The NF-κB Subunit c-Rel Stimulates Cardiac Hypertrophy and Fibrosis

Abstract

Cardiac remodeling and hypertrophy are the pathological consequences of cardiovascular disease and are correlated with its associated mortality. Activity of the transcription factor NF-κB is increased in the diseased heart; however, our present understanding of how the individual subunits contribute to cardiovascular disease is limited. We assign a new role for the c-Rel subunit as a stimulator of cardiac hypertrophy and fibrosis. We discovered that c-Rel-deficient mice have smaller hearts at birth, as well as during adulthood, and are protected from developing cardiac hypertrophy and fibrosis after chronic angiotensin infusion. Results of both gene expression and cross-linked chromatin immunoprecipitation assay analyses identified transcriptional activators of hypertrophy, myocyte enhancer family, Gata4, and Tbx proteins as Rel gene targets. We suggest that the p50 subunit could limit the prohypertrophic actions of c-Rel in the normal heart, because p50 overexpression in H9c2 cells repressed c-Rel levels and the absence of cardiac p50 was associated with increases in both c-Rel levels and cardiac hypertrophy. We report for the first time that c-Rel is highly expressed and confined to the nuclei of diseased adult human hearts but is restricted to the cytoplasm of normal cardiac tissues. We conclude that c-Rel-dependent signaling is critical for both cardiac remodeling and hypertrophy. Targeting its activities could offer a novel therapeutic strategy to limit the effects of cardiac disease.

Artificial Zinc-Finger Transcription Factor of A20 Suppresses Restenosis in Sprague Dawley Rats after Carotid Injury via the PPARα Pathway

“…It is believed that the sustained overactivation of NF-κB plays an important role in the pathogenesis of hypertrophic cardiomyopathy. Studies have shown that PPARα agonists can inhibit the myocardial remodeling induced by pressure overload and improve myocardial systolic function in rats 35, 36. PPARα also plays a significant role in the regulation of neuroinflammation in numerous CNS diseases.…”

CYP epoxygenase 2J2 prevents cardiac fibrosis by suppression of transmission of pro-inflammation from cardiomyocytes to macrophages

“…There is growing evidence that anti-inflammatory therapy may be a promising strategy against cardiac fibrosis [35]. NF-κB is a pleiotropic transcription factor that, in addition to playing fundamental roles in immunity, also regulates the expression of genes that contribute to various cardiac diseases including cardiac fibrosis [36]. Cardiac tissue consists mainly of cardiomyoctyes, which are surrounded by extracellular matrix [37].…”

SWI/SNF chromatin remodeling enzymes are associated with cardiac hypertrophy in a genetic rat model of hypertension

“…Quantitative real-time PCR was performed in SYBR Green Master Mix (Qiagen, Germantown, Maryland) with an Applied Biosystems Prism 7500 PCR system and analyzed with the SDS software as described (Keenen et al, 2010). Primer sequences for ANP and BNP were as follows: ANP 5′-ACCTGGAGGAGAAGATGCCG-3′; 5′-TGTTGCAGCCTAGTCCGCTC-3′ and BNP 5′-GTGCTGCCCCAGATGATT-3′ 5′-GGTCTATCTTCTGCCCAAAG-3′(Gaspar-Pereira et al, 2012). Primer sequences for the control 18S rRNA were 5′-AGTCCCTGCCCTTTGTACACA-3′ and 5′-GATCCGAGGGCCTCACTAAAC-3′.…”