The Renin–Angiotensin System and the Heart

2.1

Update on Tissue RAS Biotransformation Processes

There is now general agreement that the biochemical pathways accounting for the formation of bioactive angiotensins do not conform to the originally described sequence of linear steps in which angiotensinogen is converted by renin into Ang I with subsequent processing either into Ang II by ACE or Ang-(1-7) by neutral endopeptidases. As illustrated in Fig 3.1 , alternate pathways for angiotensins synthesis are present at each of the key steps in the processing of the precursors (angiotensinogen, Ang-(1-12), and Ang I). The specific situations at which these alternate pathways occur or are activated is neither understood nor has it been adequately investigated. Since the publication of our original chapter in this book, newer evidence for a significant role of Ang-(1-7) in counteracting the pressor, antinatriuretic, prothrombotic, hypertrophic, and profibrotic actions of Ang II has been affirmed through multiple publications and the development of novel orally active approaches to either administer Ang-(1-7) or boost its activity through Ang II metabolism. Two additional bioactive C-terminus peptides are gaining considerable attention as they possess functional activities similar to those of Ang-(1-7). These are the nonapeptide angiotensin-(1-9) [Ang-(1-9)] and alamandine, a heptapeptide that is cleaved from angiotensin A by ACE2 or directly from Ang-(1-7). The relative role of these peptides in terms of cardioprotection and as components of a cardiac tissue RAS remains to be ascertained.

Overshadowed by the therapeutic benefits achieved with ACE inhibitors and ARBs since their introduction into the pharmacotherapy of human diseases, the possibility that biochemical and physiological mechanisms of Ang II formation and action differ between rodents and humans have been consistently neglected even though original studies by Urata and colleagues, Husain, and Dell’Italia and associates clearly documented that the α-form of chymase in humans had a 20-fold higher catalytic activity in converting Ang I into Ang II. A renewed interest on cardiac chymase as a primary component of a cardiac RAS in humans awaited the identification of the dodecapeptide Ang-(1-12) as a functional Ang II-forming substrate in Wistar rats. Additional studies showed increased Ang-(1-12) expression and concentration in the heart of SHR, associated with increased incorporation of the substrate in cardiac myocytes, and the action of chymase rather than ACE in forming directly Ang II from Ang-(1-12), particularly in humans. Studies carried out in Ferrario’s laboratory has led to the realization of significant species differences in Ang II-forming enzymes between rodents and humans through the assessment of the metabolism of Ang-(1-12) in atrial and left ventricular tissues, and the characterization of Ang-(1-12) expression and chymase gene transcripts and enzymatic activity in heart tissue obtained from patients undergoing cardiac surgery for the treatment of ischemic heart disease, valvular disease, or resistant atrial fibrillation. The clinical significance of these species differences in accounting for Ang II formation and action are discussed in a recently published paper and are further discussed below ( Section 3 ).