Figure 1.

Effect of hypoxia (ischemia) on arginine metabolism. Direct effects of low pO₂ are the translocation of c-jun in AP-1 dimers, thereby activating AP-1 transcriptional activity, an activation of PKCα and subsequent activation of arginine transporters (CAT2) and inhibition of constitutively expressed NOS isoforms (eNOS and nNOS). Indirect effects of low pO₂ are loss of sarcolemmal integrity in some cells (see left), leading to the release of intracellular particles, such as RNA (eRNA), that activates a sheddase (TACE) thereby releasing TNFα. TNFα augments the hypoxia-induced cell damage by activation of AP-1 and increasing arginase (Arg) expression, by activation of arginase activity via nitrosylation and reducing the K_M value for the enzymatic reaction, and ROS-dependent inhibition of NOS activity.