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Heme oxygenase attenuates angiotensin II-mediated superoxide production in cultured mouse thick ascending loop of Henle cells

¹Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson; and ²Department of Medicinal Chemistry, University of Mississippi, University, Mississippi

Submitted 2 February 2008 ; accepted in final form 11 August 2008

Heme oxygenase (HO)-1 induction can attenuate the development of angiotensin II (ANG II)-dependent hypertension. However, the mechanism by which HO-1 lowers blood pressure is not clear. The goal of this study was to test the hypothesis that induction of HO-1 can reduce the ANG II-mediated increase in superoxide production in cultured thick ascending loop of Henle (TALH) cells. Studies were performed on an immortalized cell line of mouse TALH (mTALH) cells. HO-1 was induced in cultured mTALH cells by treatment with cobalt protoporphyrin (CoPP, 10 µM) or hemin (50 µM) or by transfection with a plasmid containing the human HO-1 isoform. Treatment of mTALH cells with 10^–9 M ANG II increased dihydroethidium (DHE) fluorescence (an index of superoxide levels) from 35.5 ± 5 to 136 ± 18 relative fluorescence units (RFU)/µm². Induction of HO-1 via CoPP, hemin, or overexpression of the human HO-1 isoform significantly reduced ANG II-induced DHE fluorescence to 64 ± 5, 64 ± 8, and 41 ± 4 RFU/µm², respectively. To determine which metabolite of HO-1 is responsible for reducing ANG II-mediated increases in superoxide production in mTALH cells, cells were preincubated with bilirubin or carbon monoxide (CO)-releasing molecule (CORM)-A1 (each at 100 µM) before exposure to ANG II. DHE fluorescence averaged 80 ± 7 RFU/µm² after incubation with ANG II and was significantly decreased to 55 ± 7 and 53 ± 4 RFU/µm² after pretreatment with bilirubin and CORM-A1. These results demonstrate that induction of HO-1 in mTALH cells reduces the levels of ANG II-mediated superoxide production through the production of both bilirubin and CO.

bilirubin; carbon monoxide; carbon monoxide-releasing molecule A1

This article has been cited by other articles:

				T. Vera, S. Kelsen, and D. E. Stec Response to Use of Protoporphyrins to Evaluate Heme Oxygenase Problematical Hypertension, February 1, 2009; 53(2): e16 - e16. [Full Text] [PDF]