Activation of the ubiquitin proteolytic pathway in human septic heart and diaphragm.

Objective: Mechanisms of sepsis-induced myocardial and diaphragmatic alteration are multiple and remain largely unknown, particularly in humans. In the present study, we compared the inducible nitric oxide synthase (NOS-2) expression, the peroxynitrite production and the expression and activation of the ubiquitin proteolytic pathway in the wall of the 4 cardiac chambers, in the diaphragm, and in the rectus abdominis.

Patients: Seven patients who died from septic shock associated with a myocardial depression and 5 nonseptic (control) patients.

Effects of sex differences on constitutive nitric oxide synthase expression and activity in response to pressure overload in rats.

Clinical studies have documented sex differences in left ventricular (LV) hypertrophy patterns, but the mechanisms are so far poorly defined. This study aimed to determine whether 1) severe pressure overload altered expression and/or activity of cardiac constitutive nitric oxide synthase (NOS1 and NOS3) and 2) these changes were modulated according to sex. Analyses were performed 0.

17beta-estradiol regulates constitutive nitric oxide synthase expression differentially in the myocardium in response to pressure overload.

Estrogens [E(2)] exert direct and indirect effects that can modulate the development of cardiac disease. However, the precise mechanisms that are involved remain undefined. Our objective was to investigate whether E(2) affected the activity and expression of constitutive nitric oxide synthase (NOS) isoforms (NOS3 and NOS1) in cardiac hypertrophy induced by thoracic aortic constriction (TAC).

Expression and localization of caveolins during postnatal development in rat heart: implication of thyroid hormone.

Caveolins modulate signaling pathways involved in cardiac development. Caveolin-1 exists in two isoforms: the beta-isoform derivates from an alternative translational start site that creates a protein truncated by 31 amino acids, mainly expressed in endothelial cells, whereas caveolin-3 is present in muscle cells. Our aim was to define caveolin distribution and expression during cardiac postnatal development using immunofluorescence and Western blotting.

Na+/H+ exchange inhibition in hypertrophied myocardium subjected to cardioplegic arrest: an effective cardioprotective approach.

Objective: This study was designed to assess whether the protective effects of Na+/H+ exchange (NHE) inhibition, which have been largely demonstrated in normal hearts, are also manifest in a more surgically relevant model of hypertrophied myocardium subjected to cardioplegic arrest.

Methods: Left ventricular hypertrophy was created in 3-week-old rats by coarctation of the ascending thoracic aorta with a hemoclip. Eight weeks later, hearts were excised, isovolumetrically perfused and subjected to 1 h of potassium cardioplegic arrest followed by 2 h of reperfusion.

Role of myocardial neuronal nitric oxide synthase-derived nitric oxide in beta-adrenergic hyporesponsiveness after myocardial infarction-induced heart failure in rat.

Background: An emerging concept is that a neuronal isoform of nitric oxide synthase (NOS1) may regulate myocardial contractility. However, a role for NOS1-derived nitric oxide (NO) in heart failure (HF) has not been defined.

Methods And Results: Using a model of myocardial infarction-induced HF, we demonstrated that cardiac NOS1 expression and activity increased in HF rats (P<0.

Increased neuronal nitric oxide synthase-derived NO production in the failing human heart.

Experimental data suggest that nitric oxide (NO) generated from neuronal NO synthase (nNOS) modulates the myocardial inotropic state. To assess the contribution of NO, derived from endothelial and neuronal isoforms, to the pathophysiology of congestive heart failure in human beings, we compared expression, localisation, and specific activity of NOS isoforms in myocardium from patients with dilated cardiomyopathy with those in controls who had died from head trauma or intracranial bleeds. Diseased hearts had a significant increase in nNOS mRNA and protein expression, and activity associated with the translocation of nNOS to the sarcolemma through interactions with caveolin 3.

Up-regulation of cardiac nitric oxide synthase 1-derived nitric oxide after myocardial infarction in senescent rats.

Nitric oxide (NO) has been implicated in the development of heart failure, although the source, significance, and functional role of the different NO synthase (NOS) isoforms in this pathology are controversial. The presence of a neuronal-type NOS isoform (NOS1) in the cardiac sarcoplasmic reticulum has been recently discovered, leading to the hypothesis that NOS1-derived NO may notably alter myocardial inotropy. However, the regulation and role(s) of NOS1 in cardiac diseases remain to be determined.

Temporal patterns of bone marrow cell differentiation following transplantation in doxorubicin-induced cardiomyopathy.

