Hyperglycemia‐induced TGFβ and fibronectin expression in embryonic mouse heart

Abstract

Cardiovascular defects are common in diabetic offspring, but their etiology and pathogenesis are poorly understood. Extracellular matrix accumulates in adult tissues in response to hyperglycemia, and transforming growth factor-beta1 (TGF␤1) likely mediates this effect. The objective of this study was to characterize TGF␤ expression in the organogenesisstage mouse heart and to evaluate TGF␤ and fibronectin expression in embryonic mouse heart exposed to hyperglycemia. Prominent TGF␤1, and minimal TGF␤2 or TGF␤3, protein expression was demonstrated in embryonic day (E) 9.5-E13.5 hearts. Hyperglycemia for 24 hr produced significantly increased fibronectin, slightly increased TGF␤1, and unchanged TGF␤2 or TGF␤3, by immunohistochemistry. Increased TGF␤1 was demonstrated by enzyme-linked immunosorbent assay in embryonic fluid and isolated hearts after hyperglycemia for 24 hr, but not 48 hr. Hyperglycemia increased fibronectin protein and mRNA expression in embryonic hearts after 24 hr, and pericardial injection of TGF␤1 also increased fibronectin mRNA in the embryonic heart. It is proposed that TGF␤1 and fibronectin may play a role in diabetes-induced cardiac dysmorphogenesis.

Oxidative stress is responsible for maternal diabetes-impaired transforming growth factor beta signaling in the developing mouse heart

“…We found that the total level of TGFβ ligands, especially TGFβ1 and TGFβ3, were reduced by maternal diabetes. This finding is consistent with what described by Zhao et al in E10.5 hearts 17 , but contradicts a previous in vitro study, which described a slight decrease in TGFβ1 expression in the mouse (E9.5) embryonic heart when exposed to high glucose for 24 hours 2 . This discrepancy may be explained by the different stages of hearts that were examined in the two studies.…”

“…Major cardiac defects including persistent truncus arteriosus and ventricular septal defects (VSDs) are often seen in offspring of diabetic women 1, 2 . Because the number of women of reproductive age (18-44 years old) with diabetes is increasing 3 , diabetes-induced heart defects have become an urgent health problem 4 .…”

“…The critical exposure period for diabetes-induced birth defects is during organogenesis, which occurs during gestational stage 2 to 8 weeks in humans 5 and corresponds approximately to E8.5 to 12.5 in the mouse 2, 6 . Investigations using rodent models of diabetic embryopathy have revealed many important insights into the signal transduction factors that may cause diabetic embryopathy, particularly those involved in diabetes-induced neural tube defects (NTDs) 5, 7-15 .…”

Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis

“…Because trehalose prevents alteration of gene expression that regulates autophagy, trehalose may activate autophagy by modulating gene expression. Previous studies have shown that JNK1/2 activation (23, 24), TGF␤ pathway disturbance (40), and diminished Wnt signaling (35) are critically involved in the induction of diabetic embryopathy. These three signaling pathways regulate the autophagy process (20,32,52).…”

No correlation between the p38 MAPK pathway and the contractile dysfunction in diabetic cardiomyocytes

“…The aim of the present study was to determine the direct hyperglycaemic effects on contractile functions and important intracellular signalling pathways in myocytes. The signalling molecules investigated in this study are restricted to those intracellular molecules found in the angiotensin II-induced pathway in adult ventricular cardiomocytes because there is some evidence that these molecules are also involved in the hyperglycaemic pathway [21,22,23].…”