Expression of an angiotensin-(1-7)-producing fusion protein produces cardioprotective effects in rats.
Angiotensin-(1-7) [ANG-(1-7)] is a recently described heptapeptide product of the renin-angiotensin system. Because biosynthesis of ANG-(1-7) increases in animals treated with cardioprotective drugs and inactivation of the gene for angiotensin converting enzyme 2 [an enzyme involved in the biosynthesis of ANG-(1-7)] leads to the development of cardiac dysfunction, it has been suggested that ANG-(1-7) has cardioprotective properties. To directly test this possibility, we have generated transgenic rats that chronically overproduce ANG-(1-7) by using a novel fusion protein methodology. TGR(A1-7)3292 rats show testicular-specific expression of a cytomegalovirus promoter-driven transgene, resulting in a doubling of circulating ANG-(1-7) compared with nontransgenic control rats. Radiotelemetry hemodynamic measurements showed that transgenic rats presented a small but significant increase in daily and nocturnal heart rate and a slight but significant increase in daily and nocturnal cardiac contractility estimated by dP/d t measurements. Strikingly, TGR(A1-7)3292 rats were significantly more resistant than control animals to induction of cardiac hypertrophy by isoproterenol. In addition, transgenic rats showed a reduced duration of reperfusion arrhythmias and an improved postischemic function in isolated Langendorff heart preparations. These results support a cardioprotective role for circulating ANG-(1-7) and provide a novel tool for evaluating the functional role of ANG-(1-7).
Santos
Robson A S
RA
Laboratory of Hypertension, Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, MG, 31270-901 Brazil. santos@icb.ufmg.br
Ferreira
Anderson J
AJ
Nadu
Ana Paula
AP
Braga
Aline N G
AN
de Almeida
Alvair Pinto
AP
Campagnole-Santos
Maria José
MJ
Baltatu
Ovidiu
O
Iliescu
Radu
R
Reudelhuber
Timothy L
TL
Bader
Michael
M
D000803:Angiotensin I / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D006332:Cardiomegaly / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000378:metabolism*; D015870:Gene Expression; D006339:Heart Rate; D008297:Male; D009200:Myocardial Contraction; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D013737:Testis / Q000196:embryology
D002316:Cardiotonic Agents; D010446:Peptide Fragments; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D000803:Angiotensin I; C118790:angiotensin I (1-7)