Neue erkenntnisse zur vasoprotektiven wirkung des NO-donors PETN

Pentaerythritol tetranitrate is a nitric oxide (NO) donor with vasodilatory and antioxidant properties. Experimental studies published in the nineties showed that in contrast to other long acting nitrates, PETN does induce significantly lower tolerance in animal experiments. These results were recently confirmed in humans. Increased formation of reactive oxygen species (ROS) in vascular cells is considered a crucial mechanism of tolerance development to organic nitrates. PETN is a potent inductor of proteins that mediate antioxidant actions such as heme oxygenase-1 (HO-1) and ferritin. Other long acting organic nitrates such as isosorbide dinitrate show little or no effect on the expression of these genes. The use of specific inhibitors and inducers of HO-1 has provided strong evidence that HO-1 assumes a key role in the prevention of nitrate tolerance. HO-1 activity results in the breakdown of heme and formation of the antioxidant bilirubin and the vasodilatory mediator carbon monoxide. Through these mechanisms, PETN and other inducers of HO-1 also reduce oxidant injury in the endothelium. In addition, inhibition of ROS formation by PETN improves the function of endothelial progenitor cells and thus promotes reendothelialization and angiogenesis. Transferring the HO-1 gene transfer has also been reported to suppress arteriosclerosis and induce vasoprotection whereas the absence of a functional HO-1 gene causes massive vascular lesions. These observations demonstrate the central role of HO-1 in maintaining vascular integrity and point to the potential relevance of this enzyme as therapeutic target in cardiovascular disease and other inflammatory processes.