The prosurvival protein BAG3: a new participant in vascular homeostasis

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.

Identification of the initial molecular changes in response to circulating angiogenic cells-mediated therapy in critical limb ischemia

“…Autophagy, on the other hand, is an adaptive response to environmental stresses including nutrient starvation due to tissue destruction or blood shortage, and it seems to be also required for the development of vascular ECs [80]. Downregulation of BAG3 could represent an increase in apoptosis but reduced autophagy [79,81], mainly in the CACtreated mice, although further studies should confirm such hypothesis. Overall, protein changes (upregulation and downregulation) taking place in ischemic non-treated mice indicated an upregulation of apoptosis and necrosis (according to the IPA functional Table 3 Classification of differentially expressed proteins in CAC-treated mice (SE) and non-treated mice (SC) vs shams (SH) on days 2 and 4 after femoral ligation.…”

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries

“…CHAT (10q11.23, 136 kb downstream of rs4253197) encodes an enzyme that catalyzes the biosynthesis of the neurotransmitter acetylcholine, and binge ethanol in adolescents was reported to decrease CHAT expression[ 63 ]. BAG3 (10q26.11, 183 Kb downstream of rs201383951) was also suggested to contribute to alcohol-induced neurodegenerations[ 64 ]. A mouse study suggested that BAG3 exerts a vaso-relaxing effect through the activation of the PI3K/Akt/eNOS signaling pathway, and may influence BP regulation[ 64 ].…”

“…BAG3 (10q26.11, 183 Kb downstream of rs201383951) was also suggested to contribute to alcohol-induced neurodegenerations[ 64 ]. A mouse study suggested that BAG3 exerts a vaso-relaxing effect through the activation of the PI3K/Akt/eNOS signaling pathway, and may influence BP regulation[ 64 ]. A GWAS identified association of BAG3 with dilated cardiomyopathy[ 65 ], and suggestive association with alcohol dependence[ 44 ].…”

Bcl-2-associated athanogene 3(BAG3) is associated with tumor cell proliferation, migration, invasion and chemoresistance in colorectal cancer

“…BAG3 protein is an anti-apoptotic protein involved in many other cellular processes, including cell cycle regulation, cell survival, proliferation, adhesion, migration, autophagy and EMT [ 5 , 7 , 10 , 16 , 22 , 28 ]. Some studies have shown that BAG3 can regulate these processes via the K-ras [ 29 ], EGFR [ 30 ] or AMPK/PI3K [ 31 ] signaling pathways. Studies have found that BAG3, a member of the co-chaperone family, contains the BAG domain, which can interact with the ATPase domain of heat shock protein 70 to regulate the HSP70 pathway [ 32 – 34 ].…”