Dataset Information

Piezo1 induces endothelial responses to shear stress via soluble adenylyl Cyclase-IP₃R2 circuit.

ABSTRACT: Endothelial cells (ECs) continuously sense and adapt to changes in shear stress generated by blood flow. Here, we show that the activation of the mechanosensitive channel Piezo1 by defined shear forces induces Ca²⁺ entry into the endoplasmic reticulum (ER) via the ER Ca²⁺ ATPase pump. This entry is followed by inositol trisphosphate receptor 2 (IP₃R2)-elicited ER Ca²⁺ release into the cytosol. The mechanism of ER Ca²⁺ release involves the generation of cAMP by soluble adenylyl cyclase (sAC), leading to IP₃R2-evoked Ca²⁺ gating. Depleting sAC or IP₃R2 prevents ER Ca²⁺ release and blocks EC alignment in the direction of flow. Overexpression of constitutively active Akt1 restores the shear-induced alignment of ECs lacking Piezo1 or IP₃R2, as well as the flow-induced vasodilation in endothelial restricted Piezo1 knockout mice. These studies describe an unknown Piezo1-cAMP-IP₃R2 circuit as an essential mechanism activating Akt signaling and inducing adaptive changes in ECs to laminar flow.

SUBMITTER: Santana Nunez D

PROVIDER: S-EPMC10164902 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Piezo1 induces endothelial responses to shear stress via soluble adenylyl Cyclase-IP3R2 circuit.

Santana Nunez Dianicha D Malik Asrar B AB Lee Quinn Q Ahn Sang Joon SJ Coctecon-Murillo Arnold A Lazarko Dana D Levitan Irena I Mehta Dolly D Komarova Yulia A YA

iScience 20230411 5

Endothelial cells (ECs) continuously sense and adapt to changes in shear stress generated by blood flow. Here, we show that the activation of the mechanosensitive channel Piezo1 by defined shear forces induces Ca2+ entry into the endoplasmic reticulum (ER) via the ER Ca2+ ATPase pump. This entry is followed by inositol trisphosphate receptor 2 (IP3R2)-elicited ER Ca2+ release into the cytosol. The mechanism of ER Ca2+ release involves the ge ...[more]

PMID: 37168565

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Project description:UnlabelledAnion exchanger 2 (AE2), the principal bicarbonate secretor in the human biliary tree, is down-regulated in primary biliary cholangitis. AE2 creates a "bicarbonate umbrella" that protects cholangiocytes from the proapoptotic effects of bile salts by maintaining them deprotonated. We observed that knockdown of AE2 sensitized immortalized H69 human cholangiocytes to not only bile salt-induced apoptosis (BSIA) but also etoposide-induced apoptosis. Because the toxicity of etoposide is pH-independent, there could be a more general mechanism for sensitization of AE2-depleted cholangiocytes to apoptotic stimuli. We found that AE2 deficiency led to intracellular bicarbonate accumulation and increased expression and activity of soluble adenylyl cyclase (sAC), an evolutionarily conserved bicarbonate sensor. Thus, we hypothesized that sAC regulates BSIA. H69 cholangiocytes and primary mouse cholangiocytes were used as models. The sAC-specific inhibitor KH7 not only reversed sensitization to BSIA in AE2-depleted H69 cholangiocytes but even completely prevented BSIA. sAC knockdown by tetracycline-inducible short hairpin RNA also prevented BSIA. In addition, sAC inhibition reversed BSIA membrane blebbing, nuclear condensation, and DNA fragmentation. Furthermore, sAC inhibition also prevented BSIA in primary mouse cholangiocytes. Mechanistically, sAC inhibition prevented Bax phosphorylation at Thr167 and mitochondrial translocation of Bax and cytochrome c release but not c-Jun N-terminal kinase activation during BSIA. Finally, BSIA in H69 cholangiocytes was inhibited by intracellular Ca(2+) chelation, aggravated by thapsigargin, and unaffected by removal of extracellular calcium.ConclusionsBSIA is regulated by sAC, depends on intracellular Ca(2+) stores, and is mediated by the intrinsic apoptotic pathway; down-regulation of AE2 in primary biliary cholangitis sensitizes cholangiocytes to apoptotic insults by activating sAC, which may play a crucial role in disease pathogenesis. (Hepatology 2016;64:522-534).

Dataset Information

Piezo1 induces endothelial responses to shear stress via soluble adenylyl Cyclase-IP₃R2 circuit.

Publications

Piezo1 induces endothelial responses to shear stress via soluble adenylyl Cyclase-IP<sub>3</sub>R2 circuit.

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