Expression of Connexin 43 in the hearts of rat embryos exposed to nitrofen and effects of vitamin A on it

Abstract

Rats with experimental congenital diaphragmatic hernia (CDH) have heart hypoplasia and conotruncal and great vessel malformations that are likely related to disturbed neural crest developmental control. Neural crest cells communicate through intercellular gap junctions whose main protein is Connexin 43 (Cx43). The migration and participation of neural crest cells in heart development is likely influenced by this protein which might be also directly involved in myocardial development. Vitamin A is beneficial for heart hypoplasia in CDH rats. The aims of this study were to examine the status of Cx43 in the heart of embryonal rats exposed to nitrofen and to assess if vitamin A reverts these effects. Pregnant rats received either 100 mg nitrofen or olive oil on E9.5. Each group was divided into two subgroups according to the subsequent treatment with intragastric vitamin A (15,000 i.u.) or vehicle on E10.5 and E11.5. The pups were recovered on E13, E15, and E21 and the hearts were dissected out and pooled. Cx43 mRNA expression was determined by quantitative real-time PCR. Comparisons among groups were made with ANOVA and Bonferroni post hoc tests with a threshold of significance of P<0.05. In control rats Cx43 mRNA was minimally expressed on E13 and E15 and fully expressed on E21. Nitrofen significantly increased Cx43 mRNA on E15. Additional treatment with vitamin A tended to moderate this increase on E15. Cx43 was overexpressed in the hearts of nitrofen-exposed embryonal rats on day E15 of gestation. Vitamin A tended to normalize this expression. The mechanism of action of Cx43 deserves further investigation.

Prenatal Zinc Deficiency: Influence on Heart Morphology and Distribution of Key Heart Proteins in a Rat Model

“…As the promoter region of Cx43 contains multiple consensus sequences for AP1 and Sp1 binding [75,76], low intracellular Zn level has been associated with increased AP1-DNA binding activity in other cell types [77,78]. Of note, rat fetuses exposed to the herbicide nitrofen exhibit outflow tract and great vessel defects and show a transient increased expression of Cx43 in the heart [79]. It has also been suggested that the cardiac outflow defects observed after hyperhomocysteinemia can be in part due to elevated Cx43 levels [80].…”

Prenatal retinoic acid upregulates connexin 43 (Cx43) gene expression in pulmonary hypoplasia in the nitrofen-induced congenital diaphragmatic hernia rat model

“…It has been recently revealed that molecular signalling involved in this superfamily is disrupted in murine hypoplastic lungs leading to reduced number of alveoli and abnormal alveolar structure, which may be attributed to downregulation of RARs [32]. Furthermore, it has been recently reported that either gain or loss of Cx43 function is involved in the pathogenesis of cardiac malformations in experimental CDH and that Vitamin A administration can rescue them [19,23,33].…”

“…It has been shown that lungs of Cx43 knockout mice display features of severe PH, which are also seen in the nitrofen-induced PH [20]. Furthermore, in vitro studies have demonstrated that retinoids increase Cx43 expression in rodents as well as in humans [21][22][23][24].…”

Heavy ion radiation up-regulates Cx43 and ameliorates arrhythmogenic substrates in hearts after myocardial infarction

“…Those include endothelin-1, angiotensin-II, thyroid hormones, AAP10 and nitrofen [27][28][29][30]. As to the therapeutic challenge to ameliorate arrhythmogenic substrates, however, all of these procedures have significant limitations in their clinical feasibility because of their low efficiency, undesirable cardiovascular and other side effects.…”