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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incidence of ventricular arrhythmias is higher in failing hearts than in control hearts, especially during acute ischemia. Electrophysiological and extracellular ionic changes during acute ischemia in normal and failing rabbit myocardium were assessed. Heart failure was induced in rabbits by combined volume and pressure overload. In perfused papillary muscles, the onset of electrical uncoupling and changes in action potential duration and conduction velocity during acute ischemia were determined. In Langendorff-perfused rabbit hearts the changes in extracellular potassium concentration ([K+]o) and pH during acute global ischemia were studied. In perfused papillary muscles, during the first 10 min of ischemia, action potential duration at 80% of repolarization decreased more in preparations from failing than from control hearts (from 174 to 104 ms and from 156 to 119 ms respectively (P < 0.001)). Conduction velocity was significantly lower in failing hearts during ischemia (P < 0.005). The onset of electrical uncoupling was similar in failing and control hearts (mean +/- S.E.M., 17 +/- 1 and 15 +/- 1 min respectively, n.s.). Langendorff-perfused hearts [K+]o, after 10 min of ischemia, was 11.0 +/- 0.4 mM in failing and 9.5 +/- 0.3 mM in control hearts (P < 0.01), while the change in pH was the same. After pretreatment with glibenclamide, an ATP sensitive K+ channel blocker, [K+]o reached lower values after 10 min of ischemia in both failing (8.8 +/- 0.5 mM) and control hearts (7.2 +/- 0.4 mM). During ischemia, action potential duration shortening is more pronounced and conduction velocity is lower in failing myocardium than in control myocardium. [K+]o reaches higher values during acute ischemia in failing compared with normal myocardium. These changes are not caused by an earlier activation of IK.ATP. Increased spatial dispersion in electrophysiological parameters and [K+]o over the ischemic border in failing hearts may explain the higher propensity for reentrant arrhythmias during acute regional ischemia in failing hearts.
J Mol Cell Cardiol 1996 Jan
PMID:Electrophysiologic and extracellular ionic changes during acute ischemia in failing and normal rabbit myocardium. 874 20

Recently, a significant activity of inducible nitric oxide synthase (iNOS) has been reported in biopsies from failing hearts due to idiopathic dilated cardiomyopathy (IDC). Thus, a potential pathophysiological role of iNOS in IDC has been stated. In order to investigate, whether iNOS expression is of pathophysiological relevance in human heart failure, we measured iNOS protein expression and cGMP content in left ventricular myocardium from non-failing and failing human hearts. Immunoblot analysis revealed iNOS protein expression in four out of six failing hearts from septic patients, whereas no iNOS-protein expression was detected in either non-failing human hearts (n = 6) or failing hearts due to IDC (n = 9), ischemic heart disease (IHD, n = 7), Becker muscular dystrophy (BMD, n = 2) and mitoxantrone-induced toxic cardiomyopathy TCM, n = 1). cGMP content was increased by 130% in septic hearts, whereas there was no cGMP increase in hearts with IDC. IHD and BMD compared to non-failing hearts. We conclude, that the induction of iNOS may play a role in contractile dysfunction observed in septic shock, but is unlikely to be of major pathophysiological importance in end-stage heart failure due to IDC, IHD, BMD and TCM.
J Mol Cell Cardiol 1996 Jan
PMID:Expression of inducible nitric oxide synthase in failing and non-failing human heart. 874 24

