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Burkert Pieske

Publications and source records attributed to Burkert Pieske.

30 records · Page 2Linked to original sources
PubMed2003

Insulin-like growth factor-1 exerts Ca2+-dependent positive inotropic effects in failing human myocardium.

Myocardial generation of insulin-like growth factor-1 (IGF-1) is altered in hypertrophy and heart failure, but there are no reports on acute functional effects of IGF-1 in human cardiac muscle. We examined inotropic responses and signal transduction mechanisms of IGF-1 in human myocardium. Experiments were performed in isolated trabeculae or cardiomyocytes from 46 end-stage failing hearts. The effect of IGF-1 (0.001 to 0.2 micromol/L) on isometric twitch force (37 degrees C, 1 Hz), intracellular Ca2+ transients (aequorin method), sarcoplasmic reticulum (SR) Ca2+ content (rapid cooling contractures), L-type Ca2+ current (whole-cell voltage clamp), and cAMP concentrations was assessed. In addition, the effects of blocking IGF-1 receptors, phosphoinositide 3-kinase (PI3-kinase), protein kinase C (PKC), or transsarcolemmal Ca2+ entry were tested. IGF-1 exerted concentration-dependent positive inotropic effects (twitch force increased to maximally 133+/-4% of baseline values at 0.1 micromol/L; P<0.05). The IGF-1 receptor antibody alphaIR3 or the PI3-kinase inhibitor wortmannin prevented the functional effects. The inotropic response was paralleled by increases in Ca2+ transients and SR Ca2+ content. IGF-1 (0.1 micromol/L) increased L-type Ca2+ current amplitude by 24+/-7% (P<0.05). Blockade of SR function did not affect the inotropic response to IGF-1. In contrast, L-type Ca2+ channel blockade with diltiazem partially prevented ( approximately 50%) the inotropic response to IGF-1. Inhibition of PKC (GF109203X), Na+-H+ exchange (HOE642), or reverse-mode Na+-Ca2+ exchange (KB-R7943) reduced the response to IGF-1 by approximately 60% to 70%. IGF-1 exerts Ca2+-dependent positive inotropic effects through activation of IGF-1 receptors and a PI3-kinase-dependent pathway in failing human myocardium. The increased [Ca2+]i with IGF-1 originates from both enhanced L-type Ca2+ currents and enhanced Na+-H+ exchange-dependent reverse-mode Na+-Ca2+ exchange. These nongenomic functional effects of IGF-1 may be of clinical relevance.

Calcium↗
PubMed2002

Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes.

Recent investigation has focused on identifying signaling pathways that inhibit cardiac hypertrophy, a major risk factor for cardiovascular morbidity and mortality. In this context, nitric oxide (NO), signaling via cGMP and cGMP-dependent protein kinase type I (PKG I), has been recognized as a negative regulator of cardiac myocyte (CM) hypertrophy. However, the underlying mechanisms are poorly understood. Here, we show that PKG I inhibits CM hypertrophy by targeting the calcineurin-NFAT signaling pathway. Calcineurin, a Ca2+-dependent phosphatase, promotes hypertrophy in part by activating NFAT transcription factors which induce expression of hypertrophic genes, including brain natriuretic peptide (BNP). Activation of PKG I by NO/cGMP in CM suppressed NFAT transcriptional activity, BNP induction, and cell enlargement in response to alpha(1)-adrenoreceptor stimulation but not in response to adenoviral expression of a Ca2+-independent, constitutively active calcineurin mutant, thus demonstrating NO-cGMP-PKG I inhibition of calcineurin-NFAT signaling upstream of calcineurin. PKG I suppressed single L-type Ca2+-channel open probability, [Ca2+]i transient amplitude, and, most importantly, L-type Ca2+-channel current-induced NFAT activation, indicating that PKG I targets Ca2+-dependent steps upstream of calcineurin. Adenoviral expression of PKG I enhanced NO/cGMP inhibitory effects upstream of calcineurin, confirming that PKG I mediates NO/cGMP inhibition of calcineurin-NFAT signaling. In CM overexpressing PKG I, NO/cGMP also suppressed BNP induction and cell enlargement but not NFAT activation elicited by constitutively active calcineurin, which is consistent with additional, NFAT-independent inhibitory effect(s) of PKG I downstream of calcineurin. Inhibition of calcineurin-NFAT signaling by PKG I provides a framework for understanding how NO inhibits cardiac myocyte hypertrophy.

