inositol-1-4-5-trisphosphate and Cardiomyopathies

Cardiomyocytes contain secretory granules in which chromogranins and several types of natriuretic peptides and growth factors are stored in addition to high Ca(2+) concentrations. Yet the expression and serum levels of chromogranins and natriuretic peptides have been closely correlated with pathological cardiac hypertrophy and heart failure. Moreover, in distinction from the physiological cardiac hypertrophy that appears not to involve inositol 1,4,5-trisphosphate (IP3) production as the primary signaling step, accumulating evidence underscores the central role of IP3-induced intracellular Ca(2+) releases in cardiomyocytes in the development of pathological cardiac hypertrophy. Consistent with this observation, chronic treatment of cardiomyocytes with G-protein coupled receptor agonists endothelin-1, angiotensin II, or phenylephrine, agents that are known to produce intracellular IP3, leads to cardiomyopathy and heart failure. In particular, the IP3-induced Ca(2+) release inside the nucleus has been suggested to initiate a series of nuclear activities, including 1) Ca(2+)-calmodulin (CaM) mediated protein kinase II (CaMKII) activation, 2) activation of transcription factors such as myocyte enhancer factor-2 (MEF-2) and nuclear factor κB (NF-κB), and 3) increased production of chromogranins, natriuretic peptides, and growth factors, which eventually lead to pathological hypertrophy. Although secretory granules function as the major IP3-sensitive intracellular Ca(2+) store and the IP3-mediated Ca(2+) release from secretory granules in cardiomyocytes contributes to secretion of chromogranins and natriuretic peptides, the direct cause of pathological hypertrophy appears to be due to the IP3-induced Ca(2+) release from the small nucleoplasmic IP3-sensitive Ca(2+) store vesicles, thereby initiating the Ca(2+)-activated nuclear activities that lead to formation of more secretory granules, pathologic enlargement of cardiomyocytes, and heart failure.

Topics: Calcium Channels; Calcium Signaling; Cardiomegaly; Cardiomyopathies; Chromogranins; Heart Failure; Humans; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Myocytes, Cardiac

It is now well established that immune effector mechanisms contribute to cardiac dysfunction in several heart diseases, including myocarditis and the associated dilated cardiomyopathy, heart transplant rejection and Chagas' disease. These and other pathologies, in which cellular immunity plays an important role, contribute to morbidity and mortality world-wide. As a result of numerous studies performed in this exciting field, two major mechanisms of lymphocytotoxicity have been proposed: a secretory mechanism in which perforin and granzymes are key players, and a non-secretory mechanism involving Fas/FasL activation. While the common notion is that CTL-myocyte interaction, perforin- or Fas-based, inevitably results in target cell apoptotic death, the objective of this review is to consider the concept of non-apoptotic consequences of CTL-target cell interaction. It is proposed that depending on the myocyte status as well as on the fine balance between pro- and anti-apoptotic factors, CTL-myocyte interaction may result in a non-apoptotic, potentially reversible sustained damage to the myocytes, thus contributing to immune-mediated cardiac dysfunction.

Topics: Animals; Apoptosis; Calcium; Cardiomyopathies; Cytotoxicity, Immunologic; Fas Ligand Protein; fas Receptor; Humans; Inositol 1,4,5-Trisphosphate; Membrane Glycoproteins; Myocardium; Perforin; Pore Forming Cytotoxic Proteins; T-Lymphocytes, Cytotoxic

Lipopolysaccharide (LPS) induces tumor necrosis factor-alpha (TNF-alpha) expression in cardiomyocytes, which contributes to myocardial dysfunction during sepsis. The purpose of this study was to investigate the role of phosphatidylinositol (PI) phospholipase Cgamma1 (PLCgamma1) in cardiac TNF-alpha expression, and myocardial dysfunction during endotoxemia.. In cultured mouse neonatal cardiomyocytes, LPS increased PLCgamma1 phosphorylation. Knockdown of PLCgamma1 with specific siRNA or inhibition of PLCgamma1 with U73122 attenuated TNF-alpha expression induced by LPS. This action of PLCgamma1 was mediated through inositol-1,4,5-trisphosphate (IP3)/IP3 receptor (IP3R) pathways since blocking either IP3 or IP3R decreased LPS-induced TNF-alpha expression. In contrast, neither diacylglycerol agonist nor antagonist had any evident effect on LPS-induced TNF-alpha expression in cardiomyocytes. To investigate the role of PLCgamma1 in endotoxemia in vivo, wild-type and heterozygous PLCgamma1 knockout (PLCgamma1(+/-)) mice were pre-treated with either U73122, or its inactive analog U73343, or vehicle for 15 min, followed by LPS for 4 h. Inhibition of PLCgamma1 by U73122 or by heterozygous deletion of the PLCgamma1 gene decreased cardiac TNF-alpha expression. More importantly, LPS-induced myocardial dysfunction was also attenuated in PLCgamma1(+/-) mice or by U73122 treatment.. PLCgamma1 signalling induces cardiac TNF-alpha expression and myocardial dysfunction during LPS stimulation. The action of PLCgamma1 on TNF-alpha expression is mediated through IP3/IP3R pathways. The present results suggest that PLCgamma1 may be a potential therapeutic target for myocardial dysfunction in sepsis.

