scholarly journals Neflamapimod Induces Vasodilation in Resistance Mesenteric Arteries by Inhibiting p38 Mitogen-Activated Protein Kinase Alpha (MAPKα) and Heat-Shock Protein 27 (Hsp27) Phosphorylation

2021 ◽  
Author(s):  
Ajay K. Pandey ◽  
Farzana Zerin ◽  
Sreelakshmi N. Menon ◽  
Khue P. Nguyen ◽  
Tran Vo ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Clinical Investigation ◽  
Lewy Bodies ◽  
Systemic Blood Pressure ◽  
Heat Shock Protein 27 ◽  
Mesenteric Arteries ◽  
Mitogen Activated Protein Kinase ◽  
Hsp27 Phosphorylation

Abstract Neflamapimod, a selective inhibitor of p38 MAPKα, is under clinical investigation for its efficacy in Alzheimer’s disease (AD) and dementia with Lewy Bodies (DLB). Here, we investigated if neflamapimod-mediated acute inhibition of p38 MAPKα could induce vasodilation in resistance-size rat mesenteric arteries. Our pressure myography data demonstrated that neflamapimod produced a dose-dependent vasodilation in mesenteric arteries. Our Western blotting data revealed that acute neflamapimod treatment significantly reduced the phosphorylation of p38 MAPKα and its downstream target heat-shock protein 27 (Hsp27) that is involved in cytoskeletal reorganization and smooth muscle contraction. Likewise, non-selective inhibition of p38 MAPK by SB203580 attenuated p38 MAPKα and Hsp27 phosphorylation, and induced vasodilation. Endothelium denudation or pharmacological inhibition of endothelium-derived vasodilators such as nitric oxide (NO) and prostacyclin (PGI2) had no effect on such vasodilation. Neflamapimod-evoked vasorelaxation remained unaltered by the inhibition of smooth muscle cell K+ channels. Altogether, our data for the first time demonstrates that in resistance mesenteric arteries, neflamapimod inhibits p38 MAPKα and phosphorylation of its downstream actin-associated protein Hsp27, leading to vasodilation. This novel finding may be clinically significant and is likely to improve systemic blood pressure and cognitive deficits in AD and DLB patients for which neflamapimod is being investigated.

The macromolecular associations of heat shock protein-27 in vascular smooth muscle

Surgery ◽  
2000 ◽  
Vol 128 (2) ◽  
pp. 320-326 ◽  
Author(s):  
Colleen M. Brophy ◽  
Jason R. Molinaro ◽  
Mary Dickinson
Keyword(s):  
Smooth Muscle ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Vascular Smooth Muscle ◽  
Heat Shock Protein 27

Contrasting effects of midazolam on induction of heat shock protein 27 by vasopressin and heat in aortic smooth muscle cells

2001 ◽  
Vol 84 (1) ◽  
pp. 39-46 ◽  
Author(s):  
Kumiko Tanabe ◽  
Osamu Kozawa ◽  
Masayuki Niwa ◽  
Takuji Yamomoto ◽  
Hiroyuki Matsuno ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Heat Shock Protein 27 ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle

scholarly journals Modulation of cellular thermoresistance and actin filament stability accompanies phosphorylation-induced changes in the oligomeric structure of heat shock protein 27.

1995 ◽  
Vol 15 (1) ◽  
pp. 505-516 ◽  
Author(s):  
J N Lavoie ◽  
H Lambert ◽  
E Hickey ◽  
L A Weber ◽  
J Landry
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Actin Filament ◽  
Cellular Localization ◽  
Chinese Hamster ◽  
Heat Shock Protein 27 ◽  
Cytochalasin D ◽  
Wild Type ◽  
Protective Function ◽  
Hsp27 Phosphorylation

