Histone acetylation is essential for ANG‐II‐induced IGF‐IIR gene expression in H9c2 cardiomyoblast cells and pathologically hypertensive rat heart

Abstract

The IGF-II/mannose 6-phosphate receptor (IGF-IIR/Man-6-P) up-regulation correlates with heart disease progression and its signaling cascades directly trigger pathological cardiac hypertrophy, fibrosis, and cardiomyocytes apoptosis. IGF-IIR gene expression/ suppression is able to prevent myocardial remodeling. However, the regulating mechanisms for the IGF-IIR gene remain unclear. This study performed reverse transcriptase PCR (RT-PCR) and methylation-specific PCR (MS-PCR) to detect expression and DNA methylation of CpG islands within the IGF-IIR genomic DNA region. Our finding revealed that the IGF-IIR gene was up-regulated both in H9c2 cells treated with tumor necrosis factor-alpha (TNF-α), lipopolysaccharide (LPS), angiotensin II (ANGII) and inomycin, and age-dependently in spontaneously hypertensive rat (SHR) heart. For the DNA methylation study, although there were four CpG islands within IGF-IIR genomic regions, the DNA methylation distribution showed no change either in cells treated with ANGII or in the SHR heart. Using chemical inhibitors to individually block histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity, we found that histone acetylation was essential for ANGII-induced IGF-IIR gene expression using RT-PCR and luciferase assay. The Chromatin immuno-precipitation assay indicated that acetyl-Histone H3 and acetyl-Histone H4 associated with the IGF-IIR promoter increased in the presence of ANGII, otherwise methyl-CpG binding domain protein 2 (MeCP2) is disassociated with this. Taken together, this study demonstrates that histone acetylation plays a critical role in IGF-IIR up-regulation during pathological cardiac diseases and might provide a targeting gene in transcriptional therapies for the failing heart.

ANG II promotes IGF-IIR expression and cardiomyocyte apoptosis by inhibiting HSF1 via JNK activation and SIRT1 degradation

“…These findings support our previous studies. 10,14,29 We also observed that other kinases downstream of AT 1 R were involved in IGF-IIR expression. However, these kinases may have influenced IGF-IIR expression via different mechanisms, such as protein stability and degradation.…”

“…14 ANG II has been reported to activate downstream signaling via the angiotensin type 1 and type 2 receptors (AT 1 R and AT 2 R, respectively) to elicit various biological responses. 1,2 As shown in Figure 1a, the knockdown of AT 1 R reduced the upregulation of IGF-IIR expression by ANG II, whereas the knockdown of AT 2 R had no obvious influence on IGF-IIR regulation by ANG II.…”

Upregulation of the Na+-K+-2Cl− cotransporter 1 via histone modification in the aortas of angiotensin II-induced hypertensive rats

“…32 After the demethylation of H3K27me3, Sp1 that is recruited to the promoter may lead to positive regulation of the Nkcc1 gene with co-activators such as histone acetyltransferases in hypertensive rats. Although Ang II increased the histone acetylation for IGF-IIreceptor gene expression, 33 it is still not clear whether the upregulation of the Nkcc1 gene promoter activity is caused by indirect mechanisms downstream of Ang II, such as oxidative stress and high BP, or by a direct mechanism through the activation of Ang II receptors. This question is very substantial and should be resolved in a future study.…”

Tissue-Specific Upregulation of Angiotensin-Converting Enzyme 1 in Spontaneously Hypertensive Rats Through Histone Code Modifications

“…Recently, it was reported that Ang II increases acetyl-histone H3 and acetyl-histone H4 without affecting DNA methylation when it induces insulin-like growth factor type II receptor gene expression in H9c2 cardiomyoblast cells and pathologically hypertensive rat heart. 32 Thus, further studies will be needed to clarify the relevance of epigenetic changes in the development of cardiovascular disease, including hypertension. …”