Expression of renin-angiotensin system and peroxisome proliferator-activated receptors in alcoholic cardiomyopathy.
BACKGROUND
Alcoholic cardiomyopathy (ACM) develops in response to chronic alcohol intake and it is hypothesized that activation of the renin-angiotensin system (RAS) and disorders in energy metabolism may play important roles in its onset. Given that the expression of peroxisome proliferator-activated receptors (PPARalpha and PPARgamma) changes with alterations in cardiac metabolism and myocardial remodeling, this study was designed to test the hypothesis that protein expression of PPARalpha and PPARgamma is correlated with RAS activation in ACM.


METHODS
For the first experiment, rats were divided into 3 groups: 30 received alcohol (intragastric administration with ad libitum drinking), 30 received alcohol and irbesartan (5 mg/kg/d, p.o.), and 30 served as controls. RAS activity and protein expression of PPARalpha and PPARgamma were evaluated in rats following 6 months of alcohol feeding using radioimmunoassay, reverse transcriptase PCR, and Western blot methods. For the second experiment, rats were divided into 4 groups: 10 rats received alcohol/irbesartan (5 mg/kg/d, p.o.)/PD98059 (methyl ethyl ketone [MEK]-1 inhibitor) (0.3 mg/kg/d, p.o.), 10 rats received alcohol/PD98059, 10 rats received alcohol/irbesartan, and 10 rats received alcohol alone. Myocardial PPARalpha and PPARgamma protein expression was detected following 6 months of alcohol feeding using Western blot method.


RESULTS
Compared with controls, myocardial angiotensin (Ang) I, Ang II, and renin levels were progressively increased at 2, 4, and 6 months of alcohol intake. mRNA expression of renin, angiotensinogen, angiotensin-converting enzyme (ACE), and AT1 was increased at 6 months. Moreover, activated RAS downregulated PPARalpha and upregulated PPARgamma protein expression as ACM progressed. Finally, extracellular signal regulated kinase 1 and 2 (ERK1/2) was shown to play a key role in the regulation of protein expression of PPARalpha and PPARgamma.


CONCLUSIONS
These results suggest that RAS is activated during the development of ACM. Moreover, ERK1/2 plays a key role in the regulation of protein expression of PPARalpha and PPARgamma by RAS in ACM.
Jing
Ling
L
Department of Cardiology, First Clinical College of Harbin Medical University, Harbin, Heilongjiang, China.
Li
Wei-Min
WM
Zhou
Li-Jun
LJ
Li
Shuang
S
Kou
Jun-Jie
JJ
Song
Jian
J
D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002310:Cardiomyopathy, Alcoholic / Q000378:metabolism*; D004195:Disease Models, Animal; D005419:Flavonoids / Q000494:pharmacology; D000077405:Irbesartan; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D020257:Ventricular Remodeling
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D005419:Flavonoids; D047493:PPAR alpha; D047495:PPAR gamma; D013777:Tetrazoles; D000808:Angiotensinogen; D000804:Angiotensin II; D000803:Angiotensin I; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D000077405:Irbesartan; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one