👤 Sergio Bova

The aim of this study was to evaluate the effect and molecular mechanism of albumin infusion on cardiac contractility in experimental cirrhosis with ascites. Cardiac contractility was recorded ex vivo in rats with cirrhosis and ascites and in control rats after the injection in the caudal vein of albumin, saline, or hydroxyethyl starch (HES). Gene and protein expression of β-receptors and pathways involved in their intracellular signaling such as Gα(i2) protein (Gα(i2)), adenylate cyclase 3 (Adcy3), protein expression of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS), were evaluated in cardiac tissue in both groups. Phosphorylation and membrane-translocation of the cytosolic components of nicotinamide adenine dinucleotide phosphate (NAD(P)H)-oxidase and translocation of nuclear factor kappa B (NF-κB) were also evaluated. After saline intravenous injection, cardiac contractility was significantly reduced in rats with cirrhosis as compared to control rats (P < 0.01). This was associated with: (1) increased expression of protein Gα(i2) (P < 0.05), TNF-α (P < 0.05), iNOS (P < 0.05); (2) increased NAD(P)H-oxidase activity (P < 0.05); (3) increased nuclear translocation of NF-κB (P < 0.05); and (4) lower expression of Adcy 3 (P < 0.05) in cardiac tissue of rats with cirrhosis. After albumin injection cardiac contractility (P < 0.01), protein expression of TNF-α, iNOS, Gα(i2), and Adcy3, NAD(P)H-oxidase activity and nuclear translocation of NF-κB in cardiac tissue of rats with cirrhosis were reversed to control levels (P < 0.05). HES injection did not modify cardiac contractility and nuclear translocation of NF-κB in cardiac tissue of rats with cirrhosis. Albumin exerts a positive cardiac inotropic effect in rats with cirrhosis and ascites counteracting the negative effects of oxidative stress- and TNF-α-induced activation of NF-κB-iNOS pathway and oxidative stress-induced alteration of β-receptor signaling. Show less

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. Show less