing protein HuR attenuates post-MI inflammatory response and left ventricular dysfunction in IL-10-null mice. FASEB J 24:2484-94
Losordo, Douglas W; Kishore, Raj (2009) A big promise from the very small identification of circulating embryonic stem-like pluripotent cells in patients with acute myocardial infarction. J Am Coll Cardiol 53:10-2
Krishnamurthy, Prasanna; Rajasingh, Johnson; Lambers, Erin et al. (2009) IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR. Circ Res 104:e9-18
Rajasingh, Johnson; Lambers, Erin; Hamada, Hiromichi et al. (2008) Cell-free embryonic stem cell extract-mediated derivation of multipotent stem cells from NIH3T3 fibroblasts for functional and anatomical ischemic tissue repair. Circ Res 102:e107-17
Rajasingh, Johnson; Bord, Evelyn; Hamada, Hiromichi et al. (2007) STAT3-dependent mouse embryonic stem cell differentiation into cardiomyocytes: analysis of molecular signaling and therapeutic efficacy of cardiomyocyte precommitted mES transplantation in a mouse model of myocardial infarction. Circ Res 101:910-8
Rajasingh, Johnson; Bord, Evelyn; Qin, Gangjian et al. (2007) Enhanced voluntary alcohol consumption after estrogen supplementation negates estrogen-mediated vascular repair in ovariectomized mice. Endocrinology 148:3618-24