Abstract
Bnip3 is a hypoxia-regulated member of the Bcl-2 family of proteins that is implicated in apoptosis, programmed necrosis, autophagy and mitophagy. Mitochondria are thought to be the primary targets of Bnip3 although its activities may extend to the ER, cytoplasm, and nucleus. Bnip3 is induced in the heart by ischemia and pressure-overload, and may contribute to cardiomyopathy and heart failure. Only mitochondrial-dependent programmed death actions have been described for Bnip3 in the heart. Here we describe a novel activity of Bnip3 in cultured cardiac myocytes and transgenic mice overexpressing Bnip3 in the heart (Bnip3-TG). In cultured myocytes Bnip3 bound and activated the acetyltransferase p300, increased acetylation of histones and the transcription factor GATA4, and conferred p300 and GATA4-sensitive cellular morphological changes. In intact Bnip3-TG hearts Bnip3 also bound p300 and GATA4 and conferred enhanced GATA4 acetylation. Bnip3-TG mice underwent age-dependent ventricular dilation and heart failure that was partially prevented by p300 inhibition with curcumin. The results suggest that Bnip3 regulates cardiac gene expression and perhaps myocyte morphology by activating nuclear p300 acetyltransferase activity and hyperacetylating histones and p300-selective transcription factors.
Highlights
Bnip3 (Bcl-2/adenovirus E1B 19-kDa interacting protein 3) is a member of the BH3-only family of Bcl-2 proteins and has been assigned roles in apoptosis, programmed necrosis, autophagy and mitophagy during exposure of cells and tissues to hypoxia or ischemia
Simulation of ischemia by exposure of isolated cardiac myocytes to concurrent hypoxia with acidosis (HA) revealed a markedly increased acetylation of histones H3 and H4 compared with myocytes exposed to aerobic incubation (Fig 1A–1C)
To determine whether histone hyperacetylation was a secondary consequence of cell death, cardiac myocytes were subjected to HA in the presence of caspase, calpain or mPTP inhibitors
Summary
Bnip (Bcl-2/adenovirus E1B 19-kDa interacting protein 3) is a member of the BH3-only family of Bcl-2 proteins and has been assigned roles in apoptosis, programmed necrosis, autophagy and mitophagy during exposure of cells and tissues to hypoxia or ischemia (reviewed in [1,2,3]). Bnip Regulates p300 and GATA4 in the Heart. Pro-survival properties of Bnip that are unrelated to its regulation of mitochondrial functions have been reported. Bnip was shown to regulate the activity of the mammalian target of rapamycin (mTOR1) by selectively binding the regulatory GTPase protein Rheb (Ras homolog enriched in brain) in cells exposed to hypoxia [6]. Bnip was shown to confer survival signals in glioblastoma tumor cells by suppressing transcription of the apoptosisinducing factor and death receptor 5 genes [7, 8]
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