Oxidized angiotensin II peptides as mediators of cell signaling?

Both reactive oxygen species (ROS) and angiotensin II (Ang II) play important roles in the pathogenesis of various diseases. Since Ang II was found to activates NADPH oxidase to produce ROS, many laboratories have investigated the role of Ang II-generated ROS in cellular signaling and disease progression. However, it remains unclear whether Ang II itself undergoes direct oxidation. One mechanism of protein oxidation is carbonylation, which affects arginine (Arg) and proline (Pro), making them particularly susceptible to oxidative modification. Both amino acid residues produce glutamic semialdehyde, which can be further oxidized to glutamic acid (Glu). Thus, our laboratory previously described that Arg, Pro, and Glu could be interchangeable, and that ROS could promote amino acid conversions within protein structures post-translationally in biological systems. Since Ang II contains Arg at position 2 and Pro at position 7, we hypothesize that Ang II can be oxidized to form peptides with altered amino acid sequences, where Arg or Pro residues are converted to Pro or Glu via glutamic semialdehyde formation. These oxidized Ang II peptides may exert biological activities different from wild-type Ang II. Alternatively, Ang II, which is carbonylated or oxidized at various amino acids, could be formed during oxidative stress. We propose that these oxidized Ang II molecules can trigger cell signaling, offering a new mode of redox signaling. Furthermore, our analysis suggests additional amino acid conversion mechanisms within protein or peptide structures, supporting the idea that amino acid sequences can be defined post-translationally. This Hypothesis Paper proposes novel mechanisms.