Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that ANG II increases microvascular permeability in normal dog lungs but not after pacing-induced heart failure. This study investigated how ANG II induces permeability in isolated blood-perfused canine lung lobes and what alterations occur during heart failure. In normal lobes, the protein kinase C (PKC) inhibitors staurosporine (500 nM) or chelerythrine (10 microM) did not modify ANG II-induced increases in the capillary filtration coefficient (Kf,c, ml . min-1 . cmH2O-1 . 100 g-1; an index of microvascular permeability), suggesting that PKC is not involved. Thapsigargin (150 nM) was used to stimulate capacitative Ca2+ entry in lobes from control dogs and dogs paced at 245 beats/min for 4 wk to induce heart failure. In control lobes, Kf,c rose after thapsigargin, from 0.06 +/- 0.01 to 0.17 +/- 0.03 ml . min-1 . cmH2O-1 . 100 g-1 (mean +/- SE, P < 0.05) but did not change in the paced group. A Ca2+ ionophore, A-23187, increased Kf,c in both control (10 microM; 0.05 +/- 0.01 to 0.17 +/- 0.05 ml . min-1 . cmH2O-1 . 100 g-1, P < 0.05) and pace (5 microM; 0.06 +/- 0.01 to 0. 21 +/- 0.07 ml . min-1 . cmH2O-1 . 100 g-1, P < 0.05) lobes, indicating that increasing intracellular Ca2+ is sufficient to induce pulmonary microvascular permeability after pacing. We conclude that during heart failure, Ca2+ signaling within the pulmonary microvascular endothelium is altered.
 ...
PMID:Ablation of lung endothelial injury after pacing-induced heart failure is related to alterations in Ca2+ signaling. 972 88

Diabetes mellitus is one of the diseases with the greatest risk of developing coronary disease (CD), with the estimation of this risk in relation to the general population being from 2 to 4-fold greater. The existence of diabetes worsens the prognosis of CD and thus, postinfarction mortality in these patients is double that observed in non-diabetic patients. Together with the risk factors found in the general population, those of special interest are those derived from diabetes itself, such as hyperglycemia, dyslipemia, coagulation disorders and hyperinsulinemia or insulin resistance. Among these, the most important is probably the hyperglycemia which may contribute to the appearance of CD by different mechanisms such as proteic glycosylation, accumulation of sorbitol, increase in the synthesis of protein kinase C or oxidative stress. It must not be forgotten that an old controversy has recently been brought up suggesting that sulphonylureas may have a certain cardiotoxic effect, probably acting on the potassium channels dependent on ATP. Acute myocardial infarction in diabetic patients carries a greater risk of congestive heart failure, recurrent infarction, arrhythmia and cardiogenic shock, with one of its characteristics being the possibility of being silent when autonomic neuropathy is present. The prognosis of CD may be markedly improved by obtaining optimum glycemic control during the hours following infarction using intensified treatment. Diabetic myocardiopathy as a differentiated nosology responsible for alterations in myocardial contractile function and greater prevalence of heart failure in these patients seems to be clearly demonstrated although its etiology remains unknown.
 ...
PMID:[Heart pathology of extracardiac origin. XI. Cardiac repercussions of diabetes mellitus]. 978 Jul 81

