HSP70 Contributes to Ca2+ Handling in Phenylephrine-induced Vascular Contraction
FASEB JOURNAL(2021)
摘要
Heat-shock protein 70 (HSP70), a housekeeper molecular chaperone, is an emerging player in vascular physiology. However, the specific mechanism(s) targeted by this protein in order to support this process is/are mostly unknown. The contraction of vascular structures primarily relies on changes in the intracellular concentration of Ca2+, and interestingly, previous studies have demonstrated that the genetic deletion of HSP70 affects Ca2+ homeostasis, which worsens cardiac and skeletal muscle function. However, it is yet-to-be-determined if HSP70 also contributes to Ca2+ dynamics in vascular smooth muscle. To fill in this gap, in this study, we specifically investigated if pharmacological blockade of HSP70 impacts vascular contraction by impairing Ca2+ handling mechanisms. To achieve such a goal, we performed functional studies in a wire myograph using aorta isolated from male Sprague Dawley rats. Experiments were conducted with and without exogenous Ca2+ in the presence or absence of VER155008, a pharmacological inhibitor of HSP70. Functional studies were also conducted in the presence and absence of inhibitors for the major mechanisms contributing to phenylephrine-induced contraction. Changes in the intracellular concentration of Ca2+ were determined with a biochemical assay kit. Here, we report that blockade of HSP70 influences Ca2+ handling mechanisms in phenylephrine-stimulated aorta. More importantly, we provide evidence that this protein affects fast/phasic and prolonged/tonic contraction via crosstalk with inositol triphosphate receptor-mediated Ca2+ release and voltage-independent Ca2+ channels-facilitated Ca2+ influx, respectively. Together, our findings shed light on the mechanisms targeted by HSP70 in order to assist in vascular contraction and open research avenues for disease-associated vascular complications.
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