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The role of the tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK) in offspring exposed to prenatal hypoxia

  • L. M. Reyes (a1) (a2) (a3), A. Shah (a2) (a3), A. Quon (a2), J. S. Morton (a2) (a3) and S. T. Davidge (a1) (a2) (a3)...

Abstract

Exposure to prenatal hypoxia in rats leads to intrauterine growth restriction (IUGR), decreases fetal cardiomyocyte proliferation and increases the risk to develop cardiovascular diseases (CVD) later in life. The tumor necrosis factor-related weak inducer of apoptosis (TWEAK) induces cardiomyocyte proliferation through activation of the fibroblast growth factor-inducible molecule 14 (Fn-14) receptor. The TWEAK/Fn-14 pathway becomes quiescent shortly after birth, however, it becomes upregulated with CVD; suggesting that it could be a link between the increased susceptibility to CVD in pregnancies complicated by hypoxia/IUGR. We hypothesized that offspring exposed to prenatal hypoxia will exhibit reduced cardiomyocyte proliferation due to reduced Fn-14 expression and that the TWEAK/Fn-14 pathway will be expressed in those adult offspring. We exposed pregnant Sprague Dawley rats to control (21% oxygen) or hypoxic (11% oxygen) conditions from gestational days 15 to 21. Ventricular cardiomyocytes were isolated from male and female, control and hypoxic offspring at postnatal day 1. Proliferation was assessed in the presence or absence of r-TWEAK (72 h, 100 ng/ml). Prenatal hypoxia was not associated with differences in Fn-14 protein expression in either male or female offspring. Cardiomyocytes from prenatal hypoxic male, but not female, offspring had decreased proliferation compared with controls. Addition of r-TWEAK increased cardiomyocyte proliferation in all offspring. In adult offspring of all groups, the TWEAK/Fn-14 pathway was not detectable. Cardiomyocyte proliferation was reduced in only male offspring exposed to prenatal hypoxia but this was not due to changes in the Fn-14 pathway. Studies addressing other pathways associated with CVD and prenatal hypoxia are needed.

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Corresponding author

*Address for correspondence: S. T. Davidge, Women and Children’s Health Research Institute and Departments of Obstetrics and Gynecology, and Physiology, University of Alberta, 232 HMRC Building, Edmonton, AB, Canada T6G 2S2. (Email sandra.davidge@ualberta.ca)