Objective: Recent studies have suggested benefits of bone marrow cell transplantation for the regeneration of ischemic cardiac tissue. To extend the potential of cell transplantation, we assessed this treatment in a mouse model of acute nonischemic doxorubicin-induced cardiomyopathy.

Methods: To allow detection of engrafted cells, we used transgenic mice expressing the nuclear-located LacZ under the control of either desmin or vimentin promoters, which identify muscle lineage and mesenchymal cells, respectively.

Caveolin-1 and -3 dissociations from caveolae to cytosol in the heart during aging and after myocardial infarction in rat.

Objective: Caveolins, the structural proteins of caveolae, modulate numerous signaling pathways including Nitric Oxide (NO) production. Among the caveolin family, caveolin-1 and -3 are mainly expressed in endothelial and muscle cells, respectively. In this study, we investigate whether (i) changes in caveolin abundance and/or distribution occur during cardiac aging and failure in rat, and (ii) the process could influence NO synthase (NOS) activity.

Cyclo-oxygenase-1 and -2 contribution to endothelial dysfunction in ageing.

Experiments were designed to investigate the role of cyclo-oxygenase isoforms in endothelial dysfunction in ageing. Aortic rings with endothelium of aged and young (24 vs 4 month-old) Wistar rats, were mounted in organ chambers for the recording of changes in isometric tension. In young rats, acetylcholine (ACh) caused a complete relaxation which was not affected by indomethacin (0.

Effect of pressure overload on angiotensin receptor expression in the rat heart during early postnatal life.

The development of cardiac hypertrophy during neonatal life and in adults implies different processes. The angiotensin II (Ang II) system is involved in the development of cardiac hypertrophy in adults, but its role in neonates remains unclear. The aim of this study was to estimate the influence of increased hemodynamic load on the developmental pattern of the AT1/AT2 receptor expression in the heart.

Comparison of the effects of fetal cardiomyocyte and skeletal myoblast transplantation on postinfarction left ventricular function.

Objectives: Transplantation of fetal cardiomyocytes improves function of infarcted myocardium but raises availability, immunologic, and ethical issues that justify the investigation of alternate cell types, among which skeletal myoblasts are attractive candidates.

Methods: Myocardial infarction was created in rats by means of coronary artery ligation. One week later, the animals were reoperated on and intramyocardially injected with culture growth medium alone (controls, n = 15), fetal cardiomyocytes (5 x 10(6) cells, n = 11), or neonatal skeletal myoblasts (5 x 10(6) cells, n = 16).

Expression of laminin alpha2 chain during normal and pathological growth of myocardium in rat and human.

Objectives: Fibrosis is a classical feature of cardiac hypertrophy. To date changes within the basal lamina during normal and pathological cardiac growth have been poorly investigated. The goal of the present study was to determine if the expression of the muscle specific subunit of merosin (laminin alpha2 chain) together with that of fibronectin (FN) is modified in the diseased human heart.

Expression and localization of the annexins II, V, and VI in myocardium from patients with end-stage heart failure.

Annexins II, V, and VI belong to a family of Ca(2+)-dependent phospholipid-binding proteins that have been involved mainly in signal transduction, differentiation, membrane trafficking events, or binding to the extracellular matrix, or that might be effective as Ca(2+)-channels. They are abundant in the mammalian myocardium and might play a role in ventricular remodeling and altered calcium handling during heart failure. To test this hypothesis, we compared the expression and distribution of these annexins in nonfailing (n = 9) and failing human hearts with idiopathic dilated cardiomyopathy (n = 11).

Modulation of angiotensin II receptor expression during development and regression of hypoxic pulmonary hypertension.

Lung vessel muscularization during hypoxic pulmonary hypertension is associated with local renin-angiotensin system activation. The expression of angiotensin II (Ang II) AT1 and AT2 receptors in this setting is not well known and has never been investigated during normoxia recovery. We determined both chronic hypoxia and normoxia recovery patterns of AT1 and AT2 expression and distal muscularization in the same lungs using in situ binding, reverse transcriptase/polymerase chain reaction, and histology.

Thyroid hormones differentially modulate enolase isozymes during rat skeletal and cardiac muscle development.

During muscle development, an isozymic transition of the glycolytic enzyme enolase occurs from the embryonic and ubiquitous alphaalpha-isoform to the muscle-specific betabeta-isoform. Here, we demonstrate a stimulatory role of thyroid hormones on these two enolase genes during rat development in hindlimb muscles and an inhibitory effect on the muscle-specific enolase gene in cardiac muscle. In hindlimb muscles the ubiquitous alpha-transcript level is diminished by hypothyroidism, starting at birth.

