Hypoxia selectively upregulates cation channels and increases cytosolic [Ca2+] in pulmonary, but not coronary, arterial smooth muscle cells.

Abstract

Ca2+ signaling, particularly the mechanism via store-operated Ca2+ entry (SOCE) and receptor-operated Ca2+ entry (ROCE), plays a critical role in the development of acute hypoxia-induced pulmonary vasoconstriction and chronic hypoxia-induced pulmonary hypertension. This study aimed to test the hypothesis that chronic hypoxia differentially regulates the expression of proteins that mediate SOCE and ROCE [stromal interacting molecule (STIM), Orai, and canonical transient receptor potential channel TRPC6] in pulmonary (PASMC) and coronary (CASMC) artery smooth muscle cells. The resting cytosolic [Ca2+] ([Ca2+]cyt) and the stored [Ca2+] in the sarcoplasmic reticulum were not different in CASMC and PASMC. Seahorse measurement showed a similar level of mitochondrial bioenergetics (basal respiration and ATP production) between CASMC and PASMC. Glycolysis was significantly higher in PASMC than in CASMC. The amplitudes of cyclopiazonic acid-induced SOCE and OAG-induced ROCE in CASMC are slightly, but significantly, greater than in PASMC. The frequency and the area under the curve of Ca2+ oscillations induced by ATP and histamine were also larger in CASMC than in PASMC. Na+/Ca2+ exchanger-mediated increases in [Ca2+]cyt did not differ significantly between CASMC and PASMC. The basal protein expression levels of STIM1/2, Orai1/2, and TRPC6 were higher in CASMC than in PASMC, but hypoxia (3% O2 for 72 h) significantly upregulated protein expression levels of STIM1/STIM2, Orai1/Orai2, and TRPC6 and increased the resting [Ca2+]cyt only in PASMC, but not in CASMC. The different response of essential components of store-operated and receptor-operated Ca2+ channels to hypoxia is a unique intrinsic property of PASMC, which is likely one of the important explanations why hypoxia causes pulmonary vasoconstriction and induces pulmonary vascular remodeling, but causes coronary vasodilation.

• Authors: Xi He, Shanshan Song, Ramon J Ayon, Angela Balisterieri, Stephen M Black, Ayako Makino, W Gil Wier, Wei-Jin Zang, Jason X-J Yuan
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 314 Issue 4 Pg. C504-C517 (04 01 2018) ISSN: 1522-1563 [Electronic] United States
• PMID: 29351410 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Calcium Channels
• Neoplasm Proteins
• ORAI1 Protein
• ORAI1 protein, human
• STIM1 protein, human
• Stromal Interaction Molecule 1
• TRPC6 Cation Channel
• TRPC6 protein, human
• Calcium

Topics

• Calcium (metabolism)
• Calcium Channels (drug effects, metabolism)
• Calcium Signaling (drug effects)
• Cell Hypoxia
• Cells, Cultured
• Coronary Vessels (metabolism)
• Energy Metabolism
• Humans
• Kinetics
• Membrane Potentials
• Muscle, Smooth, Vascular (drug effects, metabolism)
• Myocytes, Smooth Muscle (drug effects, metabolism)
• Neoplasm Proteins (metabolism)
• ORAI1 Protein (metabolism)
• Pulmonary Artery (metabolism)
• Stromal Interaction Molecule 1 (metabolism)
• TRPC6 Cation Channel (metabolism)
• Vascular Remodeling
• Vasoconstriction
• Vasodilation