Animals↗
PubMed2002

Rate dependence of [Na+]i and contractility in nonfailing and failing human myocardium.

BACKGROUND: In the failing human heart, altered Ca2+ homeostasis causes contractile dysfunction. Because Ca2+ and Na+ homeostasis are intimately linked through the Na+/Ca2+ exchanger, we compared the regulation of [Na+]i in nonfailing (NF) and failing human myocardium. METHODS AND RESULTS: [Na+]i was measured in SBFI-loaded muscle strips. At slow pacing rates (0.25 Hz, 37 degrees C), isometric force was similar in NF (n=6) and failing (n=12) myocardium (6.4+/-1.2 versus 7.2+/-1.9 mN/mm2), but [Na+]i and diastolic force were greater in failing (22.1+/-2.6 mmol/L and 15.6+/-3.2 mN/mm2) than in NF (15.9+/-3.1 mmol/L and 3.50+/-0.55 mN/mm2; P<0.05) myocardium. In NF hearts, increasing stimulation rates resulted in a parallel increase in force and [Na+]i without changes in diastolic tension. At 2.0 Hz, force increased to 136+/-17% of the basal value (P<0.05), and [Na+]i to 20.5+/-4.2 mmol/L (P<0.05). In contrast, in failing myocardium, force declined to 45+/-3%, whereas [Na+]i increased to 27.4+/-3.2 mmol/L (both P<0.05), in association with significant elevations in diastolic tension. [Na+]i was higher in failing than in NF myocardium at every stimulation rate. [Na+]i predicted in myocytes from Na+ (pipette)-contraction relations was 8.0 mmol/L in NF (n=9) and 12.1 mmol/L in failing (n=57; P<0.05) myocardium at 0.25 Hz. Reverse-mode Na+/Ca2+ exchange induced significant Ca2+ influx in failing but not NF myocytes, compatible with higher [Na+]i in failing myocytes. CONCLUSIONS: Na+i homeostasis is altered in failing human myocardium. At slow heart rates, the higher [Na+]i in failing myocardium appears to enhance Ca2+ influx through Na+/Ca2+ exchange and maintain sarcoplasmic reticulum Ca(2+) load and force development. At faster rates, failing myocytes with high [Na+]i cannot further increase sarcoplasmic reticulum Ca2+ load and are prone to diastolic Ca2+ overload.

Benzofurans↗
PubMed2002

Influence of pyruvate on contractile performance and Ca(2+) cycling in isolated failing human myocardium.

BACKGROUND: Application of pyruvate was shown to improve contractile function in isolated animal myocardium and hemodynamics in patients with congestive heart failure. We assessed the influence of pyruvate on systolic and diastolic myocardial function and its subcellular mode of action in isolated myocardium from end-stage failing human hearts. METHODS AND RESULTS: In muscle strip preparations, concentration-dependent effects of pyruvate on developed and diastolic force (n=6), aequorin light emission reflecting intracellular Ca(2+) transients (n=6), and rapid cooling contractures reflecting sarcoplasmic reticulum (SR) Ca(2+) content (n=11) were measured. Pyruvate resulted in a concentration-dependent increase in developed force and a decrease in diastolic force, with a maximum effect of 155% and 21%, respectively, at 20 mmol/L pyruvate (P<0.05). This was associated with a dose-dependent prolongation of time to peak tension and relaxation time. Pyruvate increased rapid cooling contractures by 51% and aequorin light signals by 85% (at 15 and 20 mmol/L; P<0.05). This indicates increased SR Ca(2+) content and increased intracellular Ca(2+) transients. The inotropic effect of pyruvate was still present after elimination of SR Ca(2+) storage function with 10 micromol/L cyclopiazonic acid and 1 micromol/L ryanodine (n=8). Pyruvate significantly increased intracellular pH from 7.31+/-0.03 to 7.40+/-0.04 by BCECF fluorescence (n=6). CONCLUSIONS: The present findings indicate that pyruvate improves contractile performance of failing human myocardium by increasing intracellular Ca(2+) transients as well as myofilament Ca(2+) sensitivity. The former seem to result from increased SR Ca(2+) accumulation and release, the latter from increased intracellular pH.

