Extracellular calcium-sensing receptor is critical in hypoxic pulmonary vasoconstriction.

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.

• Authors: Jiwei Zhang, Juan Zhou, Lei Cai, Yankai Lu, Tao Wang, Liping Zhu, Qinghua Hu
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 17 Issue 3 Pg. 471-84 (Aug 01 2012) ISSN: 1557-7716 [Electronic] United States
• PMID: 22098336 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Calcium Channel Blockers
• Cyclohexylamines
• Isoquinolines
• Macrocyclic Compounds
• N(1)-(4-chlorobenzoyl)-N(2)-(1-(1-naphthyl)ethyl)-1,2-diaminocyclohexane
• Oxazoles
• Receptors, Calcium-Sensing
• Ryanodine Receptor Calcium Release Channel
• Sulfonamides
• extracellular calcium cation-sensing receptor, rat
• xestospongin C
• Ryanodine
• Hydrogen Peroxide
• Cyclic AMP-Dependent Protein Kinases
• N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide

Topics

• Animals
• Benzamides (pharmacology)
• Calcium Channel Blockers (pharmacology)
• Calcium Signaling
• Cell Hypoxia
• Cells, Cultured
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors, metabolism)
• Cyclohexylamines (pharmacology)
• Gene Knockdown Techniques
• Hydrogen Peroxide (metabolism)
• In Vitro Techniques
• Isoquinolines (pharmacology)
• Macrocyclic Compounds (pharmacology)
• Mitochondria (metabolism)
• Myocytes, Smooth Muscle (drug effects, metabolism, physiology)
• Oxazoles (pharmacology)
• Pulmonary Artery (cytology, drug effects, physiology)
• RNA Interference
• Rats
• Rats, Sprague-Dawley
• Receptors, Calcium-Sensing (antagonists & inhibitors, genetics, metabolism)
• Ryanodine (pharmacology)
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Sulfonamides (pharmacology)
• Vasoconstriction