The role of Nitric Oxide in different diseases

Nitric oxide, (NO), is the most studied of arginine metabolite. It is an essential biological molecule for diverse physiological processes and hence its dysregulation can have pathological consequences. In spite of multiple studies regarding different diseases, the role of is controversial. This difficulty roots in part from the redundancy in the enzyme that synthesizes NO- nitric oxide synthase (NOS).  As all three NOS isoforms use arginine for substrate, we have generated animal and primary cells with deficiency in the only mammalian enzyme able to generate arginine, argininosuccinate lyase (ASL). Moreover, ASL is also structurally required for the assembly of the NO synthesis complex.  Thus, loss of ASL results in a NO deficient state which causes changes in cell signaling as well as in the regulation of different enzymes’ activity. Indeed, we have shown that patients with congenital ASL deficiency have hypertension.

ASL is required NO production- ASL is necessary for the NOS complex assembly that utilizes both exogenous arginine and endogenous arginine produced by ASL, to generate NO.

Using novel mice model of Asl conditional knock out as well as primary cells, we are uniquely positioned to dissect the role and regulation of NO in normal and pathologic conditions, at the cellular level. Since ASL deficient patients have also cognitive impairments, we study the effects of NO dysregulation on neuronal function.