Myocardial ischemia causes inflammatory response, reduced cardiac function and irreversible cell death. Formation of reactive oxygen species (ROS) upon reperfusion of the ischemic area augments the ischemic insult. Injured cells respond to this insult by activating heme oxygenase-1 (HO-1) enzyme, which provides cytoprotective effects. Recent evidence has shown that prior induction of HO-1 protects tissues against ischemia/reperfusion (I/R) mediated injury and prolongs tissue viability. Therefore it is possible that targeted overexpression of HO-1 under non-stressful conditions will protect against future insult and provide further understanding of HO-1?s protective mechanisms. We have recently developed an adeno-associated viral vector system to deliver human HO-1 (hHO-1) directly in the rat heart and have observed long term expression of the transgene and reduction in infarct size with a single treatment of the viral vector in a coronary artery ligation (LAD) model of ischemia/reperfusion. This proposal will test the hypothesis that intracardiac delivery of hHO-1 will result in long term transcription and translation of hHO-1, provide cytoprotective effects improve cardiac hemodynamics and reduce overall mortality in LAD model of I/R injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL069601-03
Application #
6752951
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Commarato, Michael
Project Start
2002-07-01
Project End
2005-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$48,928
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Pachori, Alok S; Custer, Laura; Hansen, Don et al. (2010) Bone morphogenetic protein 4 mediates myocardial ischemic injury through JNK-dependent signaling pathway. J Mol Cell Cardiol 48:1255-65
Pachori, Alok S; Smith, Anthony; McDonald, Patricia et al. (2007) Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway. J Mol Cell Cardiol 43:580-92
Pachori, Alok S; Melo, Luis G; Zhang, Lunan et al. (2006) Chronic recurrent myocardial ischemic injury is significantly attenuated by pre-emptive adeno-associated virus heme oxygenase-1 gene delivery. J Am Coll Cardiol 47:635-43
Dzau, Victor J; Gnecchi, Massimiliano; Pachori, Alok S (2005) Enhancing stem cell therapy through genetic modification. J Am Coll Cardiol 46:1351-3
Pachori, Alok S; Melo, Luis G; Hart, Melanie L et al. (2004) Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury. Proc Natl Acad Sci U S A 101:12282-7