Effect of gestational protein restriction on left ventricle hypertrophy and heart angiotensin II signaling pathway in adult offspring rats


Maternal protein restriction may be a risk factor for cardiovascular disorders in adulthood. The RAS (renin-angiotensin-system) plays a pivotal role in cardiac remodeling. Components of the RAS, including angiotensin II (AngII) and its receptors type 1 (AT1R) and 2 (AT2R) are expressed in the heart. This study investigates whether gestational protein restriction alters the expression and localization of AT1R and AT2R and RAS signaling pathway proteins in parallel with left ventricle hypertrophy and systemic hypertension in male offspring. Dams were kept on normal (NP, 17% protein) or low (LP, 6% protein) protein diet during pregnancy. Systolic blood pressure (SBP) of male offspring was measured from the 8th to 16th week and left ventricles of 16-wk-old rats were processed for histology, morphometric, immunoblotting and immunohistochemistry. LP offspring showed a significant reduction in birth body weight and SBP increased significantly from the 8th week. Left ventricle mass and cardiomyocytes area were also significantly higher in LP animals. Widespread perivascular fibrosis was not detected in the heart tissue. Analysis by immunoblotting and immunohistochemistry demonstrated a significant enhance in cardiomyocyte expression of AT1R and ERK1 in LP offspring. Expression of PI3K in LP was significantly reduced in cardiomyocytes and in the intramural coronary wall, while AT2R expression was unchanged in the NP group. We also found reduced LP expression of JAK2 and STAT3. In conclusion, our data also suggest that changes in the RAS may play a role in the ventricular growth through upregulation of the AT1-mediated ERK1/2 response, despite unchanged AT2R expression.

