Abstract
Bcl2-associated athanogene 3 (BAG3), is constitutively expressed in a few normal cell types, including myocytes, peripheral nerves and in the brain, and is also expressed in certain tumors. To date, the main studies about the role of BAG3 are focused on its pro-survival effect in tumors through various mechanisms that vary according to cellular type. Recently, elevated concentrations of a soluble form of BAG3 were described in patients affected by advanced stage of heart failure (HF), identifying BAG3 as a potentially useful biomarker in monitoring HF progression. Despite the finding of high levels of BAG3 in the sera of HF patients, there are no data on its possible role on the modulation of vascular tone and blood pressure levels. The aim of this study was to investigate the possible hemodynamic effects of BAG3 performing both in vitro and in vivo experiments. Through vascular reactivity studies, we demonstrate that BAG3 is capable of evoking dose-dependent vasorelaxation. Of note, BAG3 exerts its vasorelaxant effect on resistance vessels, typically involved in the blood pressure regulation. Our data further show that the molecular mechanism through which BAG3 exerts this effect is the activation of the PI3K/Akt signalling pathway leading to nitric oxide release by endothelial cells. Finally, we show that in vivo BAG3 administration is capable of regulating blood pressure and that this is dependent on eNOS regulation since this ability is lost in eNOS KO animals.
Highlights
The Bcl-2-associated athanogene 3 (BAG3) protein belongs to the family of co-chaperones that interact with the ATPase domain of the heat shock protein HSP70 through a structural domain known as BAG domain.[1,2]
BAG3 can be induced in many other cell types by a variety of stressors, mainly through the activation of heat shock transcription factor 1, which in turn is responsible for the transcriptional induction of a number of stress-response genes, including BAG3.2,9 Much evidence exists to suggest BAG3 has a role in sustaining cell survival,[2] through mechanisms that vary depending on the cell context, but in general depend on the ability of BAG3 to modulate levels or localization of apoptosis-regulating proteins, such as IκB kinase gamma (IKKγ),[10] Bcl-2-associated X protein (Bax)[11] or B-Raf proto-oncogene (BRAF),[12] in either an Hsp70dependent- or independent manner
BAG3 exerts its vasorelaxant effect on resistance vessels, which are the main vascular district involved in the blood pressure regulation
Summary
The Bcl-2-associated athanogene 3 (BAG3) protein belongs to the family of co-chaperones that interact with the ATPase domain of the heat shock protein HSP70 through a structural domain known as BAG domain (amino acids 110-124).[1,2] In addition to the BAG domain, BAG3 contains a WW domain and a prolinerich repeat (PXXP) that can mediate binding to other proteins. Upregulation of BAG3 gene expression has been described followed cerebral infarction.[8] BAG3 can be induced in many other cell types by a variety of stressors, mainly through the activation of heat shock transcription factor 1, which in turn is responsible for the transcriptional induction of a number of stress-response genes, including BAG3.2,9 Much evidence exists to suggest BAG3 has a role in sustaining cell survival,[2] through mechanisms that vary depending on the cell context, but in general depend on the ability of BAG3 to modulate levels or localization of apoptosis-regulating proteins, such as IκB kinase gamma (IKKγ),[10] Bax[11] or BRAF,[12] in either an Hsp70dependent- or independent manner.
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