Heme oxygenase-1 and restenosis after PTA

Percutaneous transluminal angioplasty (PTA) is a non-surgical therapy for obstructive peripheral and coronary artery disease. Restenosis after PTA causes considerable morbidity and costs occurring in 30-50 % of the patients within the first year after revascularisation There is increasing evidence that inherited factors may influence the restenotic process in certain patients, however, specific genetic risk factors for restenosis after PTA have not been described so far. Heme oxygenase (HO) degrades protoheme IX into biliverdin, carbon monoxide (CO) and free iron. The induced isoform, HO-1, is upregulated under a variety of physiological and pathological stimuli. Heme, heavy metals, and a number of oxidative stressors markedly potentiate this induction. Vascular smooth muscle cells (VSMC) express HO-1. HO-1 is upregulated by balloon angioplasty enhancing the carbon monoxide release of VSMCs. The VSCM-derived carbon monoxide suppresses VSMC proliferation and may serve as an endogenous protective antiinflammatory factor that limits the excessive VSMC proliferation which is associated with restenosis after PTA. A (GT)n dinucleotide repeat in the 5-flanking region of human HO-1 gene shows a length polymorphism. This microsatellite polymorphism in the HO-1 gene promotor was recently described to modulate the level of the gene transcription. Long dinucleotide repeats were associated with reduced HO-1 inducibility. In a Japanese cohort including smoking patients, this genotype was associated with enhanced susceptibility to emphysema. Conversely, short (<25 GT) dinucleotide repeats in the HO-1 gene promotor region facilitated upregulation of HO-1. The presence of short (GT)n dinucleotide repeats on either allele might represent an endogenous vascular protective factor through the mechanism of enhanced VSMC-derived carbon monoxide release. In the present study we want to investigate, whether the dinucleotide microsatellite length polymorphism in the HO-1 gene promoter is associated with the occurrence of restenosis after peripheral PTA in patients with peripheral artery disease (PAD). Additionally, we will search for other possible mutations in the HO-1 promoter region that might influence the level of protein expression.

A GT-dinucleotide length polymorphism in the heme oxygenase-1 promoter that regulates the up-regulation of heme oxygenase-1 in response to various stress stimuli is associated with the postintervention inflammatory response and the restenosis risk after balloon catheter angioplasty. Short GT-dinucleotide repeat lengths lead to increased heme oxygenase-1 up-regulation that ameliorates the inflammatory response and the risk of restenosis. The dinucleotide length polymorphism furthermore shows an influence on the serum bilirubin and high density lipoprotein levels, mediating important anti-oxidative and vessel-protective functions. The GT-length polymorphism is also associated with renal allograft function after kidney transplantation. Short GT repeat lengths in the donor organ are associated with significantly improved renal function up to two years after transplantation. Again, a vessel-protective and anti-inflammatory effect of the increased up-regulation of the protective enzyme heme oxgenase-1 is the most likely mechanism. In the future, the determination of the GT-dinucleotide repeat length could be used for restenosis risk assessment in balloon angioplasty and in renal allograft transplantation. Various methods for the increased (therapeutic) upregulation are intensively studied in the scientific area. In a second set of experiments five additional point-mutations were identified in enhancer and coding regions of the heme oxygenase gene, respectively. The functional relevance of these mutations is studied at present.