Localization and quantitation of cardiac annexins II, V, and VI in hypertensive guinea pigs.

Annexins are characterized by Ca2+-dependent binding to phospholipids. Annexin II mainly participates in cell-cell adhesion and signal transduction, whereas annexins V and VI also seem to regulate intracellular calcium cycling. Their abundance and localization were determined in left ventricle (LV) and right ventricle (RV) from hypertensive guinea pigs, during the transition from compensatory hypertrophy to heart failure.

Can cellular transplantation improve function in doxorubicin-induced heart failure?

Background: Transplantation of fetal cardiomyocytes has been shown to improve function of regionally infarcted myocardium, but its effects on global heart failure are still unknown.

Methods And Results: Heart failure was induced in female mice by intraperitoneal injection of doxorubicin (2 mg/kg twice per week over 2 cycles of 2 weeks separated by a 2-week drug-free period). One week after the end of treatment, left ventricular function was assessed by transthoracic echocardiography (baseline).

Cellular distribution of Ca2+ pumps and Ca2+ release channels in rat cardiac hypertrophy induced by aortic stenosis.

Background: The response of ventricular myocytes to pressure overload is heterogeneous and not spatially coordinated. We investigated whether or not the alterations in SERCA and RyR gene expression are homogeneous within the myocardium.

Methods And Results: The cellular distribution of mRNAs and proteins encoding the 2 sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) isoforms (SERCA 2a and 2b) and 2 Ca2+ release channels (the ryanodine receptor, RyR, and the IP3 receptor, IP3R) were analyzed by in situ hybridization and immunofluorescence, respectively.

Increased compliance in diaphragm muscle of the cardiomyopathic Syrian hamster.

We investigated the hypothesis that diaphragm compliance was abnormal in cardiomyopathic Syrian hamsters (CSH), an experimental model of myopathy. The passive elastic properties of isolated diaphragm muscles were analyzed at both the muscle and sarcomere levels. We used the following passive exponential relationship between stress (sigma) and strain (epsilon): sigma = (Eo/beta) (ebetaepsilon - 1), where Eo is the initial elastic modulus and beta is the stiffness constant.

Microvasculature in angiotensin II-dependent cardiac hypertrophy in the rat.

The long-lasting effect of angiotensin II (Ang II) on the microvasculature in the rat left ventricle was studied. Immunolabeling of ventricular cryosections combined with morphometric analysis allowed us to (1) distinguish between capillaries and arterioles and (2) precisely evaluate their respective densities in the endomyocardium. Ang II-induced hypertensive cardiac hypertrophy was associated with an 18% decrease in capillary density (P<0.

Cardiac senescence is associated with enhanced expression of angiotensin II receptor subtypes.

Recent studies have pointed out the differential role of angiotensin II (Ang II) receptor subtypes, AT1 and AT2, in cardiac hypertrophy and fibrosis during pathological cardiac growth. Because senescence is characterized by an important cardiovascular remodeling, we examined the age-related expression of cardiac Ang II receptors in rats. AT1 and AT2 receptor subtype messenger RNA (mRNA) levels were quantitated by RT-PCR.

Does transplantation of cardiomyocytes improve function of infarcted myocardium?

Background: The feasibility of successfully grafting fetal cardiomyocytes into infarcted myocardium is now established, but the functional effects of such a procedure still remain elusive.

Methods And Results: Twenty-three female rats underwent 45 minutes of coronary artery occlusion followed by 30 minutes of reperfusion. At this time point, 13 animals received intramyocardial injections of fetal cardiomyocytes (6 x 10(6) cells in 60 microL of culture medium) in the once ischemic area, whereas the 10 control rats were injected with an equivalent volume of culture medium alone.

Trophic effect of human pericardial fluid on adult cardiac myocytes. Differential role of fibroblast growth factor-2 and factors related to ventricular hypertrophy.

Pericardial fluid (PF) may contain myocardial growth factors that exert paracrine actions on cardiac myocytes. The aims of this study were (1) to investigate the effects of human PF and serum, collected from patients undergoing cardiac surgery, on the growth of cultured adult rat cardiac myocytes and (2) to relate the growth activity of both fluids to the adaptive changes in overloaded human hearts. Both PF and serum increased the rate of protein synthesis, measured by [14C]phenylalanine incorporation in adult rat cardiomyocytes (PF, +71.