The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

Sapra, Geeta; Tham, Yow Keat; Cemerlang, Nelly; Matsumoto, Aya; Kiriazis, Helen; Bernardo, Bianca C.; Henstridge, Darren C.; Ooi, Jenny Y. Y.; Pretorius, Lynette; Boey, Esther J. H.; Lim, Lydia; Sadoshima, Junichi; Meikle, Peter J.; Mellet, Natalie A.; Woodcock, Elizabeth A.; Marasco, Silvana; Ueyama, Tomomi; Du, Xiao‐Jun; Febbraio, Mark A.; McMullen, Julie R.

doi:10.1038/ncomms6705

Cited by 89 publications

(117 citation statements)

References 71 publications

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“…For example, the heat-shock response is enhanced by increased levels of the molecular chaperone HSP72 (21,24,26,28,29), possibly mediated by Rac-1 signaling (31, 32). BGP-15 also decreases phospho-JNK (pJNK) and p38 stress signaling (21, 23) and increases AKT and IGFR1 protective signaling (23,25). Additionally, in models of stress and injury, BGP-15 has been shown to decrease cell stress by restoring normal mitochondrial function.…”

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confidence: 99%

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BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Ohlen

Russell

Brownstein

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Hereditary sensory and autonomic neuropathy type III, or familial dysautonomia [FD; Online Mendelian Inheritance in Man (OMIM) 223900], affects the development and long-term viability of neurons in the peripheral nervous system (PNS) and retina. FD is caused by a point mutation in the gene IKBKAP/ELP1 that results in a tissue-specific reduction of the IKAP/ELP1 protein, a subunit of the Elongator complex. Hallmarks of the disease include vasomotor and cardiovascular instability and diminished pain and temperature sensation caused by reductions in sensory and autonomic neurons. It has been suggested but not demonstrated that mitochondrial function may be abnormal in FD. We previously generated an Ikbkap/Elp1 conditional-knockout mouse model that recapitulates the selective death of sensory (dorsal root ganglia) and autonomic neurons observed in FD. We now show that in these mice neuronal mitochondria have abnormal membrane potentials, produce elevated levels of reactive oxygen species, are fragmented, and do not aggregate normally at axonal branch points. The small hydroxylamine compound BGP-15 improved mitochondrial function, protecting neurons from dying in vitro and in vivo, and promoted cardiac innervation in vivo. Given that impairment of mitochondrial function is a common pathological component of neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's, Parkinson's, and Huntington's diseases, our findings identify a therapeutic approach that may have efficacy in multiple degenerative conditions.T he autonomic nervous system is essential for homeostasis, and its disruption in familial dysautonomia (FD) can have fatal consequences resulting from cardiovascular instability, respiratory dysfunction, and/or sudden death during sleep (1-3). In addition to developmental decreases in the number of sensory and autonomic neurons, FD patients undergo a progressive loss of peripheral neurons and retinal ganglion cells. The latter loss may ultimately lead to blindness (4, 5). More than 98% of FD cases result from a single base substitution (IVS20+6T > C) in the IKBKAP/ELP1 gene (3, 6). This mutation is carried by 1 in 27 to 1 in 32 Ashkenazi Jews (3, 6). The protein encoded by the IKBKAP/ELP1 gene, IKAP/ELP1, is a scaffolding protein for the six-subunit Elongator complex (ELP1-ELP6), which modifies tRNAs during translation (7). Why reduction in the IKAP/ ELP1 protein results in neuronal death is unknown, and we have sought to elucidate the cellular and molecular mechanisms that cause progressive neurodegeneration in FD to help identify treatments that improve neuronal function and viability.Accumulating evidence indicates that cells from FD patients and from mouse models with deletions in the Elongator subunits Ikbkap/Elp1 or Elp3 experience intracellular stress (4,5,(8)(9)(10) resulting from the direct and/or indirect consequences of impaired translation (7, 11). The C terminus of IKAP/ELP1 has been shown to bind c-Jun N-terminal kinase (JNK) and to regulate JNK cytosolic stress signaling (12)....

