Abstract

Infiltrating neutrophils exacerbate ischemia-reperfusion injury by releasing free radicals, proteolytic enzymes, proinflammatory cytokines, and by plugging microcapillaries. Certain chemokines, such as IL-8 in humans, play key roles in attracting neutrophils to sites of injury or inflammation. We have recently described the temporal expression of three neutrophil chemoattractant CXC chemokines - LIX (lipopolysachharide-induced CXC chemokine), KC (cytokine-induced neutrophil chemoattractant) and MIP-2 (macrophage inflammatory protein-2) - during myocardial ischemia-reperfusion injury in the rat. In addition, we found that administration of LIX induces NO production and depresses contractile performance in isolated cardiomyocytes, and depresses myocardial contractile function in vivo. These observations suggest that LIX-induced myocardial dysfunction may be mediated by a direct, neutrophil-independent, effect on myocardial production of NO and/or free radicals.
The specific aims of this proposal are as follows. (1) We will determine whether LIX depresses myocardial function in vivo via NO generation, and whether pretreatment with L-NIL, a selective inhibitor of iNOS, will reduce NO generation and prevent LIX- induced LV dysfunction. LIX will be administered in vivo either alone or after pre-treatment with L-NIL, and myocardial depression will be assessed by echocardiography. Expression and localization of nitric oxide synthases, measurement of reactive oxygen and nitrogen intermediates and peroxynitrite will be measured. (2) We will determine whether LIX-induced myocardial dysfunction in vivo is independent on neutrophil infiltration. Neutrophils will be depleted by anti-neutrophil antiserum prior to administration of LIX. (3) We will determine the cellular signaling mechanisms responsible for LIX-mediated iNOS induction in isolated cardiomyocytes. The activity of iNOS promoter-driven reporter gene constructs will be assessed in vitro in transfected adult rat cardiomyocytes. The results from these studies will further our knowledge of chemokine biology and lead to new therapeutic strategies to prevent or treat myocardial dysfunction in ischemia-reperfusion injury.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068020-04
Application #
6902621
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Massicot-Fisher, Judith
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$213,700
Indirect Cost

  Institution

Name
University of Texas Health Science Center San Antonio
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229

  Publications

Zabalgoitia, Miguel; Colston, James T; Reddy, Seenu V et al. (2008) Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-kappaB-PTEN-dependent human cardiac endothelial cell death. Free Radic Biol Med 44:284-98
Colston, James T; Boylston, William H; Feldman, Marc D et al. (2007) Interleukin-18 knockout mice display maladaptive cardiac hypertrophy in response to pressure overload. Biochem Biophys Res Commun 354:552-8
Srivastava, Sanjay; Chandrasekar, Bysani; Gu, Yan et al. (2007) Downregulation of CuZn-superoxide dismutase contributes to beta-adrenergic receptor-mediated oxidative stress in the heart. Cardiovasc Res 74:445-55
Colston, J T; de la Rosa, S D; Koehler, M et al. (2007) Wnt-induced secreted protein-1 is a prohypertrophic and profibrotic growth factor. Am J Physiol Heart Circ Physiol 293:H1839-46
Patel, Devang N; King, Carter A; Bailey, Steven R et al. (2007) Interleukin-17 stimulates C-reactive protein expression in hepatocytes and smooth muscle cells via p38 MAPK and ERK1/2-dependent NF-kappaB and C/EBPbeta activation. J Biol Chem 282:27229-38
Chandrasekar, Bysani; Mummidi, Srinivas; Mahimainathan, Lenin et al. (2006) Interleukin-18-induced human coronary artery smooth muscle cell migration is dependent on NF-kappaB- and AP-1-mediated matrix metalloproteinase-9 expression and is inhibited by atorvastatin. J Biol Chem 281:15099-109
Patel, Devang N; Bailey, Steven R; Gresham, John K et al. (2006) TLR4-NOX4-AP-1 signaling mediates lipopolysaccharide-induced CXCR6 expression in human aortic smooth muscle cells. Biochem Biophys Res Commun 347:1113-20
Chandrasekar, Bysani; Valente, Anthony J; Freeman, Gregory L et al. (2006) Interleukin-18 induces human cardiac endothelial cell death via a novel signaling pathway involving NF-kappaB-dependent PTEN activation. Biochem Biophys Res Commun 339:956-63
Chandrasekar, Bysani; Mummidi, Srinivas; Valente, Anthony J et al. (2005) The pro-atherogenic cytokine interleukin-18 induces CXCL16 expression in rat aortic smooth muscle cells via MyD88, interleukin-1 receptor-associated kinase, tumor necrosis factor receptor-associated factor 6, c-Src, phosphatidylinositol 3-kinase, Akt, c-J J Biol Chem 280:26263-77
Chandrasekar, Bysani; Mummidi, Srinivas; Claycomb, William C et al. (2005) Interleukin-18 is a pro-hypertrophic cytokine that acts through a phosphatidylinositol 3-kinase-phosphoinositide-dependent kinase-1-Akt-GATA4 signaling pathway in cardiomyocytes. J Biol Chem 280:4553-67

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