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• W3121562887 abstract "Abstract Heat-shock protein 70 (HSP70) is a ubiquitously expressed molecular chaperone with various biological functions. Recently, we demonstrated that HSP70 is key for adequate vascular reactivity. However, the specific mechanisms targeted by HSP70 to assist in this process remain elusive. Since there is a wealth of evidence connecting HSP70 to calcium ( $$hbox {Ca}^{2+}$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:msup> <mml:mtext>Ca</mml:mtext> <mml:mrow> <mml:mn>2</mml:mn> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:math> ), a master regulator of contraction, we designed this study to investigate whether blockade of HSP70 disrupts vascular contraction via impairment of $${text{Ca}}^{2+}$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:msup> <mml:mrow> <mml:mtext>Ca</mml:mtext> </mml:mrow> <mml:mrow> <mml:mn>2</mml:mn> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:math> handling mechanisms. We performed functional studies in aortas isolated from male Sprague Dawley rats in the presence or absence of exogenous $$hbox {Ca}^{2+}$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:msup> <mml:mtext>Ca</mml:mtext> <mml:mrow> <mml:mn>2</mml:mn> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:math> , and we determined the effects of VER155008, an inhibitor of HSP70, on $$hbox {Ca}^{2+}$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:msup> <mml:mtext>Ca</mml:mtext> <mml:mrow> <mml:mn>2</mml:mn> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:math> handling as well as key mechanisms that regulate vascular contraction. Changes in the intracellular concentration of $$hbox {Ca}^{2+}$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:msup> <mml:mtext>Ca</mml:mtext> <mml:mrow> <mml:mn>2</mml:mn> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:math> were measured with a biochemical assay kit. We report that blockade of HSP70 leads to $$hbox {Ca}^{2+}$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:msup> <mml:mtext>Ca</mml:mtext> <mml:mrow> <mml:mn>2</mml:mn> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:math> mishandling in aorta stimulated with phenylephrine, decreasing both phasic and tonic contractions. Importantly, in $$hbox {Ca}^{2+}$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:msup> <mml:mtext>Ca</mml:mtext> <mml:mrow> <mml:mn>2</mml:mn> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:math> free Krebs’ solution, inhibition of HSP70 only reduced the $$hbox {E}_{mathrm{max}}$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:msub> <mml:mtext>E</mml:mtext> <mml:mi>max</mml:mi> </mml:msub> </mml:math> of the phasic contraction if the protein was blocked before IP3r-mediated $$hbox {Ca}^{2+}$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:msup> <mml:mtext>Ca</mml:mtext> <mml:mrow> <mml:mn>2</mml:mn> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:math> release, suggesting that HSP70 has a positive effect towards this receptor. Corroborating this statement, VER155008 did not potentiate an IP3r inhibitor’s outcomes, even with partial blockade. In another set of experiments, the inhibition of HSP70 attenuated the amplitude of the tonic contraction independently of the moment VER155008 was added to the chamber (i.e., whether it was before or after IP3r-mediated phasic contraction). More compelling, following re-addition of $$hbox {Ca}^{2+}$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:msup> <mml:mtext>Ca</mml:mtext> <mml:mrow> <mml:mn>2</mml:mn> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:math> , VER155008 amplified the inhibitory effects of a voltage-dependent $$hbox {Ca}^{2+}$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:msup> <mml:mtext>Ca</mml:mtext> <mml:mrow> <mml:mn>2</mml:mn> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:math> channel blocker, but not of a voltage-independent $$hbox {Ca}^{2+}$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:msup> <mml:mtext>Ca</mml:mtext> <mml:mrow> <mml:mn>2</mml:mn> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:math> channel inhibitor, indicating that HSP70 has a positive impact on the latter. Lastly, the mechanism by which HSP70 modulates vascular contraction does not involve the $$hbox {Ca}^{2+}$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:msup> <mml:mtext>Ca</mml:mtext> <mml:mrow> <mml:mn>2</mml:mn> <mml:mo>+</mml:mo> </mml:mrow> </mml:msup> </mml:math> sensitizer protein, Rho-kinase, nor the SERCA pump, as blockade of these proteins in the presence of VER155008 almost abolished contraction. In summary, our findings shed light on the processes targeted by HSP70 during vascular contraction and open research avenues for potential new mechanisms in vascular diseases." @default.
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• W3121562887 date "2021-01-14" @default.
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• W3121562887 title "Dissecting the interaction between HSP70 and vascular contraction: role of $$hbox{Ca}^{2+}$$ handling mechanisms" @default.
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• W3121562887 doi "https://doi.org/10.1038/s41598-021-80966-6" @default.
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