Tin-Mediated Heme Oxygenase Gene Activation and Cytochrome P450 Arachidonate Hydroxylase Inhibition in Spontaneously Hypertensive Rats

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Abstract

ABSTRACT

The effect of SnCl2 on the transcription of the heme oxygenase gene in spontaneously hypertensive rats was examined using cDNA for the rat heme oxygenase (HO-1). An increase in renal HO-1 mRNA levels was observed in response to SnCl2 treatment. Quantitative evaluation by scanning densitometry demonstrated a maximal increase in HO-1 mRNA 24-fold over control at 8 hours after SnCl2 administration. Nuclear runoff assay using isolated renal nuclei from SnCl2-treated rats revealed an active HO-1 gene transcription. Transcription of HO-1 in rat kidney was greatly increased within 3 hours of administration of SnCl2, as evidenced by the level of [α32P]UTP incorporation into nuclear RNA. As a consequence of activation of the HO-1 gene transcription, renal enzyme activity increased eightfold at 16 hours after SnCl2, and reached maximal activity of 16-fold over control at 32 hours after injection. No significant change in cytochrome P450 fatty acid ω-hydroxylase (P450 4A) mRNA was observed after SnCl2 administration. Cytochrome P450-arachidonic acid ω/ω-1 hydroxylase(s) activity (formation of 20− and 19-HETE) was significantly reduced 24 hours after SnCl2 administration and remained lower than the control level 48 and 72 hours after injection. In addition, blood pressure was reduced from 151 ± 2.5 mm Hg to 133 ± 2.3 mm Hg after 48 hours of SnCl2 treatment. The reduction in blood pressure preceded natriuresis. It is concluded that SnCl2 induces activation of the HO-1 gene, which is followed by elevation in enzyme activity and a decrease in cytochrome P450-arachidonic acid ω-hydroxylase activity. These biochemical changes bring about a selective decrease in the synthesis of 19-HETE and 20-HETE, arachidonate metabolites with prohypertensive properties, and are associated with blood pressure reduction to normal levels. It is suggested that manipulation of heme oxygenase and cytochrome P450-arachidonic acid ω-hydroxylase expressions may be of therapeutic importance in regulating blood pressure.

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