References

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1. Barker, DJ, Winter, PD, Osmond, C, Margetts, B, Simmonds, SJ. Weight in infancy and death from ischaemic heart disease. Lancet. 1989; 2, 577580.
2. Barker, DJ. The fetal origins of hypertension. J Hypertens Suppl. 1996; 14, S117S120.
3. Barker, DJ, Gluckman, PD, Godfrey, KM, et al. Fetal nutrition and cardiovascular disease in adult life. Lancet. 1993; 341, 938941.
4. Global Status Report on Noncommunicable Diseases 2010. Global status report on noncommunicable diseases 2010. 2011, pp. 1–162.
5. Go, AS, Mozaffarian, D, Roger, VL, et al. Heart disease and stroke statistics – 2014 update: a report from the American Heart Association. Circulation. 2014; 129, e28e292.
6. Canada PHAo. Economic burden of illness in Canada 2000. Public Health Agency of Canada. 2000 [cited 2 February 2015]. Retrieved 14 June 2012 from http://www.phac-aspc.gc.ca/cd-mc/cvd-mcv/cvd_ebic-mcv_femc-eng.php
7. Imdad, A, Yakoob, MY, Siddiqui, S, Bhutta, ZA. Screening and triage of intrauterine growth restriction (IUGR) in general population and high risk pregnancies: a systematic review with a focus on reduction of IUGR related stillbirths. BMC Public Health. 2011; 11(Suppl. 3), S1.
8. Maulik, D. Fetal growth restriction: the etiology. Clin Obstet Gynecol. 2006; 49, 228235.
9. Rueda-Clausen, CF, Morton, JS, Lopaschuk, GD, Davidge, ST. Long-term effects of intrauterine growth restriction on cardiac metabolism and susceptibility to ischaemia/reperfusion. Cardiovasc Res. 2011; 90, 285294.
10. Xu, Y, Williams, SJ, O’Brien, D, Davidge, ST. Hypoxia or nutrient restriction during pregnancy in rats leads to progressive cardiac remodeling and impairs postischemic recovery in adult male offspring. FASEB J. 2006; 20, 12511253.
11. Reyes, LM, Kirschenman, R, Quon, A, et al. Aerobic exercise training reduces cardiac function in adult male offspring exposed to prenatal hypoxia. Am J Physiol Regul Integr Comp Physiol. 2015; 309, R489R498.
12. Tong, W, Xue, Q, Li, Y, Zhang, L. Maternal hypoxia alters matrix metalloproteinase expression patterns and causes cardiac remodeling in fetal and neonatal rats. Am J Physiol Heart Circ Physiol. 2011; 301, H2113H2121.
13. Marcela, SG, Cristina, RM, Angel, PG, et al. Chronological and morphological study of heart development in the rat. Anat Rec (Hoboken). 2012; 295, 12671290.
14. Clubb, FJ Jr, Bishop, SP. Formation of binucleated myocardial cells in the neonatal rat. An index for growth hypertrophy. Lab Invest. 1984; 50, 571577.
15. Bae, S, Xiao, Y, Li, G, Casiano, CA, Zhang, L. Effect of maternal chronic hypoxic exposure during gestation on apoptosis in fetal rat heart. Am J Physiol Heart Circ Physiol. 2003; 285, H983H990.
16. Paradis, A, Xiao, D, Zhou, J, Zhang, L. Endothelin-1 promotes cardiomyocyte terminal differentiation in the developing heart via heightened DNA methylation. Int J Med Sci. 2014; 11, 373380.
17. Sundgren, NC, Giraud, GD, Stork, PJ, Maylie, JG, Thornburg, KL. Angiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes. J Physiol. 2003; 548(Pt 3), 881891.
18. Giraud, GD, Louey, S, Jonker, S, Schultz, J, Thornburg, KL. Cortisol stimulates cell cycle activity in the cardiomyocyte of the sheep fetus. Endocrinology. 2006; 147, 36433649.
19. Chattergoon, NN, Giraud, GD, Thornburg, KL. Thyroid hormone inhibits proliferation of fetal cardiac myocytes in vitro. J Endocrinol. 2007; 192, R1R8.
20. Sundgren, NC, Giraud, GD, Schultz, JM, et al. Extracellular signal-regulated kinase and phosphoinositol-3 kinase mediate IGF-1 induced proliferation of fetal sheep cardiomyocytes. Am J Physiol Regul Integr Comp Physiol. 2003; 285, R1481R1489.
21. Thornburg, K, Jonker, S, O’Tierney, P, et al. Regulation of the cardiomyocyte population in the developing heart. Prog Biophys Mol Biol. 2011; 106, 289299.
22. Louey, S, Jonker, SS, Giraud, GD, Thornburg, KL. Placental insufficiency decreases cell cycle activity and terminal maturation in fetal sheep cardiomyocytes. J Physiol. 2007; 580(Pt 2), 639648.
23. Novoyatleva, T, Diehl, F, van Amerongen, MJ, et al. TWEAK is a positive regulator of cardiomyocyte proliferation. Cardiovasc Res. 2010; 85, 681690.
24. Chicheportiche, Y, Bourdon, PR, Xu, H, et al. TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis. J Biol Chem. 1997; 272, 3240132410.
25. Winkles, JA. The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting. Nat Rev Drug Discov. 2008; 7, 411425.