Phosphorylation of heat shock protein 27 (HSP27) can modulate actin filament dynamics in response to growth factors. During heat shock, HSP27 is phosphorylated at the same sites and by the same protein kinase as during mitogenic stimulation. This suggests that the same function of the protein may be activated during growth factor stimulation and the stress response. To determine the role of HSP27 phosphorylation in the heat shock response, several stable Chinese hamster cell lines that constitutively express various levels of the wild-type HSP27 (HU27 cells) or a nonphosphorylatable form of human HSP27 (HU27pm3 cells) were developed. In contrast to HU27 cells, which showed increased survival after heat shock, HU27pm3 cells showed only slightly enhanced survival. Evidence is presented that stabilization of microfilaments is a major target of the protective function of HSP27. In the HU27pm3 cells, the microfilaments were thermosensitized compared with those in the control cells, whereas wild-type HSP27 caused an increased stability of these structures in HU27 cells. HU27 but not HU27pm3 cells were highly resistant to cytochalasin D treatment compared with control cells. Moreover, in cells treated with cytochalasin D, wild-type HSP27 but not the phosphorylated form of HSP27 accelerated the reappearance of actin filaments. The mutations in human HSP27 had no effect on heat shock-induced change in solubility and cellular localization of the protein, indicating that phosphorylation was not involved in these processes. However, induction of HSP27 phosphorylation by stressing agents or mitogens caused a reduction in the multimeric size of the wild-type protein, an effect which was not observed with the mutant protein. We propose that early during stress, phosphorylation-induced conformational changes in the HSP27 oligomers regulate the activity of the protein at the level of microfilament dynamics, resulting in both enhanced stability and accelerated recovery of the filaments. The level of protection provided by HSP27 during heat shock may thus represent the contribution of better maintenance of actin filament integrity to overall cell survival.

scholarly journals Transduction of recombinant heat shock protein 27 increases contractility of vascular smooth muscle

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Christopher C. Smoke ◽  
Erica L. Morley ◽  
Charles R. Flynn ◽  
Padmini Komalavilas ◽  
Colleen M. Brophy
Keyword(s):  
Smooth Muscle ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Vascular Smooth Muscle ◽  
Heat Shock Protein 27

Regulation of actin filament dynamics by p38 map kinase-mediated phosphorylation of heat shock protein 27

1997 ◽  
Vol 110 (3) ◽  
pp. 357-368 ◽  
Author(s):  
J. Guay ◽  
H. Lambert ◽  
G. Gingras-Breton ◽  
J.N. Lavoie ◽  
J. Huot ◽  
...  
Keyword(s):  
Heat Shock ◽  
Protein Kinase ◽  
Heat Shock Protein ◽  
Chinese Hamster ◽  
Strong Support ◽  
Specific Inhibitor ◽  
Heat Shock Protein 27 ◽  
Cell Extracts ◽  
Hsp27 Phosphorylation ◽  
Homeostatic Function

We have studied the contribution of the individual kinases of the MAP (mitogen-activated protein) kinase family, including ERK (extracellular-signal regulated kinase), JNK/SAPK (c-JUN NH2-terminal kinase/stress-activated protein kinase) and p38, to activation of the HSP27 (heat shock protein 27) kinase MAPKAP kinase-2/3 and to HSP27 phosphorylation in Chinese hamster CCL39 cells stimulated by either growth factors, cytokines or stressing agents. In vitro assays using fractionated cell extracts or immunoprecipitates indicated that only fractions containing ERK or p38, and not those containing JNK/SAPK, had the capacity to activate MAPKAP kinase-2/3. In vivo, however, it appeared that only p38 is an upstream activator of HSP27 phosphorylation after both stress or growth factor stimulation: expression of an interfering mutant of ras, which blocked the activation of ERK by both types of inducers, had no effect on HSP27 phosphorylation and p38 activation; and the cell-permeant specific inhibitor of 038, SB203580, blocked MAPKAP-kinase2/3 activation and HSP27 phosphorylation. HSP27 has been suggested to have a phosphorylation-activated homeostatic function at the actin cytoskeleton level. This raises the possibility that p38 might be directly involved in mediating actin responses to external stimuli. Accordingly, we observed that a prior activation of p38 increased the stability of the actin microfilaments in cells exposed to cytochalasin D. The effect was dependent on the expression of HSP27 and was totally annihilated by blocking the p38 activity with SB203580. The results provide strong support to the idea that activation of p38 during adverse environmental conditions serves a homeostatic function aimed at regulating actin dynamics that would otherwise be destabilized during stress. Its activation during normal agonist stimulation may constitute an additional actin signaling pathway, the importance of which depends on the level of expression of HSP27.

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