Gestational diabetes influences the expression of hypertrophic genes in left ventricle of rat’s offspring

Document Type: Original Article

Authors

1 Department of Anatomical sciences, Golestan University of Medical Sciences, Gorgan, Iran

2 Gorgan Congenital Malformations research Center, Golestan University of Medical Sciences, Gorgan, Iran

3 Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

4 Molecular Genetic Research Center, Golestan University of Medical Sciences, Gorgan, Iran

5 Gorgan Congenital Malformations Research Center, Department of Anatomical sciences, Golestan University of Medical Sciences, Gorgan, Iran

Abstract

Objective(s): Gestational diabetes increases the risk of congenital heart disease in the offspring, but the molecular mechanism underlying this process remains unclear. Therefore, the current study was conducted to assess the effects of induced gestational diabetes on expression of some involved genes in cardiac hypertrophy in the offspring of diabetic rats.
Materials and Methods: Diabetes was induced in 40 adult Wistar rats by intraperitoneal injection of 45 mg/kg of streptozotocin. The day of appearance of the vaginal plug was assumed as day zero of gestation for inducing diabetes. After pregnancy, the offspring was maintained until they reach the age of 12 weeks. Then, their hearts were excised and were sectioned for molecular study. We analyzed the expression pattern of some hypertrophic genes by the quantitative real-time RT-PCR.
Results: The mRNA expression levels of all studied genes including c-jun, c-fos, c-myc, alpha-myosin heavy chain (α-MHC), atrial natriuretic factor (ANF) and β-MHC, which are important in cardiomyocyte hypertrophy, were higher in the offspring of the diabetic group compared to controls. Significant differences were found for β-MHC and c-myc with PConclusion: Gestational diabetes upregulates expression of c-jun, c-fos c-myc, α-MHC, ANF and β-MHC genes that are involved in cardiac hypertrophy in the offspring of diabetic rats.

Keywords

Main Subjects


1. Zielinsky P, Luchese S, Manica JL, Piccoli AL Jr, Nicoloso LH, Leite MF et al. Left atrial shortening fraction in fetuses with and without myocardial hypertrophy in diabetic pregnancies. Ultrasound Obstet Gynecol 2009; 33:182-187.
2. Kumar SD, Dheen ST, Tay SS. Maternal diabetes induces congenital heart defects in mice by altering the expression of genes involved in cardiovascular development. Cardiovasc Diabetol 2007; 30; 6:34.
3. Gallou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome. Diabetes 2005; 54:1899-1906.
4. Cho NH, Silverman BL, Rizzo TA, Metzger BE. Correlations between the intrauterine metabolic environment and blood pressure in adolescent offspring of diabetic mothers. J pediat 2000; 136:587-592.
5. Nazari Z, Nabiuni M, Saeidi M, Golalipour MJ. Gestational diabetes leads to down-regulation of CDK4-pRB-E2F1 pathway genes in pancreatic islets of rat offspring. Iran J Basic Med Sci 2017; 20:150-154.
6. Morgan SC, Relaix F, Sandell LL, Loeken MR. Oxidative stress during diabetic pregnancy disrupts cardiac neural crest migration and causes outflow tract defects. Birth Defects Res 2008; 82:453-463.
7. Menezes HS, Zettler CG, Calone A, Corrêa JB, Bartuscheck C, Costa CSd, et al. Regression of gestational diabetes induced cardiomegaly in offspring of diabetic rat. Acta Cir Bras 2009; 24:251-255.
8. Chen C, Gui YH, Ren YY, Shi LY. The impacts of maternal gestational diabetes mellitus (GDM) on fetal hearts. Biomed. Envir. Sciences 2012; 25:15-22.
9. Bánhidy F, Ács N, Puhó EH, Czeizel AE. Congenital abnormalities in the offspring of pregnant women with type 1, type 2 and gestational diabetes mellitus: A population‐based case‐control study. Congenit Anom 2010; 50:115-121.
10.  Kirby ML, Gale TF, Stewart DE. Neural crest cells contribute to normal aorticopulmonary septation. Science 1983; 220:1059-1061.
11. Suzuki N, Svensson K, Eriksson U. High glucose concentration inhibits migration of rat cranial neural crest cells in vitro. Diabetologia 1996; 39:401-411.
12. Ishii M, Han J, Yen H-Y, Sucov HM, Chai Y, Maxson RE. Combined deficiencies of Msx1 and Msx2 cause impaired patterning and survival of the cranial neural crest. Development 2005;132:4937-4950
13. Olson AL, Pessin JE. Regulation of c-fos expression in adipose and muscle tissue of diabetic rats. Endocrinology 1994; 134:271-276.
14. Juan Eduardo Carreño, Felipe Apablaza, María Paz Ocaranza, and Jorge E. Jalil. Cardiac Hypertrophy: Molecular and Cellular Events. Rev Esp Cardiol 2006; 59:473-486.
15. S. Lenzen. The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 2008; 51: 216-226.
16. Pasek RC & Gannon M. Advancements and challenges in generating accurate animal models of gestational diabetes mellitus. Am J Physiol Endocrinol Metab 2013; 305: 1327-1338.
17. Catalano PM, Kirwan JP, Haugel-de Mouzon S, King J. Gestational diabetes and insulin resistance: role in short-and long-term implications for mother and fetus. J Nutr 2003; 133:1674S-1683S.
18. Menezes HS, Barra M, Belló AR, Martins CB, Zielinsky P. Fetal myocardial hypertrophy in an experimental model of gestational diabetes. Cardiol Young 2001; 11:609-613.
19. H Schunkert, L Jahn, S Izumo, C S Apstein, and B H Lorell. Localization and regulation of c-fos and c-jun protooncogene induction by systolic wall stress in normal and hypertrophied rat hearts. Proc Nati Acad Sci 88, pp. 11480-11484.
20. Sandra Ullmo, Yvan Vial, Stefano Di Bernardo, Matthias Roth-Kleiner, Yvan Mivelaz, Nicole Sekarski, et al. Pathologic ventricular hypertrophy in the offspring of diabetic mothers: a retrospective study. Eur Heart J 2007; 28:1319-1325.
21. Chen QM, Tu VC, Purdom S, Wood J, Dilley T. Molecular mechanisms of cardiac hypertrophy induced by toxicants. Cardiovasc. Toxicol 2001; 1: 267-283.
22. Carreño JE, Apablaza F, Ocaranza MP, Jalil JE. Cardiac hypertrophy: molecular and cellular events. Rev Esp Cardiol 2006; 59:473-486.