title: Expression of human angiotensinogen-renin in rat: effects on transcription and heart function.
abstract: In double transgenic rats (dTGR) harboring the human angiotensinogen (hAOGEN) and human renin (hREN) genes, we studied cardiac transcript levels of hypertrophy-related, Ca(2+) regulatory, and beta-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, beta-MHC, and alpha-MHC were altered (percentage versus Sprague-Dawley rats, 100%) by 304%, 178%, and 78%, respectively. Transcript levels of L-type Ca(2+) channel, Ca(2+) 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 equivalent to 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 beta-adrenergically mediated relaxation was not impaired in the hypertrophied hearts, the extent of beta-adrenergic inotropic responsiveness was reduced.
authors.affiliation: Franz-Volhard Clinic, Humboldt University, Berlin, Germany. vkuhle@mdc-berlin.de
authors.forename: Sabine
authors.initials: S
authors.lastname: Bartel
authors.forename: Brigitte
authors.initials: B
authors.lastname: Hoch
authors.forename: Donathe
authors.initials: D
authors.lastname: Vetter
authors.forename: Ernst-Georg
authors.initials: EG
authors.lastname: Krause
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000803:Angiotensin I / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics* / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D009320:Atrial Natriuretic Factor / Q000235:genetics; D015220:Calcium Channels / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D018995:Myosin Heavy Chains / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics* / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic; D000099211:Phospholamban
chemical_list: D000318:Adrenergic beta-Agonists; D000803:Angiotensin I; D000808:Angiotensinogen; D009320:Atrial Natriuretic Factor; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D020962:Heterotrimeric GTP-Binding Proteins; D007545:Isoproterenol; D018995:Myosin Heavy Chains; D011493:Protein Kinase C; D012083:Renin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban