Potential role of cartilage oligomeric matrix protein in the modulation of pulmonary arterial smooth muscle superoxide by hypoxia.

Abstract

Changes in reactive oxygen species and extracellular matrix seem to participate in pulmonary hypertension development. Because we recently reported evidence for chronic hypoxia decreasing expression of cartilage oligomeric matrix protein (COMP) and evidence for this controlling loss of pulmonary arterial smooth muscle bone morphogenetic protein receptor-2 (BMPR2) and contractile phenotype proteins, we examined if changes in superoxide metabolism could be an important factor in a bovine pulmonary artery (BPA), organoid cultured under hypoxia for 48 h model. Hypoxia (3% O2) caused a depletion of COMP in BPA, but not in bovine coronary arteries. Knockdown of COMP by small-interfering RNA (siRNA) increased BPA levels of mitochondrial and extra-mitochondrial superoxide detected by MitoSOX and dihydroethidium (DHE) HPLC products. COMP siRNA-treated BPA showed reduced levels of SOD2 and SOD3 and increased levels of NADPH oxidases NOX2 and NOX4. Hypoxia increased BPA levels of MitoSOX-detected superoxide and caused changes in NOX2 and SOD2 expression similar to COMP siRNA, and exogenous COMP (0.5 μM) prevented the effects of hypoxia. In the presence of COMP, BMPR2 siRNA-treated BPA showed increases in superoxide detected by MitoSOX and depletion of SOD2. Superoxide scavengers (0.5 μM TEMPO or mitoTEMPO) maintained the expression of contractile phenotype proteins calponin and SM22α decreased by 48 h hypoxia (1% O2). Adenoviral delivery of BMPR2 to rat pulmonary artery smooth muscle cells prevented the depletion of calponin and SM22α by COMP siRNA. Thus, COMP regulation of BMPR2 appears to have an important role in controlling hypoxia-elicited changes in BPA superoxide and its potential regulation of contractile phenotype proteins.

• Authors: Hang Yu, Norah Alruwaili, Bing Hu, Melissa R Kelly, Bin Zhang, Dong Sun, Michael S Wolin
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 317 Issue 5 Pg. L569-L577 (11 01 2019) ISSN: 1522-1504 [Electronic] United States
• PMID: 31389735 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium-Binding Proteins
• Cartilage Oligomeric Matrix Protein
• Microfilament Proteins
• Muscle Proteins
• RNA, Small Interfering
• calponin
• transgelin
• Superoxides
• Superoxide Dismutase
• NADPH Oxidase 2
• NADPH Oxidase 4
• Bone Morphogenetic Protein Receptors, Type II
• Oxygen

Topics

• Animals
• Bone Morphogenetic Protein Receptors, Type II (genetics, metabolism)
• Calcium-Binding Proteins (genetics, metabolism)
• Cartilage Oligomeric Matrix Protein (antagonists & inhibitors, genetics, metabolism)
• Cattle
• Coronary Vessels (drug effects, metabolism)
• Gene Expression Regulation
• Heart (drug effects)
• Hypoxia (genetics, metabolism)
• Lung (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Microfilament Proteins (genetics, metabolism)
• Mitochondria (drug effects, metabolism)
• Muscle Proteins (genetics, metabolism)
• Muscle, Smooth, Vascular (drug effects, metabolism)
• Myocytes, Smooth Muscle (cytology, drug effects, metabolism)
• NADPH Oxidase 2 (genetics, metabolism)
• NADPH Oxidase 4 (genetics, metabolism)
• Oxygen (pharmacology)
• Primary Cell Culture
• Pulmonary Artery (drug effects, metabolism)
• RNA, Small Interfering (genetics, metabolism)
• Rats
• Superoxide Dismutase (genetics, metabolism)
• Superoxides (metabolism)
• Tissue Culture Techniques