[Angiotensin(1-7) attenuates left ventricular dysfunction and myocardial apoptosis on rat model of adriamycin-induced dilated cardiomyopathy].
OBJECTIVE
To investigate the effect of Angiotensin(1-7) [Ang(1-7)] on left ventricular dysfunction and myocardial apoptosis on rat model of adriamycin-induced dilated cardiomyopathy (ADR-DCM).


METHODS
Weight-matched adult male Wistar rats were randomly divided into 3 groups: (1) the ADR-DCM group (n = 25), in which 2.5 mg/kg of ADR was weekly intravenously injected for 10 weeks. (2) Ang(1-7) group (n = 25), in which ADR rats were simultaneously treated with angiotensin-(1-7) (24 µg×kg(-1)×h(-1), ip.) for 12 weeks. (3) normal control group (n = 10). Hemodynamics and echocardiography examination were performed at 12 weeks. The malondialdehyde (MDA) was measured by TBA methods. The plasma concentration of AngII was determined by immunoradiometric assay. The pathological change was analyzed by histological hematoxylin-eosin staining. Myocardial apoptosis was assessed by TUNEL method. The protein expression of pro-apoptotic protein caspase-3, Bax and anti-apoptotic protein Bcl-xl in cardiomyocytes were detected by Western blot.


RESULTS
Mortality was significantly lower in Ang(1-7) group than in ADR-DCM group (16% vs. 40%, P < 0.01). Compared to the control group, left ventricular end-diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD) and left ventricular end-diastolic pressure (LVEDP) were significantly increased in ADR-DCM group (all P < 0.01) while fractional shorting (FS), +dp/dtmax and -dp/dtmax were significantly reduced in ADR-DCM group (all P < 0.01). LVEDD, LVESD and LVEDP were significantly reduced while FS, +dp/dtmax and -dp/dtmax were significantly higher in Ang(1-7) group compared to the ADR-DCM group, but still higher than the control group (all P < 0.01). The concentrations of AngII and MDA were higher in the ADR-DCM group than in the control group (P < 0.01), which were significantly reduced by Ang(1-7) treatment (P < 0.01). The TUNEL-positive cells and apoptosis index, the expression of pro-apoptotic protein caspase-3 and Bax were significantly higher while the expression of anti-apoptotic protein Bcl-xl was significantly lower in the ADR-DCM group than in the control group (all P < 0.01) which could all be partially reversed by Ang(1-7) treatment (all P < 0.01).


CONCLUSIONS
Ang(1-7) could significantly attenuate left ventricular dysfunction and myocardial apoptosis in this model by downregulating pro-apoptotic protein caspase-3 and Bax and upregulating anti-apoptotic protein Bcl-xl expression.
Department of Cardiology, Henan Province People's Hospital, Zhengzhou 450003, China. lhzhi@sina.com
Hong-zhi
HZ
Liu
Chuan-yu
CY
Gao
Xian-qing
XQ
Wang
Hai-xia
HX
Fu
Hong-hui
HH
Yang
Xian-pei
XP
Wang
Yu-hao
YH
Liu
Mu-wei
MW
Li
Zhen-min
ZM
Niu
Guo-you
GY
Dai
Da-tun
DT
Qi
You
Y
Zhang
D000803:Angiotensin I / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D053148:Caspase 3 / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects; D006321:Heart / Q000187:drug effects; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology*; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D010446:Peptide Fragments; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D004317:Doxorubicin; D000803:Angiotensin I; C505410:Casp3 protein, rat; D053148:Caspase 3; C118790:angiotensin I (1-7)