Recent studies have implicated angiotensin II (angiotensin) in the pathogenesis of cardiac hypertrophy and heart failure. Heart failure is associated with alterations in intracellular Ca2+ movements mediated by sarcolemmal (SL) and sarcoplasmic reticular (SR) membranes in cardiac myocytes. As it was suspected that alteration gene expression of proteins responsible for controlling transmembrane Ca2+ fluxes may contribute to loss of Ca2+ homeostasis in failing hearts, we undertook a study of the effect of angiotensin on the expression of some target genes in the myocardium. Specifically, we tested the effect of angiotensin on mRNA abundance of cardiac Ca(2+)-transport genes including SL Na+/Ca2+ exchange (EX), SR ryanodine receptor (RYR), and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA). The mRNA abundance of target gene was assessed by Northern blot assay in (i) direct hormonal stimulation of cultured isolated neonatal and adult rat myocytes and (ii) adult rat hearts after implantation of osmotic mini-pumps for delivery of hormone. In all experiments, Northern blot data were normalized using cDNA (Glyceraldehyde 3-phosphate dehydrogenase signal, GAPDH) hybridization to RNA samples. The results indicate that the ratios of EX/GAPDH, RYR/GAPDH, and SERCA2/GAPDH signals were decreased by 51.6%, 55.0%, and 49.4% respectively after neonatal cardiac myocytes were treated (24 h) with 10(-7) M angiotensin. These decreases were blocked completely by treatment with angiotensin subtype 1 (AT1) receptor antagonist (losartan), whereas angiotensin subtype 2 (AT2) receptor antagonist (PD123319) treatment had no effect on the angiotensin-mediated decrease in target gene mRNA abundance. In contrast, angiotensin had no effect on EX, RYR nor SERCA2 gene mRNA abundance in cultured adult myocytes. In a separate series of experiments wherein adult male Sprague-Dawley rats were infused with different dose of angiotensin for 3 days via osmotic mini-pump, we did not detect any alterations in mRNA abundance of cardiac EX/GAPDH, RYR/GAPDH or SERCA/GAPDH genes in either left or right ventricular samples. Thus our results indicate that, in neonatal rat myocytes, angiotensin affects SL and SR calcium transport gene expression by direct agonism of AT1-receptors. As the infusion of low and high dose angiotensin did not affect the expression of target genes in adult hearts, we suggest that the mechanisms for transduction of the angiotensin signaling in neonatal and adult myocytes may be different and may depend on the stage of development. We conclude that regulation of myocardial Ca(2+)-transport gene mRNA abundance by angiotensin may differ among neonatal and adult animals. Nonetheless, our finding with respect to neonatal preparation led us to believe that in neonatal myocytes, the mRNA abundance of SL Na+/Ca2+ exchange, SR ryanodine receptor, and SR Ca(2+)-ATPase are all decreased in response to stimulation by angiotensin.
J Mol Cell Cardiol 1996 May
PMID:Altered mRNA abundance of calcium transport genes in cardiac myocytes induced by angiotensin II. 876 48

The actions of angiotensin II in the cardiovascular system are transmitted by two known and possibly some unknown angiotensin receptor types. AT1 and AT2 both correspond to G-protein-coupled receptors with seven hydrophobic transmembrane domains, several N-glycosylation sites and a potential G-protein binding site. Cloning of coding regions and promoter sequences contributed to the understanding of receptor protein function and regulation. Angiotensin receptors with atypical binding properties for the known AT1- and AT2-specific ligands are expressed on human cardiac fibroblasts and in the human ulcrus. In several animal models, receptors with high affinity for angiotensin (1-7) have been described. AT1 stimulation is mediated by the generation of phospholipid-derived second messengers, activation of protein kinase C, the MAPkinase pathway and of immediate early genes. Recently, phosphorylation and dephosphorylation of tyrosine kinases have been associated with AT1- and AT2-mediated signal transduction. ATR are regulated by phosphorylation, internalization, modification of transcription rate and mRNA stability. Regulation is highly cell and organ specific and includes upregulation of ATR in some pathophysiological situations where the renin angiotensin system is activated. Whereas the function of AT1 in the cardiovascular system is relatively well established, there is little information regarding the role of AT2. Recent hypotheses suggest an antagonism between AT1 and AT2 at the signal transduction and the functional level. Transgenic animal models, particularly with targeted disruption of the AT1 and AT2 genes, suggest the contribution of both genes to blood pressure regulation. Genetic polymorphisms have been described in the AT1 and AT2 gene or neighbored regions and are used to analyze the association between gene defects and cardiovascular diseases. AT1 antagonists are now being introduced into the treatment of hypertension and potentially heart failure, and more interesting pharmacological developments are expected from the ongoing basic studies.
J Mol Med (Berl) 1996 May
PMID:Molecular biology of angiotensin receptors and their role in human cardiovascular disease. 877 61

The regulatory myosin light chain (MLC) is phosphorylated in cardiac muscle by Ca2+/calmodulin dependent myosin light chain kinase (MLCK) and is considered to play a modulatory role in the process of force generation. In order to determine changes in MLC phosphorylation in cardiac hypertrophy and heart failure, the relative content of MLCK and MLC phosphorylation in the cardiac muscle from both sham control and experimental rats were assessed at 4 and 8 weeks following ligation of the left coronary artery. Changes in the relative MLCK content were measured by electrophoresis and immunoblot assay whereas phosphorylated and unphosphorylated MLC were separated by non-denaturing 10% acrylamide/urea gel and identified by Western blotting. The relative amount of MLCK was increased by 20-35% in the viable left ventricle, right ventricle and septum from the 8-week experimental rats in comparison to the respective control values. The MLC phosphorylation increased significantly in the right ventricle and septum but decreased markedly in the viable left ventricle from 8-week experimental rats in comparison to the control values. No appreciable changes in the relative amount of MLCK and MLC phosphorylation were seen between control and experimental rats at 4 weeks. These results suggest duration and region specific changes in the levels of MLCK and MLC phosphorylation in cardiac hypertrophy and heart failure subsequent to myocardial infarction.
J Mol Cell Cardiol 1995 Dec
PMID:Myosin light chain phosphorylation in cardiac hypertrophy and failure due to myocardial infarction. 882 82