Aequorin↗
PubMed2002

The role of SR Ca(2+)-content in blunted inotropic responsiveness of failing human myocardium.

The effects of inotropic agents are blunted in end-stage failing human myocardium. This has been related to a number of subcellular alterations including desensitization of the beta -adrenergic system. However, it is unknown whether alterations in SR Ca(2+)-handling contribute to blunted inotropic responsiveness of failing myocardium. We tested the hypothesis that the reduced effectiveness of Ca(2+)-dependent inotropic interventions results from the inability of the SR to sufficiently increase its Ca(2+)-content in failing human myocardium. Experiments were performed in ventricular muscle preparations from a total of four non-failing and 18 end-stage failing hearts. Isometric twitch force and SR Ca(2+)-content (using rapid cooling contractures; RCCs) were assessed under basal experimental conditions (1 Hz, 37 degrees C, [Ca(2+)](o) 2.5 mmol/l), and at increasing [Ca(2+)](o) (1.25-15 mmol/l), increasing concentrations of the beta -adrenergic agonist isoproterenol (ISO; 0.01-10 micromol/l), or the glycolytic substrate pyruvate (5-15 mmol/l). In addition, paired RCCs were evoked in a subset of experiments to investigate the relative contribution of SR Ca(2+)-uptake v Na(+)/Ca(2+)-exchange to cytosolic Ca(2+)-elimination. In non-failing human myocardium, Ca(2+), ISO, and pyruvate exerted significant positive inotropic effects (increase in twitch force by maximally 396%, 437%, and 82%, respectively). The inotropic effects were associated with increasing RCCs (by 147%, 193%, and 51%, respectively). In failing myocardium, the inotropic effects of Ca(2+) and ISO were significantly less pronounced (with maximal increases in twitch force by 226% and 138%, respectively), associated with blunted effects on RCCs (increase by 33% and 79%, respectively). In contrast, the inotropic effect of pyruvate was unchanged in failing myocardium (increase by 66%), while the corresponding RCCs increased only by 30%. We conclude that the inotropic effects of Ca(2+), ISO, and pyruvate are associated with a significant increase in SR Ca(2+)-content in non-failing human myocardium. In end-stage failing myocardium, the reduced inotropic response to Ca(2+) and ISO is associated with the inability of the SR to appropriately increase its Ca(2+)-content, possibly related to decreased SR Ca(2+)-ATPase and increased Na(+)/Ca(2+)-exchanger expression. In contrast, the maintained inotropic response to pyruvate despite reduced SR Ca(2+)-loading points to additional subcellular effects such as enhanced myofilament Ca(2+)-responsiveness.

Calcium↗
PubMed2002

Sarcoplasmic reticulum Ca2+ load in human heart failure.

Excitation-contraction coupling and intracellular Ca2+ homeostasis are altered in heart failure. We tested the hypothesis that these changes are related to disturbed Ca2+ handling of the sarcoplasmic reticulum (SR). Isolated, electrically stimulated trabeculae were obtained from end-stage failing (NYHA IV) and nonfailing human hearts. Isometric twitch tension, intracellular Ca2+ transients (aequorin method) and SR Ca2+ content (rapid cooling contractures) were assessed under basal conditions (1 Hz, 37 degrees C) as well as after stepwise increasing rest intervals from 2-240 s (post-rest contractions). Protein expression of SERCA2a and phospholamban (Western blot) was assessed in a subset of failing trabeculae. In addition, the effects of SERCA1 overexpression on contractile function of isolated myocytes was tested. On average, post-rest twitch tension continuously increased with increasing rest intervals in nonfailing, but declined with rest intervals longer than 15 s in failing myocardium. The rest-dependent contractile changes were accompanied by parallel changes in intracellular Ca2+ transients. Failing trabeculae (n = 40) were grouped (group A: post-rest potentiation (force of contraction > pre-rest twitch force) after 120 s rest interval; group B: post-rest decay (force of contraction < pre-rest twitch force) after 120 s rest interval), and post-rest contractile function was related to SERCA2a and PLB expression. While PLB protein expression was not different, SERCA2a protein expression as well as SERCA2a/PLB ratio was significantly higher in group A vs. group B. Transfection of SERCA1 increased shortening amplitude and enhanced relaxation kinetics in failing human myocytes. In conclusion, SR Ca2+ handling is severely altered in human heart failure. Reduced SR Ca2+ release is due to diminished SR Ca2+ content directly related to a depressed expression of SERCA2a protein. Enhancing SERCA function or expression may improve SR Ca2+ handling in failing human myocardium.