26. Mustonen, E, Sakkinen, H, Tokola, H, et al. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 during cardiac remodelling in rats. Acta Physiol (Oxf). 2010; 199, 1122.
27. Chorianopoulos, E, Heger, T, Lutz, M, et al. FGF-inducible 14-kDa protein (Fn14) is regulated via the RhoA/ROCK kinase pathway in cardiomyocytes and mediates nuclear factor-kappaB activation by TWEAK. Basic Res Cardiol. 2010; 105, 301313.
28. Yang, B, Yan, P, Gong, H, et al. TWEAK protects cardiomyocyte against apoptosis in a PI3K/AKT pathway dependent manner. Am J Transl Res. 2016; 8, 38483860.
29. Reyes, LM, Morton, JS, Kirschenman, R, DeLorey, DS, Davidge, ST. Vascular effects of aerobic exercise training in rat adult offspring exposed to hypoxia-induced intrauterine growth restriction. J Physiol. 2015; 1913–1929.
30. Novoyatleva, T, Janssen, W, Wietelmann, A, Schermuly, RT, Engel, FB. TWEAK/Fn14 axis is a positive regulator of cardiac hypertrophy. Cytokine. 2013; 64, 4345.
31. Jain, M, Jakubowski, A, Cui, L, et al. A novel role for tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in the development of cardiac dysfunction and failure. Circulation. 2009; 119, 20582068.
32. Rueda-Clausen, CF, Dolinsky, VW, Morton, JS, et al. Hypoxia-induced intrauterine growth restriction increases the susceptibility of rats to high-fat diet-induced metabolic syndrome. Diabetes. 2011; 60, 507516.
33. Rueda-Clausen, CF, Morton, JS, Davidge, ST. Effects of hypoxia-induced intrauterine growth restriction on cardiopulmonary structure and function during adulthood. Cardiovasc Res. 2009; 81, 713722.
34. Shah, A, Reyes, LM, Morton, JS, et al. Effect of resveratrol on metabolic and cardiovascular function in male and female adult offspring exposed to prenatal hypoxia and a high-fat diet. J Physiol. 2016; 594, 14651482.
35. Black, MJ, Siebel, AL, Gezmish, O, Moritz, KM, Wlodek, ME. Normal lactational environment restores cardiomyocyte number after uteroplacental insufficiency: implications for the preterm neonate. Am J Physiol Regul Integr Comp Physiol. 2012; 302, R1101R1110.
36. Botting, KJ, McMillen, IC, Forbes, H, Nyengaard, JR, Morrison, JL. Chronic hypoxemia in late gestation decreases cardiomyocyte number but does not change expression of hypoxia-responsive genes. J Am Heart Assoc. 2014; 3, e000531.
37. Bubb, KJ, Cock, ML, Black, MJ, et al. Intrauterine growth restriction delays cardiomyocyte maturation and alters coronary artery function in the fetal sheep. J Physiol. 2007; 578(Pt 3), 871881.
38. Morrison, JL, Botting, KJ, Dyer, JL, et al. Restriction of placental function alters heart development in the sheep fetus. Am J Physiol Regul Integr Comp Physiol. 2007; 293, R306R313.
39. Burrell, JH, Boyn, AM, Kumarasamy, V, et al. Growth and maturation of cardiac myocytes in fetal sheep in the second half of gestation. Anat Rec A Discov Mol Cell Evol Biol. 2003; 274, 952961.
40. Shi, J, Jiang, B, Qiu, Y, et al. PGC1alpha plays a critical role in TWEAK-induced cardiac dysfunction. PLoS One. 2013; 8, e54054.
41. Sun, L, Zhao, M, Yu, XJ, et al. Cardioprotection by acetylcholine: a novel mechanism via mitochondrial biogenesis and function involving the PGC-1alpha pathway. J Cell Physiol. 2013; 228, 12381248.
42. Gerdes, J, Lemke, H, Baisch, H, et al. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984; 133, 17101715.
43. Gratzner, HG. Monoclonal antibody to 5-bromo- and 5-iododeoxyuridine: a new reagent for detection of DNA replication. Science. 1982; 218, 474475.
44. van Dierendonck, JH, Wijsman, JH, Keijzer, R, van de Velde, CJ, Cornelisse, CJ. Cell-cycle-related staining patterns of anti-proliferating cell nuclear antigen monoclonal antibodies. Comparison with BrdUrd labeling and Ki-67 staining. Am J Pathol. 1991; 138, 11651172.
45. Drewinko, B, Yang, LY, Barlogie, B, Trujillo, JM. Cultured human tumour cells may be arrested in all stages of the cycle during stationary phase: demonstration of quiescent cells in G1, S and G2 phase. Cell Tissue Kinet. 1984; 17, 453463.
46. Scholzen, T, Gerdes, J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000; 182, 311322.
47. Cohen, E, Wong, FY, Horne, RS, Yiallourou, SR. Intrauterine growth restriction: impact on cardiovascular development and function throughout infancy. Pediatr Res. 2016; 79, 821830.
48. Murphy, PJ. The fetal circulation. Continuing Education in Anaesthesia, Critical Care & Pain. 2005; 5, 107112.
49. Baschat, AA. Fetal responses to placental insufficiency: an update. BJOG. 2004; 111, 10311041.

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