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confidence: 99%

“…BGP-15 is a hydroxylamine derivative that has been shown to exert cyto-and neuroprotective effects in mammalian models of injury, stress, and disease (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). These improvements in cellular function have been correlated with the activation of several intracellular pathways.…”

mentioning

confidence: 99%

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Ohlen

Russell

Brownstein

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The HS response inducer BGP-15 has proven to efficiently reverse the noxious effects of HFD-induced obesity in the muscle and adipose tissue, by increasing the HS response [12]. BGP-15 improves cardiac function and reduces arrhythmic episodes in different mouse models that progressively develop heart failure and atrial fibrillation and can provide cytoprotection and normalization of cell signaling, which are often defective in the aged and diseased heart [287]. Therefore, if BGP-15 was developed to simulate the beneficial effects of exercise, it is plausible to suppose that exercise itself should present better (or the best) accomplishment.…”

Section: Physical Exercise Glutamine and Hs Response In Agingmentioning

confidence: 99%

Physiological regulation of the heat shock response by glutamine: implications for chronic low-grade inflammatory diseases in age-related conditions

Leite

Cruzat

Krause

et al. 2016

Nutrire

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Aging is an intricate process modulated by different molecular and cellular events, such as genome instability, epigenetic and transcriptional changes, molecular damage, cell death and senescence, inflammation, and metabolic dysfunction. Particularly, protein quality control (chaperone systems) tends to be negatively affected by aging, thus leading to cellular senescence in metabolic tissues and, as a consequence, to the increasing dissemination of inflammation throughout the body. The heat shock (HS) response and its associated expression of the 70 kDa family of heat shock proteins (HSP70), which are anti-inflammatory molecular chaperones, are found to be markedly decreased during muscle inactivity and aging, while evidence supports the loss of HSP70 as a key mechanism which may drive muscle atrophy, contractile dysfunction, and reduced regenerative capacity. In addition, abnormal stress response is linked with higher incidence of neurodegenerative diseases as well as low-grade inflammatory diseases that are associated with physical inactivity and obesity. Therefore, strategies to increase or, at least, to maintain the levels of HSP70, and its accompanying HS response to stress, are key to reduce biological cell dysfunctions that occur in aging. In this sense, physical exercise is of note as it is the most powerful inducer of the HS response, comparable only to heat stress and fever-like conditions. On the other hand, the amino acid L-glutamine, whose production within the skeletal muscle and liberation into the blood stream is dependent on muscle activity, is a potentializer of HSP70 expression and HS response, particularly via its entering in hexosamine biosynthetic pathway (HBP). Herein, we discuss the collaborative role of glutamine (and its donors/precursors) and physical exercise (mostly responsible for glutamine release into the circulation) as potential tools to increase HSP70 expression and the HS response in the elderly.

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“…Further supporting that insulin signalling is involved in membrane sensing of heat the protection of a small molecule, BGP-15 against heart failure and atrial fibrillation was associated with an increased phosphorylation of the insulin-like growth factor 1 receptor (IGF1R) (Sapra et al 2014). Since BGP-15 was also shown to be an HSP coinducer and its ability to activates stress signal transduction pathways by remodeling plasma membrane rafts (Gombos et al 2011).…”

Section: Igf1r Signallingmentioning

confidence: 99%

“…In atrial fibrillation susceptible animal model, depressed IGF1R in atrial samples is correlated with the increase ganglioside levels that reduces membrane fluidity and inhibits phosphorylation of IGF1R. In the presence of BGP-15, membrane fluidity is increased and ganglioside levels are reduced, therefore it is suggested that BGP15 attenuates ganglioside interaction to restore IGF1R signalling (Sapra et al 2014). Another report is the activation of IGF1R by sheer stress causing the downstream ERK 1/2 activation in an IGF1R dependent manner.…”

Section: Membrane Sensor Theorymentioning

confidence: 99%

Sensing mechanisms and individuality of heat stress in mammalian cells

Şahin

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The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

Cited by 89 publications

References 71 publications

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Physiological regulation of the heat shock response by glutamine: implications for chronic low-grade inflammatory diseases in age-related conditions

Sensing mechanisms and individuality of heat stress in mammalian cells

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