RETRACTED: Differential expression of the angiotensin-(1-12)/chymase axis in human atrial tissue

Abstract

Objective Heart chymase rather than angiotensin converting enzyme has higher specificity for angiotensin (Ang) I conversion into Ang II in humans. A new pathway for direct cardiac Ang II generation has been revealed through the demonstration that Ang-(1-12) is cleaved by chymase to generate Ang II directly. We address here whether Ang-(1-12) and chymase gene expression and activity are detected in the atrial appendages of 44 patients (10 females) undergoing heart surgery for the correction of valvular heart disease, resistant atrial fibrillation or ischemic heart disease. Methods and Results Immunoreactive- (Ir-) Ang-(1-12) expression was 54% higher in left atrial compared to right atrial appendages and this was associated with higher abundance of left atrial appendage chymase gene transcripts and chymase activity but no differences in angiotensinogen mRNA. Atrial chymase enzymatic activity was highly correlated with left atrial but not right atrial enlargement as determined by echocardiography while both tyrosine hydroxylase and NPY atrial appendages mRNAs correlated with atrial angiotensinogen mRNAs. Conclusions Higher Ang-(1-12) expression and upregulation of chymase gene transcripts and enzymatic activity from the atrial appendages connected to the enlarged left versus right atrial chambers of subjects with left heart disease defines a role of this alternate Ang II forming pathway in the processes accompanying adverse atrial and ventricular remodeling.

Mast Cell Inhibition Attenuates Cardiac Remodeling and Diastolic Dysfunction in Middle-aged, Ovariectomized Fischer 344 × Brown Norway Rats

“…20,21 Briefly, 50-100 μg of LV native plasma membranes (PMs) were preincubated with or without chymase inhibitor (chymostatin, 50 μM) for 15 min. Other inhibitors (lisinopril, SCH39373, MLN-4760, amastatin, bestatin, benzylsuccinate and p-chlomercuribenzoate, each 50 μM) were also added to inhibit the renin-angiotensin enzymes (ACE/ACE2/neprilysin), peptidases and metalloprotease.…”

Role of Tissue Renin-angiotensin System and the Chymase/angiotensin-( 1-12) Axis in the Pathogenesis of Diabetic Retinopathy

“…The amino acid sequence of this novel RAS peptide [Ang-(1-12)] is similar to the sequence of Ang I plus -Val 11 -Ile 12 (in human) and -Leu 11 -Try 12 (in rodent) position of the C-terminus. Compared to Ang I, higher concentration of Ang-(1-12) has been detected in hypertensive rat and diseased human tissues [88, 89]. …”

An evolving story of angiotensin-II-forming pathways in rodents and humans

“…In addition, recent work showed that ir-Ang-(1-12) expression is significantly higher in human left atria appendage (35.37 ± 6.24 units) compared to the expression of the peptide in the right atrium (19.38 ± 2.38 units, p=0.031). The increased Ang-(1-12) expression was associated with high left atrium chymase activity [76]. A differential content or expression of endocrine peptides in the heart has been reported in several species [77;78].…”