Hypoxia/Reoxygenation Promotes Myocardial Angiogenesis via anÈNF κ B-dependent Mechanism in a Rat Model of Chronic Myocardial Infarction (original) (raw)

Abstract

H. S, P. S. R, L. Z, H. O, T. A  N. M. Hypoxia/Reoxygenation Promotes Myocardial Angiogenesis via an NF B-dependent Mechanism in a Rat Model of Chronic Myocardial Infarction. Journal of Molecular and Cellular Cardiology (2001) 33, 283-294. 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 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 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% O 2 ) 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 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.

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References (33)

  1. and Disease: Basic Mechanisms and Clinical as Ang-Tie system protein expression 11 might also Applications. New York: Marcel Dekker, Inc., 2000; be one of the possible mechanisms besides NF B- 199-214.
  2. iNOS-NO pathway by which hypoxia re- 10.
  3. L SH, W PL, E R, D R, J oxygenation triggers myocardial angiogenesis in SW, T PA. Early expression of angio- genesis factors in acute myocardial ischemia and this model. It is very difficult at this point to spec- infarction. N Engl J Med 2000; 342: 626-633.
  4. R PS, E-H T, S H, Z L, preconditioning stimulates myocardial angio- M N. Early effects of hypoxia/reoxygenation genesis. However, inhibition of angiogenesis by the on VEGF, Ang-1, Ang-2 and their receptors in the administration of PDTC was successful in dem- rat myocardium: implications for myocardial angio- genesis. Mol Cell Biochem, In press.
  5. onstrating the essential and important role of NF B 12. G E, S N, G D. NF B in- in myocardial angiogenesis. This document clearly duction during in vivo hypoxia in dorsocaudal brain- emphasizes the role of NF B activation in mediating stem of rat: effect of MK 801 and L-NAME. J Appl angiogenesis in response to hypoxia in a rat model Physiol 1998; 85: 372-376.
  6. of chronic myocardial infarction.
  7. L SF, Y X, M AB. Inhibition of NF B activation by pyrrolidine dithiocarbamate prevents in vivo ex- pression of proinflammatory genes. Circulation 1999; 100: 1330-1337. References during the onset of experimental cardiac failure. J Clin Invest 1995; 95: 619-627.
  8. S D, I A, S D, K E. Vascular 16. O S, B V, O S, M L, H G, R HA, R J J. In vivo assessment of left endothelial growth factor induced by hypoxia-ini- tiated angiogenesis. Nature 1992; 359: 843-845. ventricular remodelling after myocardial infarction by digital videocontrast angiography in the rat.
  9. M T, A K. Endothelial receptor tyrosine kinases involved in angiogenesis. J Cell Biol 1995; Cardiovasc Res 1994; 28: 349-357.
  10. O B-H, O S, R HA, R J J. Myocardial 129: 895-898.
  11. D C, E JA, U H, H K, F hypertrophy in the ischemic zone induced by exercise in rats after coronary reperfusion. Circulation 1993;
  12. N, W LT. The fms-like tyrosine kinase, re- ceptor for vascular endothelial growth factor. Science 87: 598-607.
  13. X Z, G M, B S, K T. The capillary of 1992; 255: 989-991.
  14. D DK, M N. Evaluation of antioxidant ef- left ventricular tissue of rats subjected to coronary artery occlusion. Cardiovasc Res 1997; 33: 671-676. fectiveness in ischemic reperfusion tissue injury. Methods Enzymol 1994; 233: 601-610.
  15. L J, Q MJ, P M, K , K RA. Adenovirus-mediated gene transfer into in-
