title: 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.affiliation: Department of Surgery, Wake Forest School of Medicine, Winston Salem, North Carolina; Departments of Medicine-Nephrology and Physiology-Pharmacology, Wake Forest School of Medicine, Winston Salem, North Carolina.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Ferrario
authors.affiliation: Department of Surgery, Wake Forest School of Medicine, Winston Salem, North Carolina; Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina;
authors.forename: Jessica
authors.initials: J
authors.lastname: VonCannon
authors.affiliation: Department of Surgery, Wake Forest School of Medicine, Winston Salem, North Carolina;
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina;
authors.forename: Sarfaraz
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.affiliation: Division of Cardiovascular Disease, University of Alabama at Birmingham and Department of Veterans Affairs, Birmingham Veterans Affairs Medical Center, Birmingham, Alabama;
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dell'Italia
authors.affiliation: Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina; Department of Anesthesiology, Wake Forest School of Medicine, Winston Salem, North Carolina; and.
authors.forename: Leanne
authors.initials: L
authors.lastname: Groban
authors.affiliation: Department of Surgery, Wake Forest School of Medicine, Winston Salem, North Carolina; Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina; Departments of Medicine-Nephrology and Physiology-Pharmacology, Wake Forest School of Medicine, Winston Salem, North Carolina jvaragic@wakehealth.edu.
authors.forename: Jasmina
authors.initials: J
authors.lastname: Varagic
mesh_terms: D000808:Angiotensinogen / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D062186:Arterial Pressure; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005838:Genotype; D006339:Heart Rate; D006720:Homozygote; D006801:Humans; D006868:Hydrolysis; D006973:Hypertension / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012084:Renin-Angiotensin System / Q000235:genetics; D013997:Time Factors; D014463:Ultrasonography; D016277:Ventricular Function, Left
chemical_list: C534931:AGT protein, human; D010446:Peptide Fragments; C000610416:angiotensin-(1-12), human; D000808:Angiotensinogen
keywords: angiotensin II; angiotensin converting enzyme inhibitors; angiotensin-(1–12); angiotensinogen; cardiac angiotensins; chymase; renin