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Silva, R. , Mesquita, F. , Andreo, M. , Assalin, H. , Rocha Gontijo, J. and Boer, P. (2013) Effect of gestational protein restriction on left ventricle hypertrophy and heart angiotensin II signaling pathway in adult offspring rats. Health, 5, 78-84. doi: 10.4236/health.2013.54A011.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Barker, D. (1998) In uteroprogramming of chronic disease. Clinical Science, 95, 115-128. doi:10.1042/CS19980019
[2] Unger, T. (2003) Blood pressure lowering and reninangiotensin system blockade. Journal of Hypertension, Suppl. 2, S3-S7. doi:10.1097/00004872-200307006-00002
[3] Varagic, J. and Frohlich, E.D. (2002) Local cardiac reninangiotensin system: Hypertension and cardiac failure. Journal of Molecular and Cellular Cardiology, 34, 1435-1442. doi:10.1006/jmcc.2002.2075
[4] Berecek, K.H., Reaves, P. and Raizada, M. (2005) Effects of early perturbation of the renin-angiotensin system on cardiovascular remodeling in spontaneously hypertensive rats. Vascular Pharmacology, 42, 93-98. doi:10.1016/j.vph.2005.01.010
[5] Holemans, K., Aerts, L. and Van Assche, F.A. (2003) Fetal growth restriction and consequences for the offspring in animal models. Journal of the Society for Gynecologic Investigation, 10, 392-399. doi:10.1016/S1071-5576(03)00134-5
[6] Ozaki, T., Nishina, H., Hanson, M.A. and Poston, L. (2001) Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring. Journal of Physiology, 530, 141-152. doi:10.1111/j.1469-7793.2001.0141m.x
[7] Rasch, R., Skriver, E. and Woods, L.L. (2004) The role of the RAS in programming of adult hypertension. Acta Physiologica Scandinavica, 181, 537-542. doi:10.1111/j.1365-201X.2004.01328.x
[8] Mesquita, F.F., Gontijo, J.A.R. and Boer, P.A. (2010) Expression of rennin-angiotensin system signalling compounds in maternal protein-restricted rats: Effect on renal sodium excretion and blood pressure. Nephrology Dialysis Transplantation, 25, 380-388. doi:10.1093/ndt/gfp505
[9] Mesquita, F.F., Gontijo, J.A.R. and Boer, P.A. (2010) Maternal undernutrition and the offspring kidney: From fetal to adult life. Brazilian Journal of Medical and Biological Research, 43, 1010-1018. doi:10.1590/S0100-879X2010007500113
[10] Michelotto, J.B., Carvalheira, J.B., Saad, M.J. and Gontijo, J.A. (2002) Effects of intracerebroventricular insulin microinjection on renal sodium handling in kidney-denervated rats. Brain Research Bulletin, 57, 613-618. doi:10.1016/S0361-9230(01)00754-7
[11] Menegon, L., Zaparolli, A., Boer, P.A., de Almeida, A.R. and Gontijo, JA. (2008) Long-term effects of intracerebroventricular insulin microinjection on renal sodium handling and arterial blood pressure in rats. Brain Research Bulletin, 76, 344-348. doi:10.1016/j.brainresbull.2008.02.027
[12] Romero-Calvo, I., Ocón, B. and Martínez-Moya, P. (2010) Reversible Ponceau staining as a loading control alternative to actin in Western blots. Analytical Biochemistry, 401, 318-320. doi:10.1016/j.ab.2010.02.036
[13] Langley-Evans, S.C. (2001) Fetal programming of cardiovascular function through exposure to maternal undernutrition. Proceedings of the Nutrition Society, 60, 505-513. doi:10.1079/PNS2001111
[14] Breier, B.H., Vickers, M.H., Ikenasio, B.A., Chan, K.Y. and Wong, W.P. (2001) Fetal programming of appetite and obesity. Molecular and Cellular Endocrinology, 185, 73-79. doi:10.1016/S0303-7207(01)00634-7
[15] Zhu, Y.C., Zhu, Y.Z., Lu, N., Wang, M.J., Wang, Y.X. and Yao, T. (2003) Role of angiotensin AT1 and AT2 receptors in cardiac hypertrophy and cardiac remodelling. Clinical and Experimental Pharmacology and Physiology, 30, 911-918. doi:10.1111/j.1440-1681.2003.03942.x
[16] Segar, J.L., Dalshaug, G.B., Bedell, K.A., Smith, O.M. and Scholz, T.D. (2001) Angiotensin II in cardiac pressure-overload hypertrophy in fetal sheep. American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 281, R2037-R2047.
[17] Sundgren, N.C., Giraud, G.D., Stork, P.J., Maylie, J.G. and Thornburg, K.L. (2003) Angiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes. Journal of Physiology, 548, 881-891. doi:10.1113/jphysiol.2003.038778
[18] Lumbers, E.R., Boyce, A.C., Joulianos, G., Kumarasamy, V., Barner, E., Segar, J.L. and Burrell, J.H. (2005) Effects of cortisol on cardiac myocytes and on expression of cardiac genes in fetal sheep. American Journal of Physiology —Regulatory, Integrative and Comparative Physiology, 288, R567-R574. doi:10.1152/ajpregu.00556.2004
[19] Dostal, D.E. (2000) The cardiac renin-angiotensin system: Novel signaling mechanisms related to cardiac growth and function. Regulatory Peptides, 91, 1-11. doi:10.1016/S0167-0115(99)00123-8
[20] Alvin, Z.V., Laurence, G.G., Coleman, B.R., Zhao, A., Hajj-Moussa, M. and Haddad, G.E. (2011) Regulation of the instantaneous inward rectifier and the delayed outward rectifier potassium channels by Captopril and Angiotensin II via the Phosphoinositide-3 kinase pathway in volume-overload-induced hypertrophied cardiac myocytes. Medical Science Monitor, 17, 165-172. doi:10.12659/MSM.881843
[21] Schaper, J., Froede, R., Hein, S., Buck, A., Hashizume, H., Speiser, B., Friedl, A. and Bleese, N. (1991) Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation, 82, 504-514. doi:10.1161/01.CIR.83.2.504
[22] Sugden, P.H. and Clerk, A. (1997) Regulation of the ERK subgroup of MAP kinase cascades through G proteincoupled receptors. Cell Signal, 9, 337-351. doi:10.1016/S0898-6568(96)00191-X
[23] Ishida, M., Ishida, T., Thomas, S.M. and Berk, B.C. (1998) Activation of extracellular signal-regulated kinases (ERK1/2) by angiotensin II is dependent on c-Src in vascular smooth muscle cells. Circulation Research, 82, 7-12. doi:10.1161/01.RES.82.1.7
[24] Sharfe, N., Dani, H.K. and Roifman, C.M. (1995) JAK3 protein tyrosine kinase mediates interleukin-7-induced activation of phosphatidylinositol-3' kinase. Blood, 86, 2077-2085.
[25] Takahasi-Tezuka, M., Hibi, M., Fujitani, Y., Fukada, T., Yamaguchi, T. and Hirano, T. (1997) Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK. Oncogene, 14, 2273-2282. doi:10.1038/sj.onc.1201071
[26] David, M., Petricoin III, E., Benjamin, C., Pine, R., Weber, M.J. and Larner, A.C. (1995) Requirement for MAP kinase (ERK2) activity in interferon alphaand interferon beta-stimulated gene expression through STAT proteins. Science, 269, 1721-1723. doi:10.1126/science.7569900
[27] Boccaccio, C., Andò, M., Tamagnone, L., Bardelli, A., Michieli, P., Battistini, C. and Comoglio P.M. (1998) Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature, 391, 285-288. doi:10.1038/34657

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