Endothelins (ETs) are 21-amino-acid peptides produced in many cells and tissues. The vascular ET system is represented mainly by ET-1 produced in endothelial cells. PreproET-1 gene expression is regulated by transactivating signals dependent on cooperative interaction of GATA-2 and AP-1 sites. ProET-1 is acted on by a furin-like enzyme to generate big ET-1, a 38-39-amino-acid peptide, which is converted to the mature 21-amino-acid peptide ET-1 by ET-converting enzyme (ECE) in endothelial cells, both intracellularly and on the cell membrane, and on the surface of underlying smooth muscle cells. The mature peptide ET-1 acts in a paracrine manner on smooth muscle cell ET(A) and ET(B) receptors to induce contraction and growth, and in an autocrine or paracrine manner on endothelial cells to induce production of the vasorelaxant and growth-inhibitory agents nitric oxide (NO) and prostacyclin. ET receptors are G-protein-coupled, resulting in activation of phospholipase C and generation of two second messengers, inositol triphosphate and diacylglycerol, which respectively stimulate calcium release and protein kinase C activation. Phospholipase D activation with generation of diacylglycerol, phospholipase A2 stimulation with release of arachidonic acid, activation of the Na+/H+ exchanger, and activation of tyrosine kinases and MAP kinases, are other pathways that contribute to contraction and growth induced by ET receptor stimulation. ET receptors may be downregulated by ET, especially under conditions in which large amounts of ET are being produced in the vasculature. This has been demonstrated in some models of experimental hypertension and in some forms of human hypertension. Some of the effects of angiotensin II, particularly growth of the smooth muscle media of blood vessels, have been shown under some conditions to be mediated by ET-1 via ET(A) receptors. Many ET-induced effects on smooth muscle cells can be blocked by ET(A)-selective ET antagonists, which makes possible an identification of the physiologic and pathophysiologic roles of the ET system in cardiovascular diseases such as hypertension, heart failure, atherosclerosis, coronary heart disease, restenosis after angioplasty, primary pulmonary hypertension, and other pathologic conditions.
 ...
PMID:Vascular biology of endothelin. 988 41

We tested the hypothesis that activation of protein kinase C (PKC) isoforms in pressure-overload heart failure was prevented by angiotensin-converting enzyme (ACE) inhibition, resulting in normalization of cardiac sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA) 2a and phospholamban protein levels and improvement in intracellular Ca2+ handling. Aortic-banded and control guinea pigs were given ramipril (5 mg. kg-1. day-1) or placebo for 8 wk. Ramipril-treated banded animals had lower left ventricular (LV) and lung weight, improved survival, increased isovolumic LV mechanics, and improved cardiomyocyte Ca2+ transients compared with placebo-treated banded animals. This was associated with maintenance of SERCA2a and phospholamban protein expression. Translocation of PKC-alpha and -epsilon was increased in placebo-treated banded guinea pigs compared with controls and was attenuated significantly by treatment with ramipril. We conclude that ACE inhibition attenuates PKC translocation and prevents downregulation of Ca2+ cycling protein expression in pressure-overload hypertrophy. This represents a mechanism for the beneficial effects of this therapy on LV function and survival in heart failure.
 ...
PMID:Effect of angiotensin-converting enzyme inhibition on protein kinase C and SR proteins in heart failure. 988 17

Currently at least 11 protein kinase C (PKC) isoforms have been identified and may play different roles in cell signaling pathways leading to changes in cardiac contractility, the hypertrophic response, and tolerance to myocardial ischemia. The purpose of the present study was to test the hypothesis that responses of individual PKC isoforms to distinct pathological stimuli were differentially regulated in the adult guinea pig heart. Isolated hearts were perfused by the Langendorff method and were exposed to ischemia, hypoxia, H(2)O(2), or angiotensin II. Hypoxia and ischemia induced translocation of PKC isoforms alpha, beta(2), gamma, and zeta, and H(2)O(2) translocated PKC isoforms alpha, beta(2), and zeta. Angiotensin II produced translocation of alpha, beta(2), epsilon, gamma, and zeta isoforms. Inhibition of phospholipase C with tricyclodecan-9-yl-xanthogenate (D609) blocked hypoxia-induced (alpha, beta(2), and zeta) and angiotensin II-induced (alpha, beta(2), gamma, and zeta) translocation of PKC isoforms. Inhibition of tyrosine kinase with genistein blocked translocation of PKC isoforms by hypoxia (beta(2) and zeta) and by angiotensin II (beta(2)). By contrast, neither D609 nor genistein blocked H(2)O(2)-induced translocation of any PKC isoform. We conclude that hypoxia-induced activation of PKC isoforms is mediated through pathways involving phospholipase C and tyrosine kinase, but oxidative stress may activate PKC isoforms independently of Galphaq-phospholipase C coupling and tyrosine kinase signaling. Because oxidative stress may directly activate PKC, and PKC activation appears to be involved in human heart failure, selective inhibition of the PKC isoforms may provide a novel therapeutic strategy for the prevention and treatment of this pathological process.
 ...
PMID:Responses of cardiac protein kinase C isoforms to distinct pathological stimuli are differentially regulated. 1043 69