Abnormalities in intracellular Ca2+ handling play a crucial role in the pathogenesis of heart failure. The reduced capacity of failing human myocardium to restore low resting Ca2+ levels during diastole has been explained by the impairment of Ca2+ uptake into the sarcoplasmic reticulum (SR) via the SR Ca2+ATPase. It is unclear whether Ca2+ATPase function, protein levels, and mRNA steady-state levels correspond to one other, and whether the cause of heart failure, namely idiopathic dilated or ischemic cardiomyopathy, produces different changes. The present study examined SR Ca2+ATPase activity and both mRNA and protein levels of SR Ca2+ATPase, phospholamban, and Gi alpha 2 in left ventricular myocardium from eight nonfailing hearts, from eight hearts of patients with idiopathic dilated cardiomyopathy (DCM), and from six hearts from patients with ischemic cardiomyopathy (ICM). Compared to nonfailing myocardium, the activity of the SR Ca2+ATPase was significantly reduced in failing myocardium from patients with DCM (36%, P < 0.01) and from patients with ICM (37%, P < 0.001). Significantly lower levels of SR Ca2+ATPase mRNA levels (55% and -56%, P < 0.001 for DCM and ICM, respectively) and phospholamban mRNA (45%, P < 0.001 for DCM; 31%, P < 0.05 for ICM) were observed in failing than in nonfailing myocardium. In contrast, no significant changes were observed at the level of proteins, Gi alpha 2 mRNA and protein levels were both significantly increased in failing myocardium. There were no differences between idiopathic dilated and ischemic cardiomyopathy concerning the examined parameter. It is concluded that reduced SR Ca2+ATPase activity contributes to an altered intracellular Ca2+ handling by the SR in both dilated and ischemic cardiomyopathic hearts. However, changes in SR Ca2+ATPase and phospholamban steady-state protein levels do not contribute to these alterations. The dissociation between protein and mRNA levels provides evidence for a posttranscriptional or post-translational regulation of these proteins. The observed alterations are not dependent on the underlying cause of end-stage heart failure.
J Mol Med (Berl) 1996 Jun
PMID:Sarcoplasmic reticulum Ca2+ATPase and phospholamban mRNA and protein levels in end-stage heart failure due to ischemic or dilated cardiomyopathy. 886 13

In this review, a rationale is presented for how hypercholesterolemia, hypertension, diabetes mellitus, end-stage renal disease, renal dialysis, and prolonged stress can all lead to atherosclerosis, ischemic heart disease, and stroke. The data indicate that Mg deficiency caused either by poor diet and/or errors in Mg metabolism may be a missing link between diverse cardiovascular risk factors and atherosclerosis. Data from our laboratories and others indicate that reduction in extracellular and intracellular free Mg ions (Mg2+) can induce an entire array of pathophysiological phenomena known to be important in atherogenesis, that is, vasospasm, increased vascular reactivity, elevation in [Ca2+]i, formation of proinflammatory agents, oxygen radicals, platelet aggegation, reduction in cardiac bioenergetics, cardiac failure, oxidation of lipoproteins, gender-related modulation of endothelial-derived relaxing factor/NO, changes in membrane fatty acid saturation, changes in membrane plasmalogens and N-phospholipids (suggesting changes in intracellular phospholipid signals), and probably transcription factors.
Cell Mol Biol Res 1995
PMID:Magnesium and cardiovascular biology: an important link between cardiovascular risk factors and atherogenesis. 886 81

