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 angiog enic proteins or by gene therapy is fast emerging as a highly attractive tr eatment modality for ischemic heart disease. Herein we examine a novel meth od of stimulating myocardial angiogenesis by hypoxic preconditioning at bot h capillary and arteriolar levels, and the potential role of NF kappaB in m ediating such a response, We also investigate the functional relevance of s uch 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-D awley 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 preco nditioning + permanent LAD occlusion (HMI), PDTC (NF kappaB inhibitor) + hy poxic preconditioning + LAD occlusion (PHMI), PDTC + normoxia + LAD occlusi on (PNMI), PDTC + hypoxic preconditioning + sham surgery (PHS) and PDTC + n ormoxia + sham surgery (PNS). Rats in the preconditioned groups were subjec ted to systemic hypoxemic hypoxic exposure (10 +/- 0.4% O-2) for 4 h follow ed by a 24-h period of normoxic reoxygenation prior to undergoing LAD occlu sion, Rats in the normoxia groups were time matched with the preconditioned group and maintained under normoxic conditions for the 28-h period prior t o LAD occlusion, The HMI group displayed significant increases in capillary as well as arteriolar density after 2, 4 and 7 days post-operation compare d to the NMI. Prior PDTC administration prevented such increases in the PHM I group and effectively abolished the pro-angiogenic effect of hypoxic prec onditioning (HP). One week after sham surgery or LAD occlusion, rats underw ent a pharmacological stress test with dobutamine in progressively increasi ng 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 pr econditioning also decreases endothelial cell injury as determined by the e xtent of endothelial cell apoptosis using anti-VWF factor labelling and TUN EL assay, The results suggest that HP stimulates myocardial angiogenesis vi a redox-regulated transcription factor, NF kappaB-dependent pathway to an e xtent sufficient to exert significant preservation of contractile functiona l reserve in a rat model of myocardial infarction progressing to heart Fail ure. (C) 2001 Academic Press.