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Overexpression of cationic amino acid transporter‐1 increases nitric oxide production in hypoxic human pulmonary microvascular endothelial cells
Author(s) -
Cui Hongmei,
Chen Bernadette,
Chicoine Louis G,
Nelin Leif D
Publication year - 2011
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2011.05609.x
Subject(s) - hypoxia (environmental) , nitric oxide , medicine , nitric oxide synthase , pulmonary hypertension , endocrinology , endogeny , chemistry , endothelium , biology , microbiology and biotechnology , oxygen , organic chemistry
Summary 1. The endogenous production of and/or the bioavailability of nitric oxide (NO) is decreased in pulmonary hypertensive diseases. l ‐arginine ( l ‐arg) is the substrate for NO synthase (NOS). l ‐arg is transported into cells via the cationic amino acid transporters (CAT), of which there are two isoforms in endothelial cells, CAT‐1 and CAT‐2. 2. To test the hypothesis that hypoxia will decrease CAT expression and l ‐arg uptake resulting in decreased NO production in human pulmonary microvascular endothelial cells (hPMVEC), cells were incubated in either normoxia (21% O 2 , 5% CO 2 , balance N 2 ) or hypoxia (1% O 2 , 5% CO 2 , balance N 2 ). 3. The hPMVEC incubated in hypoxia had 80% less NO production than cells incubated in normoxia ( P < 0.01). The hPMVEC incubated in hypoxia had significantly lower CAT‐2 mRNA levels than normoxic hPMVEC ( P < 0.005), and the transport of l ‐arg was 40% lower in hypoxic than in normoxic hPMVEC ( P < 0.01). In hypoxic cells, overexpression of CAT‐1 resulted in significantly greater l ‐arg transport and NO production ( P < 0.05). 4. These results demonstrate that in hPMVEC, hypoxia decreased CAT‐2 expression, l ‐arg uptake and NO production. Furthermore, the hypoxia‐induced decrease in NO production in hPMVEC can be attenuated by overexpressing CAT in these cells. We speculate that the CAT may represent a novel therapeutic target for treating pulmonary hypertensive disorders.