Topics: Animals; Animals, Newborn; Cardiomyopathies; Cells, Cultured; Diglycerides; Disease Models, Animal; Endotoxemia; Estrenes; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Contraction; Myocytes, Cardiac; Phosphodiesterase Inhibitors; Phospholipase C gamma; Phosphorylation; Pyrrolidinones; RNA Interference; Signal Transduction; Transfection; Tumor Necrosis Factor-alpha

The effects of exogenous phosphatidic acid (PA) on Ca2+ transients and contractile activity were studied in cardiomyocytes isolated from chronic streptozotocin-induced diabetic rats. In control cells, 25 microM PA induced a significant increase in active cell shortening and Ca2+ transients. PA increased IP3 generation in the control cardiomyocytes and its inotropic effects were blocked by a phospholipase C inhibitor. In cardiomyocytes from diabetic rats, PA induced a 25% decrease in active cell shortening and no significant effect on Ca2+ transients. Basal and PA-induced IP3 generation in diabetic rat cardiomyocytes was 3-fold lower as compared to control cells. Sarcolemmal membrane PLC activity was impaired. Insulin treatment of the diabetic animals resulted in a partial recovery of PA responses. Our results, therefore, identify an important defect in the PA-PLC signaling pathway in diabetic rat cardiomyocytes, which may have significant implications for heart dysfunction during diabetes.

Topics: Animals; Calcium; Cardiomyopathies; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Inositol 1,4,5-Trisphosphate; Isoenzymes; Kinetics; Male; Myocardial Contraction; Myocytes, Cardiac; Phosphatidic Acids; Phospholipase C delta; Rats; Rats, Sprague-Dawley; Signal Transduction; Type C Phospholipases

Phospholipase C (PLC) activity is known to influence cardiac function. This study was undertaken to examine the status of PLC beta3 in the cardiac cell plasma membrane (sarcolemma, SL) in an experimental model of chronic diabetes. SL membrane was isolated from diabetic rat hearts at 8 weeks after a single i.v. injection of streptozotocin (65 mg/kg body weight). The total SL PLC was decreased in diabetes and was associated with a decrease in SL PLC beta3 activity, which immunofluorescence in frozen diabetic left ventricular tissue sections revealed to be due to a decrease in PLC beta3 protein abundance. In contrast, the SL abundance of Gqalpha was significantly increased during diabetes. These changes were associated with a loss of contractile function (+/- dP/dt). A 2-week insulin treatment of 6-week diabetic animals partially normalized all of these parameters. These findings suggest a defect in PLC beta3-mediated signaling processes may contribute to the cardiac dysfunction seen during diabetes.

Topics: Animals; Cardiomyopathies; Diabetes Mellitus, Experimental; Diabetic Angiopathies; GTP-Binding Protein alpha Subunits, Gq-G11; Heart Ventricles; Inositol 1,4,5-Trisphosphate; Insulin; Isoenzymes; Male; Myocytes, Cardiac; Phospholipase C beta; Rats; Sarcolemma; Type C Phospholipases

In human ventricular trabeculae carneae 100 microM AP4A (diadenosine tetraphosphate) increased force of contraction to 162.8+/-15.7% of predrug value (n=9). This positive inotropic effect was accompanied by a prolongation of time parameters: time to peak tension and time of relaxation were prolonged by 7.8+/-1.3% and 14.9+/-3.8%, respectively (P<0.05). In the same trabeculae, AP4A increased IP3 (inositol-1,4,5-trisphosphate) content from 9.0+/-1.3 pmol/mg to 22.9+/-5.4 pmol/mg protein (n=5-9). In conclusion, the positive inotropic effect of AP4A in the human myocardium is likely due to an increase of IP3 mediated probably via Gq-coupled P2Y-purinoceptors. Because of the prominent role of Gq in the development of cardiac disease, these findings may lay the ground to further investigate the possible role of AP4A and/or related ligands (e.g. AP2A and AP3A) in heart failure.

Topics: Cardiomyopathies; Dinucleoside Phosphates; Electric Stimulation; Heart Ventricles; Humans; In Vitro Techniques; Inositol 1,4,5-Trisphosphate; Male; Middle Aged; Myocardial Contraction; Time Factors

The molecular basis of human heart failure is unknown. Alterations in calcium homeostasis have been observed in failing human heart muscles. Intracellular calcium-release channels regulate the calcium flux required for muscle contraction. Two forms of intracellular calcium-release channels are expressed in the heart: the ryanodine receptor (RyR) and the inositol 1,4,5-trisphosphate receptor (IP3R). In the present study we showed that these two cardiac intracellular calcium release channels were regulated in opposite directions in failing human hearts. In the left ventricle, RyR mRNA levels were decreased by 31% (P < 0.025) whereas IP3R mRNA levels were increased by 123% (P < 0.005). In situ hybridization localized both RyR and IP3R mRNAs to human cardiac myocytes. The relative amounts of IP3 binding sites increased approximately 40% compared with ryanodine binding sites in the failing heart. RyR down-regulation could contribute to impaired contractility; IP3R up regulation may be a compensatory response providing an alternative pathway for mobilizing intracellular calcium release, possibly contributing to the increased diastolic tone associated with heart failure and the hypertrophic response of failing myocardium.

Topics: Adolescent; Adult; Blotting, Northern; Calcium Channels; Cardiomyopathies; Cells, Cultured; DNA Probes; Female; Gene Expression; Heart Failure; Heart Transplantation; Homeostasis; Humans; In Situ Hybridization; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Male; Middle Aged; Muscle Proteins; Myocardium; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Ryanodine; Ryanodine Receptor Calcium Release Channel