inositol-1-4-5-trisphosphate and Cardiac-Output--Low

Volume overload due to arteriovenous (AV) shunt results in cardiac hypertrophy followed by the progression to heart failure. The phosphoinositide phospholipase C (PLC) converts phosphatidylinositol 4,5-bisphosphate (PIP(2)) to 1,2-diacylglycerol (DAG) and inositol (1,4,5)-trisphosphate (IP(3)), which are known to influence cardiac function. Therefore, we examined the time course of changes in DAG and IP(3) as well as PLC isozyme gene expression, protein content, and activities in cardiac hypertrophy and heart failure induced by AV shunt in Sprague-Dawley rats by the needle technique. An increase in the left ventricle (LV)-to-body weight ratio demonstrated that LV hypertrophy was established at 4 wk after the induction of the shunt. PLC-beta(1) activity was increased two- and sevenfold at 3 days and 1 and 2 wk after the induction of volume overload, respectively. These changes were associated with increases in the mRNA and sarcolemmal (SL) protein content; however, no changes in PLC-beta(1) were detected at 4 wk. On the other hand, a significant increase in PLC-gamma(1) activity as well as mRNA and SL protein was seen at 3 days and 4 wk. A progressive decrease in PLC-delta(1) activity with concomitant reductions in the gene expression and SL protein abundance was detected during 1 to 4 wk. Activity of gamma(1)- and delta(1)-isozymes was significantly depressed during the 8- and 16-wk time points, whereas beta(1)-isozyme was increased significantly during these time points. A progressive decrease in the SL PIP(2) content was observed during cardiac hypertrophy and heart failure. Our findings indicate that PLC isozyme signaling processes are increased in hypertrophy and decreased in heart failure due to volume overload.

Topics: Animals; Cardiac Output, Low; Cardiomegaly; Cytosol; Diglycerides; Gene Expression; Hyperemia; Inositol 1,4,5-Trisphosphate; Isoenzymes; Male; Phosphatidylinositol 4,5-Diphosphate; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sarcolemma; Type C Phospholipases; Ventricular Function, Left

Activation of the Fas receptor in various cell types, including myocytes, triggers apoptotic as well as nonapoptotic effects. Recent studies suggest that Fas activation in the heart participates in the development of major pathologies such as myocarditis and ischemic/reperfusion insults, which are manifested by arrhythmias and mechanical dysfunction. To decipher the contribution of the Fas/FasL pathway to myocardial pathologies, we have investigated the functional consequences of Fas activation in normoxic and hypoxic ventricular myocytes. Our major findings were as follows. (1) Although Fas is constitutively expressed in ventricular myocytes, normoxic myocytes are resistant to Fas-mediated apoptosis. In contrast, hypoxia predisposes myocytes to apoptosis induced by Fas activation. The underlying mechanism is a shift in the balance between proapoptotic proteins (including Fas) and antiapoptotic proteins toward the former. (2) In normoxic myocytes, Fas activation causes a wide range of functional disturbances, which include reduction in resting potential and action potential amplitude, prolonged action potential duration, development of delayed and early after-depolarizations, occasionally culminating into arrhythmias, diastolic [Ca(2+)](i) level increase, decreased I(to) and increased I(Ca,L). (3) The above-mentioned effects in normoxic myocytes (but not Fas-mediated apoptosis in hypoxic myocytes) depend on the phospholipase C --> 1,4,5-IP(3) --> SR [Ca(2+)](i) release cascade. (4) Inhibition of tyrosine kinases with genistein blocks both the apoptotic and nonapoptotic consequences of Fas activation in ventricular myocytes. Based on these studies we propose that tyrosine phosphorylation in ventricular myocytes can serve as a novel potential target for attenuating Fas-mediated dysfunction in normoxic and hypoxic myocardium.

Topics: Animals; Arrhythmias, Cardiac; Cardiac Output, Low; fas Receptor; Inositol 1,4,5-Trisphosphate; Phosphorylation; Protein-Tyrosine Kinases