Biological and mechanical stressors such as ischemia, hypoxia, cellular ATP depletion, Ca2+ overload, free radicals, pressure and volume overload, catecholamines, cytokines, and renin-angiotensin may independently cause reversible and/or irreversible cardiac dysfunction. As a defense against these forms of stress, several endogenous self-protective mechanisms are exerted to avoid cellular injury. Adenosine, a degradative substance of ATP, may act as an endogenous cardioprotective substance in pathophysiological conditions of the heart, such as myocardial ischemia and chronic heart failure. For example, when brief periods of myocardial ischemia precede sustained ischemia, infarct size is markedly limited, a phenomenon known as ischemic preconditioning. We found that ischemic preconditioning activates the enzyme responsible for adenosine release, ie, ecto-5'-nucleotidase. Furthermore, the inhibitor of ecto-5'-nucleotidase reduced the infarct size-limiting effect of ischemic preconditioning, which establishes the cause-effect relationship between activation of ecto-5'-nucleotidase and the infarct size-limiting effect. We also found that protein kinase C is responsible for the activation of ecto-5'-nucleotidase. Protein kinase C phosphorylated the serine and threonine residues of ecto-5'-nucleotidase. Therefore, we suggest that adenosine produced via ecto-5'-nucleotidase gives cardioprotection against ischemia and reperfusion injury. Also, we found that plasma adenosine levels are increased in patients with chronic heart failure. Ecto-5'-nucleotidase activity increased in the blood and the myocardium in patients with chronic heart failure, which may explain the increases in adenosine levels in the plasma and the myocardium. In addition, we found that further elevation of plasma adenosine levels due to either dipyridamole or dilazep reduces the severity of chronic heart failure. Thus, we suggest that endogenous adenosine is also beneficial in chronic heart failure. We propose potential mechanisms for cardioprotection attributable to adenosine in pathophysiological states in heart diseases. The establishment of adenosine therapy may be useful for the treatment of either ischemic heart diseases or chronic heart failure.
 ...
PMID:Adenosine and cardioprotection in the diseased heart. 1047 69

The regulatory protein troponin (Tn) located on actin filament consists of three subunits: TnT--binds troponin to tropomyosin, TnC--binds divalent calcium ions, and TnI--affects myosin-actin interactions. Tn subunits display several molecular and calcium binding variations. During ontogenetic development of cardiac and skeletal muscles the synthesis of multiple isoforms of Tn subunits was detected. Expression of Tn isoforms and the extent of phosphorylation of both TnT and TnI via protein kinase C or protein kinase A under different pathological situations (e.g. ischemia, congenital heart disease, heart failure) can affect the Ca2+-stimulated contraction function and the myofibrillar ATPase activity of the heart.
 ...
PMID:Isoforms of troponin in normal and diseased myocardium. 1063 75

Targeted cardiac overexpression of the alpha-subunit of the heterotrimeric G protein G(q) in transgenic mice evokes hypertrophy and depressed stimulation of cardiac inotropy and chronotropy by beta-adrenergic receptor (betaAR) agonists in vivo, which is a hallmark of many forms of experimental and human heart failure. The molecular basis of this betaAR dysfunction was explored in transgenic mice overexpressing G(alphaq) approximately 5-fold over background. Isoproterenol-stimulated adenylyl cyclase activities in myocardial membranes were significantly depressed in G(alphaq) mice compared with nontransgenic controls (19.7 +/- 2.6 versus 43.7 +/- 5. 6 pmol/min/mg) without a decrease in betaAR expression levels. Functional coupling of both betaAR subtypes was impaired. Similarly, in whole-cell patch-clamp studies, betaAR stimulation of L-type Ca(2+) channel currents was depressed approximately 75% in the G(alphaq) mice. Cardiac betaAR from these mice showed decreased formation of the active high-affinity conformation (R(H) = 29% versus 62% for nontransgenic littermates), confirming a receptor-G(s)-coupling defect. Of the three candidate kinases that might impose this uncoupling by receptor phosphorylation (protein kinase A, betaAR kinase, protein kinase C), only protein kinase C activity was elevated in G(alphaq) mouse hearts. Type V adenylyl cyclase was decreased approximately 45% in these mice, consistent with decreased basal, NaF, and forskolin-stimulated enzyme activities. Although cellular G(s) levels were unaltered, G(i2) and G(i3) were increased in G(alphaq) mice. Pertussis toxin treatment of isolated G(alphaq) myocytes resulted in an improvement in betaAR, but not that of forskolin or NaF, stimulation of adenylyl cyclase. Thus three distinct mechanisms contribute to impaired betaAR function by in vivo G(q) signaling cross-talk in myocytes. Because many elements of hypertrophy and/or failure in cellular and animal models can be initiated by increased G(alphaq) signaling, the current work may be broadly applicable to interfaces whereby modification of heart failure might be considered.
 ...
PMID:Mechanisms of impaired beta-adrenergic receptor signaling in G(alphaq)-mediated cardiac hypertrophy and ventricular dysfunction. 1064 37

