CCAAT/enhancer‐binding protein β overexpression alleviates myocardial remodelling by regulating angiotensin‐converting enzyme‐2 expression in diabetes

Abstract

Diabetic cardiomyopathy, a major cardiac complication, contributes to heart remodelling and heart failure. Our previous study discovered that CCAAT/enhancer‐binding protein β (C/EBPβ), a transcription factor that belongs to a family of basic leucine zipper transcription factors, interacts with the angiotensin‐converting enzyme 2 (ACE2) promoter sequence in other disease models. Here, we aimed to determine the role of C/EBPβ in diabetes and whether ACE2 expression is regulated by C/EBPβ. A type 1 diabetic mouse model was generated by an intraperitoneal injection of streptozotocin. Diabetic mice were injected with a lentivirus expressing either C/EBPβ or sh‐C/EBPβ or treated with valsartan after 12 weeks to observe the effects of C/EBPβ. In vitro, cardiac fibroblasts and cardiomyocytes were treated with high glucose (HG) to investigate the anti‐fibrosis, anti‐apoptosis and regulatory mechanisms of C/EBPβ. C/EBPβ expression was down‐regulated in diabetic mice and HG‐induced cardiac neonatal cells. C/EBPβ overexpression significantly attenuated collagen deposition and cardiomyocyte apoptosis by up‐regulating ACE2 expression. The molecular mechanism involved the binding of C/EBPβ to the ACE2 promoter sequence. Although valsartan, a classic angiotensin receptor blocker, relieved diabetic complications, the up‐regulation of ACE2 expression by C/EBPβ overexpression may exert greater beneficial effects on patients with diabetic cardiomyopathy.

Analysis of extracellular vesicle miRNA profiles in heart failure

“…Intriguingly, approximately 72% of targets anticipated to be up-regulated were confirmed to be elevated indeed in diseased conditions by previous reports, [40][41][42][43][44][45][46][47][48][49][50][51] and 50% of targets expected to be down-regulated were actually reduced. [52][53][54][55][56][57] This result proves that EV miRs from failing hearts substantially affect gene expressions in the heart.…”

IRF‐1 promotes renal fibrosis by downregulation of Klotho

“…For example, C/EBP‐β reduced fibronectin synthesis by regulating the transcription of TINag while the deficiency of C/EBP‐β aggravated renal fibrosis . In UUO‐induced renal fibrosis and STZ‐induced rat diabetic nephropathy, C/EBP‐β was notably decreased in fibrotic kidneys and contributes to ameliorate renal fibrosis . Although some study indicated that TGF‐β1 could upregulate C/EBP‐β in human lung fibroblasts, compelling evidence suggested that in primary renal tubular epithelial cells TGF‐β1 reduce C/EBP‐β expression .…”

“…Dependent on bioinformatics and IRF-1 transfection, we performed Human Klotho promoter analysis and focused on C/EBP-β which is a ubiquitously transcription factor belongs to C/EBPs family and affects expression of multiple genes by binding to their promoters. 39,50,51 Previous studies have shown that the transcription factor IRF-1 could form a function complex with other transcription factors to regulate gene expression in a cooperative manner. 52,53 However, it is unclear whether IRF-1 and C/EBP-β could interact physically each other to regulate the Klotho expression.…”

“…39 In UUO-induced renal fibrosis and STZ-induced rat diabetic nephropathy, C/EBP-β was notably decreased in fibrotic kidneys and contributes to ameliorate renal fibrosis. 30,51 Although some study indicated that TGF-β1 could upregulate C/EBP-β in human lung fibroblasts, 56 compelling evidence suggested that in primary renal tubular epithelial cells TGF-β1 reduce C/EBP-β expression. 30 In this study, our results demonstrate that elevated IRF-1 expression inhibits Klotho expression through C/EBP-β in HK-2 cells, and the specific C/EBP-β-binding site in KL is located in the promoter region between nt − 1039 and − 1029.…”

Association of ACE inhibitors and angiotensin type II blockers with ACE2 overexpression in COVID-19 comorbidities: A pathway-based analytical study

“…The enhancer-binding protein β is a specific sequence CCAAT associated transcription factor which up-regulates of ACE2 expression by its overexpression. The transcription factor C/EBPβ also increased angiotensin (1–7) levels, but a less significant difference was determined ( Tie et al 2017 ).…”