An abnormal gene expression of the beta-adrenergic system contributes to the pathogenesis of cardiomyopathy in cirrhotic rats.
Decreased cardiac contractility and beta-adrenergic responsiveness have been observed in cirrhotic cardiomyopathy, but their molecular mechanisms remain unclear. To study beta-adrenergic-stimulated contractility and beta-adrenergic gene expression patterns, 20 Wistar Kyoto rats were treated with carbon tetrachloride to induce cirrhosis and 20 rats were used as controls. Left ventricular contractility was recorded in electrically driven isolated hearts perfused at constant flow with isoproterenol (10(-10) to 10(-6) M). A cardiac gene expression profile was obtained using a microarray for the myocyte adrenergic pathway. The cardiac contractility maximal response to isoproterenol was significantly reduced in cirrhotic rats in comparison to control rats, whereas the half-maximal effective concentration was not different. In cirrhotic rats, cardiac gene expression analysis showed a significant overexpression of G protein alpha-inhibiting subunit 2 (Galpha(i2)), cyclic nucleotide phosphodiesterase (PDE2a), regulator of G-protein signaling 2 (RGS2), and down-expression of adenylate cyclase (Adcy3). These results indicate that overexpression of Galpha(i2), PDE2a, and RGS2 down-regulates the beta-adrenergic signaling pathway, thus contributing to the pathogenesis of cirrhotic cardiomyopathy.
Ceolotto
Giulio
G
Department of Clinical and Experimental Medicine, University of Padova Medical School, Padova, Italy.
Papparella
Italia
I
Sticca
Antonietta
A
Bova
Sergio
S
Cavalli
Maurizio
M
Cargnelli
Gabriella
G
Semplicini
Andrea
A
Gatta
Angelo
A
Angeli
Paolo
P
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002251:Carbon Tetrachloride; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D011943:Receptors, Adrenergic, beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
D000318:Adrenergic beta-Agonists; D020710:RGS Proteins; C514563:RGS2 protein, rat; D011943:Receptors, Adrenergic, beta; D002251:Carbon Tetrachloride; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517278:Pde2a protein, rat; D051960:GTP-Binding Protein alpha Subunit, Gi2; D000262:Adenylyl Cyclases; D007545:Isoproterenol