The number of atrial angiotensin II binding sites is reduced in end-stage human heart failure. The goals of our study were the development of a quantitative polymerase chain reaction for angiotensin II receptor type 1 mRNA to determine the angiotensin receptor type 1 (AT1) mRNA content in the atria of patients with end-stage heart failure. We established a quantitative PCR based on coamplification of AT1 wild-type and an internal standard in the same PCR, followed by liquid-phase hybridization of PCR products in microtiter plates and quantitation by ELISA. Glyceraldehyde phosphate dehydrogenase mRNA in the same samples was used to relate the AT1 mRNA content to a stably expressed reference gene. Atrial samples from 11 patients with end-stage heart failure obtained at cardiac transplantation were compared with atrial samples from 11 patients with normal cardiac function undergoing routine cardiac surgery. A PCR/ELISA system with a variance of about 6% after reverse transcription and a linear measuring range was established. In the samples from 11 patients with end-stage heart failure a 58% decrease in AT1 mRNA content was found in comparison with 11 controls (heart failure: 185,680 +/- 196,912 AT1 mRNA copies/microgram RNA, controls: 440,555 +/- 268,456, P < 0.02). When AT1 mRNA content was related to glyceraldehyde phosphate dehydrogenase mRNA, a 65% decrease was detected (AT1/glyceraldehyde phosphate dehydrogenase: heart failure: 4.84 +/- 5.18; controls: 13.74 +/- 7.77; P < 0.005). Standardization of PCR resulting in a low coefficient of variance, high reproducibility, and large sample capacity is possible using optimal internal standardization and the liquid-phase hybridization/ELISA system for detection. The optimized PCR procedure indicated downregulation of atrial AT1 in end-stage human heart failure, suggesting a reduced capacity of the atria to respond to angiotensin II stimulation in end-stage heart failure.
J Mol Med (Berl) 1996 Aug
PMID:Reduced atrial angiotensin receptor type 1 mRNA content in end-stage human heart failure: assessment by a novel quantitative PCR-ELISA technique. 887 58

Congestive heart failure is often associated with skeletal muscle abnormalities that contribute to early fatigue and acidosis. Up to the present time, however, the mechanisms responsible for these changes are unclear. Myocardial infarctions were produced by coronary ligation in adult Sprague-Dawley rats. At 20 weeks, 10 control rats, and 15 animals with heart failure [defined by elevated LVEDP (26.1 +/- 3.1 v 2.5 +/- 0.5 mmHg) and RV hypertrophy (300 +/- 21 g v 158 +/- 9 mg)] underwent in vivo measurements of total body, and soleus total protein and myosin heavy chain (MHC) synthesis by [3H]leucine constant infusion. Soleus muscle was also analysed for protein content, and MHC isoenzyme content by SDS-PAGE. Northern blotting also was used to determine levels of the mRNA's encoding type I, IIa, IIb, and IIx MHC, alpha-skeletal actin, COX III, SDH and GAPDH. Soleus muscles in heart failure rats were smaller than controls (112 +/- 6 v 126 +/- 5 mg) and the degree of atrophy was significant when corrected for body mass (0.38 +/- 0.02 v 0.46 +/- 0.02 mg/g. P = 0.007). Although there was no significant difference in plasma leucine flux (an index of whole-body protein synthesis), soleus muscle total and MHC synthesis was reduced in heart failure animals. Whereas the Type I MHC isoenzyme (beta MHC) was the only MHC detected in the soleus of control animals, type II MHC isoenzyme comprised 11.8 +/- 3.1% of the MHC in the heart failure group. Furthermore, steady-state mRNA levels encoding beta MHC were significantly depressed in the heart failure rats, where those encoding Types IIb and IIx MHC were increased. Steady-state mRNA levels of alpha-skeletal actin, cytochrome C oxidase (COX III) and succinate dehydrogenase (SDH) were also significantly depressed. This animal model of chronic heart failure is associated with quantitative and qualitative alterations in skeletal muscle gene expression that are similar to those reported in skeletal muscle of patients with chronic heart failure. The altered phenotype and impaired metabolic capacity may contribute to exercise intolerance in CHF.
J Mol Cell Cardiol 1996 Aug
PMID:Alterations in skeletal muscle gene expression in the rat with chronic congestive heart failure. 887 78

Heart failure is a problem of increasing importance in cardiovascular medicine. An important characteristic of heart failure is reduced agonist-stimulated adenylyl cyclase activity (receptor desensitization) due to both diminished receptor number (receptor downregulation) and impaired receptor function (receptor uncoupling). These changes in the section-adrenergic receptor (section-AR) system may in part account for some of the abnormalities of contractile function in this disease. Myocardial contraction is closely regulated by G protein coupled beta-adrenergic receptors through the action of the second messenger cAMP. The beta-adrenergic receptors themselves are regulated by a set of specific kinases, termed the G-protein-coupled receptor kinases. The study of this complex system in vivo has recently been advanced by the development of transgenic and gene targeted ("knockout") mouse models. Combining transgenic technology with sophisticated physiological measurements of cardiac hemodynamics is an extremely powerful strategy to study the regulation of myocardial contractility in the normal and failing heart.
J Mol Med (Berl) 1996 Sep
PMID:Myocardial beta-adrenergic receptor signaling in vivo: insights from transgenic mice. 889 53


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