Background: Nitric oxide just as prolyl hydroxylase domain-containing protein (PHD) is a regulator of hypoxia inducible factor-1 α (HIF-1α), a transcription factor complex that controls the expression of most genes involved in hypoxia and cardiovascular diseases. In the absence of nitric oxide, it is not clear how HIF-1α and PHD are regulated and to what extent they contribute to the ensuing disorder.
Method: Using the nitric oxide withdrawal/high salt diet model of hypertensive renal injury, this study tested the hypothesis that removal of the inhibition by nitric oxide on PHD predisposes to increased PHD but reduced HIF-1α expression, hypertension and renal injury.
Results: In animals treated with NG-nitro-L-arginine (L-NNA; 250 mg/l in drinking water for 14 days) and high salt diet (4% NaCl), there was hypertension (41 ± 5%, P < 0.05), proteinuria (three-fold, P < 0.05), kidney (22 ± 3%, P < 0.05) and heart enlargement (24 ± 3%, P < 0.05), as well as increased renal osteopontin (21 ± 3%, P < 0.05) and collagen IV (24 ± 4%, P < 0.05) expression. Accompanying these effects were increased expression of PHD1 (24 ± 4%, P < 0.05) and PHD2 (36 ± 4%, P < 0.05) but reduced HIF-1α (35 ± 6%, P < 0.05) expression. Dimethyloxallyl glycine (5 mg/kg), a PHD inhibitor, paradoxically exacerbated hypertension (46 ± 7%, P < 0.05), proteinuria (two-fold, P < 0.05), and increased osteopontin (15 ± 2%, P < 0.05) and HIF-1α (31 ± 5%, P < 0.05) expression with no change in PHD1/2 expression or kidney and heart enlargement.
Conclusion: These data suggest that the protective effect of physiological levels of nitric oxide may be by virtue of inhibition of PHD or increased HIF-1α expression, hence, the pathological changes produced following its withdrawal was accompanied by increased PHD or decreased HIF-1α expression. Exacerbation of hypertension and renal injury following PHD inhibition suggests a deleterious effect in the chronic setting and challenges the dogma that inhibition of PHD is useful in cardiovascular diseases.
Center for Cardiovascular Diseases, Texas Southern University, Houston, Texas, USA
Correspondence to Adebayo O. Oyekan, Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA. Tel: +1 713 3134258/4341; fax: +1 713 313 4342; e-mail: Oyekan_AO@TSU.EDU
Abbreviations: CVD, cardiovascular diseases; DMOG, dimethyloxallyl glycine; HIF-1α, hypoxia inducible factor-1 alpha; LNNA, NG-nitro-l-arginine; PHD, prolyl hydroxylase domain-containing protein
Received 1 April, 2013
Accepted 14 May, 2013