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Extracellular Calcium-Sensing Receptor Is Critical in Hypoxic Pulmonary Vasoconstriction

Extracellular Calcium-Sensing Receptor Is Critical in Hypoxic Pulmonary Vasoconstriction

Jiwei Zhang, Juan Zhou, Lei Cai, Yankai Lu, Tao Wang, Liping Zhu, Qinghua Hu

Antioxid Redox Signal. 2012 Aug 1;17(3):471-84.

PMID: 22098336

Abstract:

Aims:
The initiation of hypoxic pulmonary vasoconstriction (HPV) involves an increase in cytosolic calcium ([Ca(2+)](i)) in pulmonary artery (PA) smooth muscle cells (PASMCs). Both the processes depend on extracellular Ca(2+). Extracellular Ca(2+) can be sensed by extracellular calcium-sensing receptor (CaSR). This study aims at determining whether CaSR is pivotal in the initiation of HPV.
Results:
Experiments were performed in cultured PASMCs, isolated PAs, and rats including CaSR knockdown preparations. Both hypoxia and H(2)O(2) equivalent to the level achieved by hypoxia increased [Ca(2+)](i) in an extracellular Ca(2+)-dependent manner in PASMCs, and this was inhibited by CaSR knockdown or its negative allosteric modulator, Calhex231. Hypoxia-increased H(2)O(2) generation was diminished by mitochondria depletion. Mitochondria depletion abolished hypoxia-induced [Ca(2+)](i) increase (HICI), which was reversed by H(2)O(2) repletion. CaSR knockdown or Calhex231, however, prevented the reversible effect of H(2)O(2). HICI was abolished by catalase-polyethylene glycol (PEG-Catalase), not superoxide dismutase-polyethylene glycol (PEG-SOD) pretreatment, attenuated by ryanodine receptor3-knockdown or inhibition of store-operated Ca(2+) entry. HPV in vitro and in vivo was inhibited by Calhex231 and by CaSR knockdown.
Innovation:
A novel mechanism underlying HPV is revealed by the role of CaSR in orchestrating reactive oxygen species and [Ca(2+)](i) signaling.
Conclusions:
The activation of mitochondrial H(2)O(2)-sensitized CaSR by extracellular Ca(2+) mediates HICI in PASMCs and, thus, initiates HPV.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42415096	Catalase−polyethylene glycol			Price

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