Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The report is a discussion of previously published and newly analyzed results concerning the association between heart diseases and alterations in the force-frequency relation (FFR). The optimum stimulation frequency of the FFR is measured and compared in isolated left ventricular myocardium from non-failing hearts with atrial septal defect, coronary artery disease (without and with insulin dependent diabetes mellitus) and from failing hearts with mitral regurgitation, or idiopathic dilated cardiomyopathy. Specifically, we examine the role of altered control of the excitation-contraction coupling system in blunting the force-frequency relation. We use the percent slope of the FFR as a measure of changes in the frequency sensitivity of this control. Our finding of a linear, direct relation between optimum stimulation frequency and % slope across all disease types suggests both parameters are coupled to the same underlying mechanism. To investigate the possible role of altered control of the calcium pump in this mechanism, we analyzed the detailed relation between isometric twitch relaxation kinetics and stimulation frequency in mitral regurgitation myocardium (MR). In the presence of 0.5 microM forskolin the depressed slope and optimum frequency of the FFR and the prolonged half-time of twitch relaxation were all restored to values found in non-failing myocardium. We use the kinetics of isometric twitch relaxation as an index of changes in pumping rate that occur in response to changes in stimulation frequency or in intracellular cyclic adenosine monophosphate concentration. A mathematical model based on the Hill relations for calcium pump uptake rate and for isometric tension as a function of intracellular pCa is developed to simulate isometric twitch relaxation in MR and non-failing myocardium. The success of this model in simulating non-failing and failing twitch relaxation supports a proposed mechanism for the prolonged relaxation time and depressed FFR in MR involving depressed protein kinase-A activity (due to lowered cAMP or to a defect in the Ser16 site of phospholamban) as a mechanism of altered control of the calcium pump in MR heart disease.
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PMID:Role of cAMP in modulating relaxation kinetics and the force-frequency relation in mitral regurgitation heart failure. 920 49

We have used molecular dynamics simulations to investigate the effect of phosphorylation and mutation on the cytoplasmic domain of phospholamban (PLB), a 52-residue protein that regulates the calcium pump in cardiac muscle. Simulations were carried out in explicit water systems at 300 K for three peptides spanning the first 25 residues of PLB: wild-type (PLB(1-25)), PLB(1-25) phosphorylated at Ser16 and PLB(1-25) with the R9C mutation, which is known to cause human heart disease. The unphosphorylated peptide maintains a helical conformation from 3 to 15 throughout a 26-ns simulation, in agreement with spectroscopic data. Comparison with simulations of a fourth peptide truncated at Pro21 showed the importance of the region from 17 to 21 in preventing local unfolding of the helix. The results suggest that residues 11-16 are more likely to unfold when specific capping motifs are not present. It is proposed that protein kinase A exploits the intrinsic flexibility of the 11-21 region when binding PLB. In agreement with available CD and NMR data, the simulations show a decrease in the helical content upon phosphorylation. The phosphorylated peptide is characterized by helix spanning residues 3-11, followed by a turn that optimizes the salt-bridge interaction between the side chains of the phosphorylated Ser-16 and Arg-13. Replacing Arg-9 with Cys results in unfolding of the helix from C9 and an overall decrease of the helical conformation. The simulations show that initiation of unfolding is due to increased solvent accessibility of the backbone atoms near the smaller Cys. It is proposed that the loss of inhibitory potency upon Ser-16 phosphorylation or R9C mutation of PLB is due to a similar mechanism, in which the partial unfolding of the cytoplasmic helix of PLB results in a conformation that interacts with the cytoplasmic domain of the calcium pump to relieve its inhibition.
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PMID:The alpha-helical propensity of the cytoplasmic domain of phospholamban: a molecular dynamics simulation of the effect of phosphorylation and mutation. 1576 55

There is an increased incidence of heart disease in patients with chronic nephrotic syndrome (NS), which may be attributable to the malnutrition and activated inflammatory state accompanying the sustained proteinuria. In this study, we evaluated renal function, cardiac morphometry, contractile function, and myocardial gene expression in the established puromycin aminonucleoside nephrosis rat model of NS. Two weeks after aminonucleoside injection, there was massive proteinuria, decreased creatinine clearance, and a negative sodium balance. Skeletal and cardiac muscle atrophy was present and was accompanied by impaired left ventricular (LV) hemodynamic function along with decreased contractile properties of isolated LV muscle strips. The expression of selected cytokines and proteins involved in calcium handling in myocardial tissue was evaluated by real time polymerase chain reaction. This revealed that the expression of interleukin-1beta, tumor necrosis factor-alpha, and phospholamban were elevated, whereas that of cardiac sarco(endo)plasmic reticulum calcium pump protein was decreased. We suggest that protein wasting and systemic inflammatory activation during NS contribute to cardiac remodeling and dysfunction.
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PMID:Cardiac remodeling and dysfunction in nephrotic syndrome. 1745 79

Although pharmacologic therapies have provided gains in reducing the mortality of heart failure, the rising incidence of the disease requires new approaches to combat its health burden. Twenty-five years ago, abnormal calcium cycling was identified as a characteristic of failing human myocardium. Sarcoplasmic reticulum calcium ATPase (SERCA2a), the sarcoplasmic reticulum calcium pump, was found to be a key factor in the alteration of calcium cycling. With the advancement of gene vectors, SERCA2a emerged as an attractive clinical target for gene delivery purposes. Using adeno-associated virus constructs, SERCA2a upregulation has been found to improve myocardial function in animal models. The clinical benefits of overexpressing SERCA2a have been demonstrated in the phase I study Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID). This study has demonstrated that a persistent expression of the transgene SERCA2a is associated with a significant improvement in associated biochemical alterations and clinical symptoms of heart failure. In the coming years, additional targets will likely emerge that are amenable to genetic manipulations along with the development of more advanced vector systems with safer delivery approaches.
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PMID:Targeting sarcoplasmic reticulum calcium ATPase by gene therapy. 2416 41