In normal myocardium multiple cell-cell junctions allow for close membrane apposition (via adherens junctions) that are very stable (via desmosomes) and support the formation of electrical junctions (gap junctions). The formation of this junctional triad is ideal for maintaining the normal function of cardiac tissue. A junctional type found in other systems, but lacking in normal myocardium is the tight junction (TJ), formed from a protein complex that includes isoforms of the Claudin proteins. These TJs provide a barrier function in many tissues, and increase extracellular resistance within tissues, which would have a negative impact in normal myocardium. This application focuses on mapping the formation of tight junctions in ischemic myocardium. We hypothesize that the release of cytokines, particularly Interleukin-1beta (IL-1beta) and Tumor Necrosis Factor alpha (TNFalpha) from myofibroblasts upregulate the tight junction- associated protein Claudin-1 at the transcriptional level. Studies in this application focus on mapping the timing of appearance of these junctions as well as determining which signaling pathways are involved in this novel protein upregulation following ischemia. We also propose to use sophisticated computer modeling to assess the impact on propagation that the addition of these extracellular barriers would provide. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083205-02
Application #
7269817
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Lathrop, David A
Project Start
2006-08-04
Project End
2008-07-01
Budget Start
2007-08-01
Budget End
2008-07-01
Support Year
2
Fiscal Year
2007
Total Cost
$273,579
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pharmacology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Duffy, Heather S (2012) The molecular mechanisms of gap junction remodeling. Heart Rhythm 9:1331-4
Dolmatova, Elena; Spagnol, Gaelle; Boassa, Daniela et al. (2012) Cardiomyocyte ATP release through pannexin 1 aids in early fibroblast activation. Am J Physiol Heart Circ Physiol 303:H1208-18
Baum, Jennifer R; Long, Biao; Cabo, Candido et al. (2012) Myofibroblasts cause heterogeneous Cx43 reduction and are unlikely to be coupled to myocytes in the healing canine infarct. Am J Physiol Heart Circ Physiol 302:H790-800
Baum, Jennifer; Duffy, Heather S (2011) Fibroblasts and myofibroblasts: what are we talking about? J Cardiovasc Pharmacol 57:376-9
Duffy, Heather S (2011) Inflammatory responses in the atria: should they stay or should they go? Heart Rhythm 8:286-7
Macia, Ester; Dolmatova, Elena; Cabo, Candido et al. (2011) Characterization of gap junction remodeling in epicardial border zone of healing canine infarcts and electrophysiological effects of partial reversal by rotigaptide. Circ Arrhythm Electrophysiol 4:344-51
Hussain, Wajid; Patel, Pravina M; Chowdhury, Rasheda A et al. (2010) The Renin-Angiotensin system mediates the effects of stretch on conduction velocity, connexin43 expression, and redistribution in intact ventricle. J Cardiovasc Electrophysiol 21:1276-83
Berdichevski, Alexandra; Meiry, Gideon; Milman, Felix et al. (2010) TVP1022 protects neonatal rat ventricular myocytes against doxorubicin-induced functional derangements. J Pharmacol Exp Ther 332:413-20
Duffy, Heather S (2009) The ever-shrinking world of cardiac ion channel remodeling: the role of microRNAs in heart disease. Heart Rhythm 6:1810-1
Kieken, Fabien; Mutsaers, Nancy; Dolmatova, Elena et al. (2009) Structural and molecular mechanisms of gap junction remodeling in epicardial border zone myocytes following myocardial infarction. Circ Res 104:1103-12

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