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

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) render 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. Compared with Sprague-Dawley (SD) control rats (n= 11), male homozygous TGR(hAGT)L1623 (n= 9) demonstrated sustained daytime and nighttime hypertension associated with no changes in heart rate but increased heart rate lability. Increased heart weight/tibial length ratio and echocardiographic indexes 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 fourfold 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 angiotensin-converting enzyme (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 underscore the existence in the rat of alternate enzymes capable of acting on hAGT protein. Homozygous transgenic rats expressing the hAGT gene represent a novel tool to investigate the contribution of human relevant renin-independent cardiac ANG II formation and function.

• Authors: Carlos M Ferrario, Jessica VonCannon, Yan Jiao, Sarfaraz Ahmad, Michael Bader, Louis J Dell'Italia, Leanne Groban, Jasmina Varagic
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 310 Issue 8 Pg. H995-1002 (Apr 15 2016) ISSN: 1522-1539 [Electronic] United States
• PMID: 26873967 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AGT protein, human
• Peptide Fragments
• angiotensin-(1-12), human
• Angiotensinogen

Topics

• Angiotensinogen (blood, genetics, metabolism)
• Animals
• Arterial Pressure
• Cardiomegaly (diagnostic imaging, genetics, metabolism, physiopathology)
• Disease Models, Animal
• Genotype
• Heart Rate
• Homozygote
• Humans
• Hydrolysis
• Hypertension (diagnostic imaging, genetics, metabolism, physiopathology)
• Male
• Myocardium (metabolism, pathology)
• Peptide Fragments (blood, genetics, metabolism)
• Phenotype
• Rats, Sprague-Dawley
• Rats, Transgenic
• Renin-Angiotensin System (genetics)
• Time Factors
• Ultrasonography
• Ventricular Function, Left