Abstract
BackgroundAngiotensin-(1–12) [Ang-(1–12)] functions as an endogenous substrate for the productions of Ang II and Ang-(1–7) by a non-renin dependent mechanism. This study evaluated whether Ang-(1–12) is incorporated by neonatal cardiac myocytes and the enzymatic pathways of 125I-Ang-(1–12) metabolism in the cardiac myocyte medium from WKY and SHR rats.Methodology/Principal FindingsThe degradation of 125I-Ang-(1–12) (1 nmol/L) in the cultured medium of these cardiac myocytes was evaluated in the presence and absence of inhibitors for angiotensin converting enzymes 1 and 2, neprilysin and chymase. In both strains uptake of 125I-Ang-(1–12) by myocytes occurred in a time-dependent fashion. Uptake of intact Ang-(1–12) was significantly greater in cardiac myocytes of SHR as compared to WKY. In the absence of renin angiotensin system (RAS) enzymes inhibitors the hydrolysis of labeled Ang-(1–12) and the subsequent generation of smaller Ang peptides from Ang-(1–12) was significantly greater in SHR compared to WKY controls. 125I-Ang-(1–12) degradation into smaller Ang peptides fragments was significantly inhibited (90% in WKY and 71% in SHR) in the presence of all RAS enzymes inhibitors. Further analysis of peptide fractions generated through the incubation of Ang-(1–12) in the myocyte medium demonstrated a predominant hydrolytic effect of angiotensin converting enzyme and neprilysin in WKY and an additional role for chymase in SHR.Conclusions/SignificanceThese studies demonstrate that neonatal myocytes sequester angiotensin-(1–12) and revealed the enzymes involved in the conversion of the dodecapeptide substrate to biologically active angiotensin peptides.
Highlights
Advances in the biochemical physiology of tissue renin angiotensin systems (RAS) document the existence of alternate pathways for the generation and metabolism of angiotensin peptides
Total cellular uptake of 1 nM 125I-Ang-(1–12) by Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) myocytes were investigated in the presence of all RAS and peptidases inhibitors
Prior experimental [1,3,4,5,6,7,8] and pilot studies in human atrial tissue [9] demonstrated that Ang-(1–12) may serve as an alternate pathway for the generation of angiotensin peptides, a pathway that may be of relevance in situations of suppressed renin activity or secretion, as well as possibly acting as an intracellular precursor for the formation of angiotensin peptides
Summary
Advances in the biochemical physiology of tissue renin angiotensin systems (RAS) document the existence of alternate pathways for the generation and metabolism of angiotensin peptides. Adding to this knowledge are new findings showing that additional alternate mechanisms exist for the formation of angiotensin peptides upstream from angiotensin I (Ang I). In keeping with the nomenclature approved by the Council for High Blood Pressure Research [2] we refer to proangiotensin-(1–12) as angiotensin-(1–12) [Ang-(1–12)] In their studies Nagata et al [1] reported the capacity of the docadecapeptide to serve as a functional substrate for the production of angiotensin II (Ang II). This study evaluated whether Ang-(1–12) is incorporated by neonatal cardiac myocytes and the enzymatic pathways of 125I-Ang-(1–12) metabolism in the cardiac myocyte medium from WKY and SHR rats
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