Hypoxia/reoxygenation promotes myocardial angiogenesis via an NF kappa B-dependent mechanism in a rat model of chronic myocardial infarction.
Therapeutic angiogenesis achieved either through the use of discreet angiogenic proteins or by gene therapy is fast emerging as a highly attractive treatment modality for ischemic heart disease. Herein we examine a novel method of stimulating myocardial angiogenesis by hypoxic preconditioning at both capillary and arteriolar levels, and the potential role of NF kappa B in mediating such a response. We also investigate the functional relevance of such treatment by assessing whether the induced neovascularization can help preserve left ventricular contractile functional reserve in the setting of developing heart failure secondary to myocardial infarction. Male Sprague-Dawley rats were randomly divided into eight groups: normoxia + sham surgery (NS), normoxia + permanent left anterior descending coronary artery (LAD) occlusion (NMI), hypoxic preconditioning + sham surgery (HS), hypoxic preconditioning + permanent LAD occlusion (HMI), PDTC (NF kappa B inhibitor) + hypoxic preconditioning + LAD occlusion (PHMI), PDTC+normoxia + LAD occlusion (PNMI), PDTC + hypoxic preconditioning + sham surgery (PHS) and PDTC + normoxia + sham surgery (PNS). Rats in the preconditioned groups were subjected to systemic hypoxemic hypoxic exposure (10+/-0.4% O2) for 4 h followed by a 24-h period of normoxic reoxygenation prior to undergoing LAD occlusion. Rats in the normoxia groups were time matched with the preconditioned group and maintained under normoxic conditions for the 28-h period prior to LAD occlusion. The HMI group displayed significant increases in capillary as well as arteriolar density after 2, 4 and 7 days post-operation compared to the NMI. Prior PDTC administration prevented such increases in the PHMI group and effectively abolished the pro-angiogenic effect of hypoxic preconditioning (HP). One week after sham surgery or LAD occlusion, rats underwent a pharmacological stress test with dobutamine in progressively increasing doses which revealed significantly elevated values of dp/dt(max) at each dose point in the HMI group compared to the NMI or PHMI groups. Hypoxic preconditioning also decreases endothelial cell injury as determined by the extent of endothelial cell apoptosis using anti-VWF factor labelling and TUNEL assay. The results suggest that HP stimulates myocardial angiogenesis via redox-regulated transcription factor, NF kappa B-dependent pathway to an extent sufficient to exert significant preservation of contractile functional reserve in a rat model of myocardial infarction progressing to heart failure.
Sasaki
H
H
Department of Surgery, University of Connecticut Health Center, Farmington, Connecticut, 06030-1110, USA.
Ray
P S
PS
Zhu
L
L
Otani
H
H
Asahara
T
T
Maulik
N
N
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001158:Arteries / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002196:Capillaries / Q000378:metabolism; D003331:Coronary Vessels / Q000378:metabolism*; D004280:Dobutamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors
D000975:Antioxidants; D016328:NF-kappa B; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D004280:Dobutamine; D011392:Proline; D010100:Oxygen