Coupling NOS to endothelial function and inflammation in cardiovascular disease

Abstract

Nitric oxide synthases (NOS) regulate cardiovascular homeostasis through nitric oxide (NO) production, for example in the vascular endothelium. Loss of NO mediated endothelial function is a characteristic of cardiovascular disease states. However, deranged NOS function in is not reflected in loss of NOS enzyme protein, or absent NOS enzymatic activity. Rather, NOS uncoupling, mediated by loss of the co-factor tetrahydrobiopterin (BH4), generates ROS rather than NO, thus altering the signalling repertoire of NOS and contributing to cardiovascular pathophysiology. In the endothelium, transgenic mouse models have demonstrated that increasing endothelial cell BH4 is sufficient to rescue eNOS uncoupling, leading to beneficial effects on atherosclerotic plaque, remodelling after vascular injury and endothelial cell repopulation. However, in a clinical trial of oral BH4 therapy in patients with coronary artery disease, there was no beneficial effect on endothelial function, in part due to oxidation of the administered BH4. Oxidative loss of BH4 in cardiovascular diseases is related local and systemic inflammation. In coronary artery disease, increased markers of systemic inflammation are associated with increased plasma levels of BH4, but with reduced vascular tissue levels of BH4 and endothelial dysfunction. Acute inflammatory stimulus by vaccination rapid increases circulating BH4, but impairs endothelial function. Variants in the GCH1 gene, that regulates BH4 synthesis, are associated with altered responses to inflammatory stimulation and endothelial function. Future studies need to improve understanding of endothelial versus systemic BH4 regulation in inflammation, in order to identify and target new therapies that take advantage of BH4 dependent NOS regulation.