In addition to having anti-sympathotonic effects, beta-blockers are thought to have some adrenoceptor-independent properties. Such ancillary effects are described for carvedilol acting as oxygen radical scavenger and for propranolol which blocks protein kinase C and phosphatidate phosphohydrolase. The goal of our in vitro experiments was to identify ancillary effects of the widely used beta-blockers metoprolol and atenolol in neutrophils. Neutrophil chemotaxis was tested using the leading front assay in a modified Boyden microchemotaxis chamber. Respiratory burst activity was detected fluorometrically. Inhibition of protein kinase C activity was tested with purified alpha-, beta- and gamma-isoenzyme preparation. Metoprolol dose-dependently inhibited formyl peptide-stimulated neutrophil chemotaxis and formylpeptide- and phorbol myristate acetate-triggered oxygen free radical production. These actions were not affected by the competitive presence of the beta-receptor agonist, orciprenaline. Effects of metoprolol, as well as of propranolol, and the signaling enzyme blockers were strongly time dependent. Propranolol mimicked effects of staurosporine on respiratory burst, whereas the effects of metoprolol were similar to bisindolylmaleimide, a specific protein kinase C blocker. Atenolol, a hydrophilic beta-blocker, neither affected neutrophil chemotaxis nor respiratory burst. In a cell-free system, metoprolol did not interfere with the activity of the purified protein kinase C alpha-, beta- and gamma-isoenzymes. Adrenoceptor-independent inhibition of neutrophil chemotaxis and free radical production is a novel mode of action of metoprolol that may be relevant for beneficial effects ot the beta-blocker in heart failure and endothelial preconditioning.
 ...
PMID:Modulation of neutrophil migration and superoxide anion release by metoprolol. 1088 46

The epsilon isoform of protein kinase C (PKC) has a critical cardiotrophic function in normal postnatal developing heart as demonstrated by cardiac-specific transgenic expression of epsilonPKC-selective translocation inhibitor (epsilonV1) and activator (psiepsilonRACK) peptides (Mochly-Rosen, D., Wu, G., Hahn, H., Osinska, H., Liron, T., Lorenz, J. N., Robbins, J., and Dorn, G. W., II (2000) Circ. Res. 86, 1173-1179). To define the role of epsilonPKC signaling in pathological myocardial hypertrophy, epsilonV1 or psiepsilonRACK were co-expressed in mouse hearts with Galpha(q), a PKC-linked hypertrophy signal transducer. Compared with Galpha(q) overexpression alone, co-expression of psiepsilonRACK with Galpha(q) increased epsilonPKC particulate partitioning by 30 +/- 2%, whereas co-expression of epsilonV1 with Galpha(q) reduced particulate-associated epsilonPKC by 22 +/- 1%. Facilitation of epsilonPKC translocation by psiepsilonRACK in Galpha(q) mice improved cardiac contractile function measured as left ventricular fractional shortening (30 +/- 3% Galpha(q) versus 43 +/- 2% psiepsilonRACK/Galpha(q), p < 0.05). Conversely, inhibition of epsilonPKC by epsilonV1 modified the Galpha(q) nonfailing hypertrophy phenotype to that of a lethal dilated cardiomyopathy. These opposing effects of epsilonPKC translocation activation and inhibition in Galpha(q) hypertrophy indicate that epsilonPKC signaling is a compensatory event in myocardial hypertrophy, rather than a pathological event, and support the possible therapeutic efficacy of selective epsilonPKC translocation enhancement in cardiac insufficiency.
 ...
PMID:Epsilon protein kinase C in pathological myocardial hypertrophy. Analysis by combined transgenic expression of translocation modifiers and Galphaq. 1089 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>