Multiple pathways are responsible for transducing mechanical and hormonal stimuli into changes in gene expression during heart failure. In this study our goals were (i) to develop a sound statistical method to establish a comprehensive cutoff point for identification of differentially expressed genes, (ii) to identify a gene expression fingerprint for heart failure, (iii) to attempt to distinguish different etiologies of heart failure by their gene expression fingerprint, and (iv) to identify gene clusters that show coordinated up-or downregulation in human heart failure. We used oligonucleotide microarrays to profile seven nonfailing (NF) and eight failing (F) human hearts with a diagnosis of end-stage dilated cardiomyopathy. Biological and experimental variability of the hybridization data were analyzed, and then a statistical analysis procedure was developed, including Student's t test after log-transformation and Wilcoxon Mann-Whitney test. A comprehensive cutoff point composed of fold change, average difference, and absolute call was then established and validated by TaqMan PCR. Of 6,606 genes on the GeneChip, 103 genes in 10 functional groups were differentially expressed between F and NF hearts. A dendrogram identified a gene expression fingerprint of F and NF hearts and also distinguished two F hearts with distinct etiologies (familial and alcoholic cardiomyopathy, respectively) with different expression patterns. K means clustering also revealed two potentially novel pathways associated with up-regulation of atrial natriuretic factor and brain natriuretic peptide and with increased expression of extracellular matrix proteins. Gene expression fingerprints may be useful indicators of heart failure etiologies.
Inositol 1,4,5-trisphosphate (InsP3) caused Ca release and tension development in rabbit main pulmonary artery smooth muscle permeabilized with saponin or digitonin. Both of these responses to single additions of uM) were repeatable and occurred in the presence of 0.0-1.9 mM free Mg +. Sustained contractions were induced by InsP3. The amount of Ca released by InsP3, measured with a Ca21-selective electrode, was also estimated to be sufficient to stimulate contraction in intact smooth muscle. Ca release was not influenced by inhibitors of mitochondrial oxidative phosphorylation. The uptake of Ca21 from the medium into the InsP3-sensitive pool was ATP-dependent. The present results support the hypothesis that, in smooth muscle, InsP3 is the messenger, or one of the messengers, involved in transmitterinduced (pharmacomechanical) Ca release from the sarcoplasmic reticulum, which is the intracellular Ca store identified previously as the source of Ca released by norepinephrine in main pulmonary artery.Activation of smooth muscle by transmitters and drugs involves, at least in part, the release of intracellular Ca (1-3), followed by Ca activation ofthe calmodulin-regulated myosin light chain kinase (4). The release of intracellular Ca does not require influx of extracellular Ca (5-7) and can be triggered by pharmacomechanical coupling, a process independent of changes in surface membrane potential (8). Recent electron probe analytic studies have directly demonstrated that the sarcoplasmic reticulum (SR) is the source of intracellular Ca released by norepinephrine in rabbit main pulmonary artery (MPA) (1), portal vein (7), and, probably, other smooth muscles. However, until very recently, the mechanism through which drugs and transmitters released Ca from the SR remained unknown.The recognition, in nonmuscle cells, that stimulation of phosphatidylinositol turnover, stimulated by cholinergic agents and other secretogogues (9, 10), is associated with the production of a metabolite, inositol 1,4,5-trisphosphate (Ins-P3), that can release Ca from the endoplasmic reticulum (11, 12) indicated that InsP3 may also function as an excitatory messenger in smooth muscle. In this study, we demonstrate that InsP3 can, indeed, release Ca from smooth muscle cells of the rabbit MPA, as indicated by Ca2+-selective electrode measurements and by InsP3-induced contraction of vascular strips permeabilized with saponin or digitonin. The quantity of Ca2' released by InsP3, like that released from the SR by norepinephrine in this tissue (1), is sufficient for the activation of contraction. These and other recent studies of phosphatidylinositol turnover (including its stimulation by norepinephrine) and of the effects of InsP3 in smooth muscle (13)(14)(15)(16)(17) provide further evidence for the possibility that InsP3 is a physiological messenger mediating agonist-induced Ca release in smooth muscle. MATERIALS AND METHODSTissue Preparation. Male New Zealand rabbits (1-2 kg of body weight) were killed by a blow on the back of the head...
In the present study, we developed transgenic mice overexpressing the N-terminal truncated cTnI (cTnI-ND) in the heart to examine its biochemical and physiological significance. Ca 2؉ -activated actomyosin ATPase activity showed that cTnI-ND myofibrils had lower affinity for Ca 2؉ than controls, similar to the effect of isoproterenol treatment. In vivo and isolated working heart experiments revealed that cTnI-ND hearts had a significantly faster rate of relaxation and lower left ventricular end diastolic pressure compared with controls. The higher baseline relaxation rate of cTnI-ND hearts was at a level similar to that of wild type mouse hearts under -adrenergic stimulation. The decrease in cardiac output due to lowered preload was significantly smaller for cTnI-ND hearts compared with controls. These findings indicate that removal of the N-terminal extension of cTnI via restricted proteolysis enhances cardiac function by increasing the rate of myocardial relaxation and lowering left ventricular end diastolic pressure to facilitate ventricular filling, thus resulting in better utilization of the Frank-Starling mechanism.
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