Calcium↗
PubMed2002

Expression of ten RGS proteins in human myocardium: functional characterization of an upregulation of RGS4 in heart failure.

OBJECTIVE: RGS proteins (regulators of G protein signalling) negatively regulate G protein function as GTPase activating proteins. By controlling heterotrimeric G proteins they may regulate myocardial hypertrophy and contractility. We investigated the expression of RGS proteins in the human heart and whether they take part in the pathophysiological changes of heart failure. METHODS AND RESULTS: Using RNase protection assays (RPAs) RGS2, 3L, 3S, 4, 5 and 6 were identified in the myocardium from terminally failing human hearts with dilated (DCM, n=22) or ischemic (ICM, n=18) cardiomyopathy and from nonfailing donor hearts (NF, n=9). With reverse transcriptase polymerase chain reaction in addition mRNA of RGS1, 9, 12, 14 and 16 were detectable. Compared to NF in failing LV myocardium RGS4 mRNA and protein was upregulated 2-3-fold (mRNA, 10(-21) mol/microg+/-S.E.M.: NF: 22+/-5, DCM: 51+/-10*, ICM: 37+/-8; P<0.05 vs. DCM+ICM, *P<0.05 vs. NF, P<0.05 vs. DCM+ICM; protein, % of NF+/-S.E.M.: NF: 100+/-35, DCM 266+/-60*, ICM: 205+/-64, n=5, *P<0.05 vs. NF). In contrast, RGS2, 3L, 3S, 5, 6, and 16 protein and mRNA levels did not vary between failing and NF hearts. In order to investigate the impact of RGS4 on Gq/11 mediated signalling, PLC activity was measured in human LV membranes. Recombinant RGS4 blunted the endothelin-1 (ET-1) stimulated PLC activity. When overexpressed by adenoviral mediated gene transfer in rabbit ventricular myocytes RGS4 abolished the inotropic effect of ET-1. CONCLUSION: The upregulation of RGS4 in failing human myocardium diminishes Gq/11-mediated signalling and can be involved in the desensitization of Gq/11-mediated positive inotropic effects.

Animals↗
PubMedDate not supplied

High plasma levels of N-terminal pro-atrial natriuretic peptide associated with low anxiety in severe heart failure.

OBJECTIVE: Plasma levels of natriuretic peptides are elevated in congestive heart failure (CHF). These peptides show anxiolytic properties in studies of rodents and patients with panic disorder, but their possible effect on anxiety has never been studied in cardiac patients. We therefore assessed associations of the Atrial Natriuretic Pro-Peptide (pro-ANP) with anxiety in patients with CHF and controls. METHOD: This was a cross-sectional study of 119 patients (46 with CHF, 76 controls with cardiovascular risk factors) in a tertiary care center. The study included assessment of CHF severity, ejection fraction, pro-ANP (microtiter assay), and psychosocial status (self-rating questionnaires for anxiety, depression, vital exhaustion, and quality of life). RESULTS: The diagnosis and severity of CHF was significantly related to pro-ANP levels, bad physical quality of life, vital exhaustion, and depression. However, there was no significant effect of disease severity on anxiety. In CHF patients, pro-ANP was negatively correlated with anxiety (rho = -0.30, p =.041). In the whole group, anxiety was independently predicted by vital exhaustion, depression, and younger age (overall adjusted R2 = 0.48). Pro-ANP plasma levels showed an additional, inverse association with anxiety (beta = -0.17, p =.013, adjusted R2 = 0.50). Predicted mean anxiety scores derived from this model showed a good fit with anxiety scores observed in subgroups defined by CHF severity. CONCLUSION: Pro-ANP plasma levels are independently and inversely related to anxiety. Even in severe CHF with severely compromised quality of life, anxiety tends to decrease with high pro-ANP levels. This might be part of a negative feedback loop limiting psychological distress and its adverse autonomic consequences in severe heart failure.

Aged↗