Both humans and experimental animals with heart failure exhibit increased expression in the heart of inflammatory cytokines, including TNF, IL-1beta and IL-6, as well as iNOS, in the absence of evidence of infection. While maladaptive cardiac remodeling has been attributed to these proteins, the proximal events that trigger and sustain their expression are not well understood. Each of these mediators, however, are now known to be related to innate immunity, an evolutionarily ancient arm of the immune system that is triggered by pattern recognition receptors (PRRs), such as the toll-like receptors (TLRs) expressed by invertebrates and vertebrates, that recognize largely invariant structural motifs on pathogens. It is now recognized that innate immune PRRs also may have evolved in eukaryotes to recognize and repair or remove injured or dying cells, again by recognizing relatively invariant motifs found on injured cells or on cells programmed to die. Based on these observations and our own preliminary data, we hypothesize that vertebrate TLR4, which is expressed by cardiac myocytes, plays a pivotal role in the response to injury in the heart. Specifically, we will examine: 1) the regulation of TLR4 expression in cardiac myocytes in vitro in response to injury induced by UV light, by anthracycline antibiotics and by cyclic biaxial strain coupled with electric field pacing, as well as in cardiac myocytes in situ in remodeling murine ventricular muscle following experimental myocardial infarction; 2) the signal transduction pathways leading to NFkappaB and MAP kinase activation by activated TLR4 in cardiac myocytes and their possible localization to caveolar microdomains; and 3) the functional role(s) of TLR4 in the response to myocyte injury in vitro and in vivo; specifically, we will test the hypothesis that: i) a constitutively activated TLR4 construct conveys a survival signal in vitro; ii) that TLR4 participates in the recognition and removal of apoptotic cells; and iii) that animals with targeted disruption of TLR4, or of its immediate downstream signaling target MyD88, exhibit altered rates of ventricular remodeling in response to myocardial infarction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063927-03
Application #
6499034
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Massicot-Fisher, Judith
Project Start
2000-02-05
Project End
2004-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
3
Fiscal Year
2002
Total Cost
$422,315
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Morrison, Helena; Frye, Jennifer; Davis-Gorman, Grace et al. (2011) The contribution of mannose binding lectin to reperfusion injury after ischemic stroke. Curr Neurovasc Res 8:52-63
Dahlke, Katja; Wrann, Christiane D; Sommerfeld, Oliver et al. (2011) Distinct different contributions of the alternative and classical complement activation pathway for the innate host response during sepsis. J Immunol 186:3066-75
Ceonzo, Kathleen; Gaynor, Anne; Shaffer, Lisa et al. (2006) Polyglycolic acid-induced inflammation: role of hydrolysis and resulting complement activation. Tissue Eng 12:301-8
Hart, Melanie L; Ceonzo, Kathleen A; Shaffer, Lisa A et al. (2005) Gastrointestinal ischemia-reperfusion injury is lectin complement pathway dependent without involving C1q. J Immunol 174:6373-80
Walsh, Mary C; Bourcier, Todd; Takahashi, Kazue et al. (2005) Mannose-binding lectin is a regulator of inflammation that accompanies myocardial ischemia and reperfusion injury. J Immunol 175:541-6
Buras, Jon A; Rice, Lauren; Orlow, Daniel et al. (2004) Inhibition of C5 or absence of C6 protects from sepsis mortality. Immunobiology 209:629-35
Oyama, Jun-ichi; Blais Jr, Charles; Liu, Xiaoli et al. (2004) Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4-deficient mice. Circulation 109:784-9
Weinberg, Ellen O; Shimpo, Masahisa; Hurwitz, Shelley et al. (2003) Identification of serum soluble ST2 receptor as a novel heart failure biomarker. Circulation 107:721-6
Weinberg, Ellen O; Shimpo, Masahisa; De Keulenaer, Gilles W et al. (2002) Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation 106:2961-6