  16. D DK, E RM. Phospholipids and myo- cardial reperfusion injury. In: Das DK (ed.). Patho- farcted myocardium: feasibility, timimg and location of expression. J Mol Cell Cardiol 1996; 28: 2057- physiology of reperfusion injury. Florida: CRC Press, 1992: 149-179. 2060.
  17. S JE, Q YZ, G GJ, K RC. The
  18. K M, V EE, A S, B LV, T-  S, T M, K RY, R RM, C ischemia-selective K ATP channel antagonist, 5-hydro- xydecanoate, blocks ischemic preconditioning in the KA, Y KT, A AP. Reactive oxygen inter- mediates increases vascular endothelial growth fac- rat heart. J Mol Cell Cardiol 1997; 29: 1055-1060.
  19. G RJ, S JE, Y Z, K D, W tor expression in vitro and in vivo. J Clin Invest 1996; 98: 1667-1175.
  20. DC, N PJ, G GJ. Antibody to platelet/ endothelial cell adhesion molecule-1 reduces myo-
  21. P' J, S D, I I, H I, G H, K E. Hypoxia-induced expression of vascular cardial infarct size in a rat model of ischemia-re- perfusion injury. Circulation 1996; 94: 3327-3333. endothelial growth factor by retinal cells is a com- mon factor in neovascularizing ocular diseases. Lab 22. MN PH, D A, W JM. Glycogen depletion contributes to ischemic preconditioning in Invest 1995; 72: 638-645.
  22. L PI, H KA, K S, S DH. Hy- the rat heart in vivo. Am J Physiol 1996; 271: H2283-H2289.
  23. poxia/reoxygenation enhances tube formation of cultured human microvascular endothelial cells: role 23. A M, T JR, B M, T J, L A, J A, D M, R L. of reactive oxygen species. In: Maragoudakis ME (ed.). Angiogenesis. New York and London: Plenum Pattern of superoxide dismutase enzymatic activity and RNA changes in rat heart ventricles after myo- Press, 1998: 321-336.
  24. L PI, W CR. Reactive oxygen species and cardial infarction. Am J Pathol 1997; 151: 549-555.
  25. P MA, P JM, F MC, F PJ, angiogenesis. In: Rubanyi GM (ed.). Angiogenesis in S J, K RA, B E. Myocardial Vascular endothelial growth factor/vascular per- meability factor expression in a mouse model of infarct size and ventricular function in rats. Circ Res 1979; 44: 503-512. retinal neivascularization. Proc Natl Acad Sci USA 1995; 92: 905-909.
  26. M N, S M, P PD, D DK. An essential role of NF B in tyrosine kinase signaling of p38 30. L A, F C. Expression of vascular endo- thelial growth factor by cultured endothelial cells MAP kinase regulation of myocardial adaptation to ischemia. FEBS Letts 1998; 429: 365-369. from brain microvessels. Biochem Biophys Res Com- mun 1993; 194: 799-803.
  27. E DT, W M, E RM, R JA, K E, K VE, M N, D DK. Hypoxic 31. D EJ, M WJ, F TM, F AS, R AB. Tumor necrosis factor alpha activates human preconditioning preserves antioxidant reserve in the working rat heart. Cardiovasc Res 1995; 29: 133- immuno-deficiency virus type 1 through induction of nuclear factor binding to the NF B sites in the 140.
  28. T MA, K DA, R SL, A CA, long terminal repeat. Proc Natl Acad Sci USA 1989; 86: 5974-5978.
  29. B CM. Characterization of human proximal tu- bular cells after hypoxic preconditioning: con- 32.
  30. M S, V IM. REL/NF kB/IkB story. Adv Cancer Res 1995; 66: 255-292.
  31. stitutive and hypoxia-induced expression of heat shock proteins HSP70 (A, B, and C), HSC70, and 33. Y A, Y S, I T, K M, I H. Suppression of retinal neo- HSP90. Biochem Mol Med 1997; 60: 49-58.
  32. S RM. Tumor hypoxia and gene ex- vascularization by the NF B inhibitor pyrrolidine dithiocarbamate in mice. Invest Ophthalmol Vis Sci pression. Acta Oncol 1998; 37: 567-574.
  33. P EA, A L, F ED, A LP, S LE. 1999; 40: 1624-1629.