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(Hypertension. 2002;39:219.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Expression of Human Angiotensinogen-Renin in Rat

Effects on Transcription and Heart Function

Sabine Bartel; Brigitte Hoch; Donathe Vetter; Ernst-Georg Krause

From the Franz-Volhard Clinic, Humboldt University (S.B.), Berlin, Germany; and Max Delbrück Center for Molecular Medicine (B.H., D.V., E-G.K.), Berlin, Germany.

Correspondence to Sabine Bartel, Max Delbrück Center for Molecular Medicine, Robert Rössle Strasse 10, D-13125 Berlin, Germany. E-mail vkuhle{at}mdc-berlin.de

In double transgenic rats (dTGR) harboring the human angiotensinogen (hAOGEN) and human renin (hREN) genes, we studied cardiac transcript levels of hypertrophy-related, Ca²⁺ regulatory, and ß-adrenoceptor–associated proteins. The contractile properties and the cellular signaling of isolated hearts exposed to (-)isoproterenol and/or angiotensin (Ang) I were evaluated. dTGR developed hypertension of 174.1±7.6 versus 109.6±2.0 mm Hg (P<0.05) in Sprague-Dawley rats and heart hypertrophy. In hearts of dTGR, the transcript levels of ANP, ß-MHC, and -MHC were altered (percentage versus Sprague-Dawley rats, 100%) by 304%, 178%, and 78%, respectively. Transcript levels of L-type Ca²⁺ channel, Ca²⁺ release channel, SERCA2a, phospholamban, G_i- and G_s-proteins were unchanged. Isolated hearts of dTGR indicated higher baseline contractility versus Sprague-Dawley rats. (-)Isoproterenol-modified contractility occurred in both groups; however, the extent (predrug value, 100%) was less in hearts of dTGR versus Sprague-Dawley rats (+dP/dt, 310±42% versus 534±63%; P<0.05). Interestingly, (-)isoproterenol shortened the relaxation time by 25% in both groups. This finding was reflected by a protein kinase A–related phospholamban phosphorylation. Ang I depressed the heart contractility but did not interact with the protein kinase A pathway. In conclusion, we have found that expression of the hAOGEN-hREN complex in dTGR elicited specific effects on transcripts of ANP and myofibrillar proteins. Although the ß-adrenergically mediated relaxation was not impaired in the hypertrophied hearts, the extent of ß-adrenergic inotropic responsiveness was reduced.

Key Words: hypertrophy • contraction • relaxation • angiotensin I • adrenergic receptor agonists

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