Gadd45α: A Novel Diabetes-Associated Gene Potentially Linking Diabetic Cardiomyopathy and Baroreflex Dysfunction

Abstract

Both diabetic cardiomyopathy (DCM) and baroreflex dysfunction independently contribute to sudden cardiac death (SCD), however the inherent connections between them under diabetic state remains unclear. As microRNAs (miRNAs) have been reported to participate in various physiological and pathological processes, we presume they may also be involved in DCM and DM-induced impairment of baroreflex sensitivity. Two sets of gene expression profiles data from streptozotocin (STZ)-induced diabetic heart and diabetic dorsal root ganglia (DDRG) were retrieved from GEO and ArrayExpress. Co-differentially-expressed genes in diabetic heart and DDRG were identified by t test and intersection analysis. Human Protein Reference Database (HPRD) was applied to find direct interacting proteins of Gadd45α. Differentially-expressed miRNAs in left ventricle from 4-week STZ-induced diabetic rats were screened by miRNA microarray. Expression of miR-499 and its regulating effect on Gadd45α were then verified by quantitative real-time PCR (qRT-PCR), western blot, computational predication, and dual-luciferase reporter analysis. Four co-differentially-expressed genes in DCM and DDRG were identified. Among these genes, Gadd45α has 16 direct interacting proteins and 11 of them are documentedly associated with DM. Accompanied with significantly increased miR-499 expression, Gadd45α expression was increased at mRNA level but decreased at protein level in both diabetic heart and nucleus ambiguous. Furthermore, miR-499 was confirmed negatively regulating Gadd45α by targeting its 3′UTR. Collectively, reduced Gadd45α protein expression by forced miR-499 expression indicated it's a diabetes-associated gene which might potentially be involved in both DCM and DM-induced baroreflex dysfunction.

Silencing of miR-195 reduces diabetic cardiomyopathy in C57BL/6 mice

“…It is important to mention that other miRs may also be involved in the development of diabetic cardiomyopathy, such as miR-133 [43], miR-1 [44] and miR-499 [45]. It is currently unknown whether simultaneously silencing multiple miRs provides better protective effects in the diabetic heart.…”

The inhibition of apoptosis through myocardial postconditioning by affecting Fas/FasIg signaling through miR139‐3p and miR181a‐1

“…It was also reported that Gadd45a can disrupt the formation of Becn1 and the phosphatidylinositol 3‐kinase complex that is required for the initiation of autophagy 34 . Another study showed that the mRNA levels of Gadd45a expression were increased while protein levels were decreased in diabetic hearts 47 . Selenite therapy suppressed Gadd45a expression significantly in Keshan disease, which is a fatal form of cardiomyopathy, while expression was increased in the presence of a selenium deficiency 48 .…”

“…34 Another study showed that the mRNA levels of Gadd45a expression were increased while protein levels were decreased in diabetic hearts. 47 Selenite therapy suppressed Gadd45a expression significantly in Keshan disease, which is a fatal form of cardiomyopathy, while expression was increased in the presence of a selenium deficiency. 48 These data suggest that PostC may exert protective effects by inhibiting both the extrinsic pathway through affecting Fas and FasIg levels and the intrinsic pathway through Gadd45a.…”

In vitro effects of low-level aldehyde exposures on human umbilical vein endothelial cells

“…50,51 In addition to this, a gene associated with DNA damage signaling and apoptosis, 52 CXXC5 was significantly upregulated. 53,54 Upregulation of GADD45A has been found to contribute to the stress response effect that causes cardiomyopathy under diabetic conditions 55 and dysregulated blood pressure in pregnant women. The function of this CXXC5 (CXXC finger 5 (CF5)) is not well known but in a recent study, the CXXC5 gene has been identified as a critical component in the DNA damage-signaling pathway.…”