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Cardiac angiotensin-(1-12) expression and systemic hypertension in rats expressing the human angiotensinogen gene

Item Type:Article
Title:Cardiac angiotensin-(1-12) expression and systemic hypertension in rats expressing the human angiotensinogen gene
Creators Name:Ferrario, C.M. and VonCannon, J.L. and Jiao, Y. and Ahmad, S. and Bader, M. and Dell'Italia, L.J. and Groban, L. and Varagic, J.
Abstract:Angiotensin-(1-12) [Ang-(1-12)] is processed into Ang II by chymase in rodent and human heart tissue. Differences in the amino acid sequence of rat and human Ang-(1-12) renders the human angiotensinogen (hAGT) protein refractory to cleavage by renin. We used transgenic rats harboring the hAGT gene [TGR(hAGT)L1623] to assess the non-renin dependent effects of increased hAGT expression on heart function and arterial pressure. When compared to Sprague Dawley (SD) control rats (n=11), male homozygous TGR(hAGT)L1623 (n=9) demonstrated sustained day and night-time hypertension associated with no changes in heart rate but increased heart rate lability. Increased heart weight/tibial length ratio and echocardiographic indices of cardiac hypertrophy were associated with modest reduction of systolic function in hAGT rats. Robust human Ang-(1-12) immunofluorescence within myocytes of TGR(hAGT)L1623 rats was associated with a 4-fold increase in cardiac Ang II content. Chymase enzymatic activity, using the rat or human Ang-(1-12) as a substrate, was not different in the cardiac tissue of SD and hAGT rats. Since both cardiac ACE and ACE2 activities were not different among the two strains, the changes in cardiac structure and function, blood pressure, and left ventricular Ang II content might be a product of an increased cardiac expression of Ang II generated through a non-renin dependent mechanism. The data also underscores the existence in the rat of alternate enzymes capable of acting on hAGT protein. Homozygous transgenic rats expressing the human AGT gene represent a novel tool to investigate the contribution of human relevant renin-independent cardiac Ang II formation and function.
Keywords:Angiotensin Converting Enzyme Inhibitors, Angiotensin II, Angiotensinogen, Cardiac Angiotensins, Chymase, Angiotensin-(1-12), Renin, Animals, Rats
Source:American Journal of Physiology Heart and Circulatory Physiology
ISSN:0363-6135
Publisher:American Physiological Society
Volume:310
Number:8
Page Range:H995-H1002
Date:15 April 2016
Official Publication:https://doi.org/10.1152/ajpheart.00833.2015
PubMed:View item in PubMed

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