Lydie Rappaport

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, +71.9 +/- 8.2% [n = 17]; serum, +14.9 +/- 6.5% [n = 13]; both P < .01 versus control medium). The effects of both PF and serum on cardiomyocyte growth correlated positively with the respective left ventricular (LV) mass. However, the magnitude of change with PF was 3-fold greater than with serum (P < .01). These trophic effects of PF were mimicked by exogenous basic fibroblast growth factor (FGF2) and inhibited by anti-FGF2 antibodies and transforming growth factor-beta (TGF-beta), suggesting a relationship to FGF2. In addition, FGF2 concentration in PF was 20 times greater than in serum. On the other hand, the LV mass-dependent trophic effect, present in both fluids, was independent of FGF2 concentration or other factors, such as angiotensin II, atrial natriuretic factor, and TGF-beta. These data suggest that FGF2 in human PF is a major determining factor in normal myocyte growth, whereas unidentified LV mass-dependent factor(s), present in both PF and serum, participates in the development of ventricular hypertrophy.

Self-Protection by Cardiac Myocytes Against Hypoxia and Hyperoxia

Cardiac muscle must maintain a continuous balance between its energy supply and work performed. An important mechanism involved in achievement of this balance is cross talk via chemical signals between cardiac myocytes and the cardiac muscle vascular system. This has been demonstrated by incubating isolated cardiac myocytes in different concentrations of oxygen and then assaying the conditioned media for vasoactive substances on isolated aortic rings and small-resistance arteries. With increasing oxygen concentrations above 6%, cardiac myocytes produce increasing amounts of angiotensin I, which is converted to angiotensin II by the blood vessel. The angiotensin II stimulates vascular endothelial cells to secrete endothelin and increase vascular tone. Below 6% oxygen, cardiac myocytes secrete adenosine, which acts directly on vascular smooth muscle to block the effect of alpha-adrenergic agonists and reduce vascular tone. In an intact heart, the net effect of these 2 regulatory systems would be the maintenance of oxygen concentration within a narrow range at the cardiac myocytes. By acting as oxygen sensors, cardiac myocytes modulate vascular tone according to the needs of the myocytes and reduce potential problems of hypoxia and extensive formation of reactive oxygen species.

Vascular Endothelial Cell-Cardiac Myocyte Crosstalk in Achieving a Balance between Energy Supply and Energy use

In isolated perfused hearts, endothelial cells in the coronary arterial vascular system release substances that can alter the contractility of the cardiac myocytes. There are at least two different substances, one that increases and another that decreases the contractility of cardiac myocytes. The rate of release of these endothelial-derived cardioactive substances depends on the oxygen tension in the immediate vicinity of the cardiac myocytes. As the local oxygen tension increases the contractility changes in the same direction. The oxygen sensor in this regulatory system is the cardiac myocyte, which then releases substances that regulate the secretion of endothelin and a relaxant by endothelial cells. The result is a loop involving cross talk between coronary endothelial cells and cardiac myocytes to modulate cardiac contractility in accordance with the oxygen supply to the cardiac myocytes. Preliminary data suggest that the change in contractility is related to a change in structure and position of the cross bridge due to phosphorylation of a protein in the thick filament.

A review of the renin-angiotensin system in the normal heart.

This review describes the vascular and cardiac-tissue renin-angiotensin system (RAS), a so-called autocrine hormonal system as opposed to the circulating endocrine system. The existence of this autocrine system is suggested by the persistence of elevated concentrations of angiotensin II (Ang II) following binephrectomy. There is considerable evidence to support the concept of an autocrine RAS. but the functional aspects of such a system remain controversial: (a) Cultured endothelial cells from blood vessels can, for example, synthesize renin, but angio-tensiogen messenger RNA (mRNA) is only present in perivascular adipocytes, (b) In the myocardium, there are obviously problems raised depending on the animal species considered: only rats apparently lack ventricular RAS, but tissue RAS is present in their atrial and conducting tissue system. In other species such as rabbit, the situation is quite different. In addition to the inotropic effect of Ang II, it has recently been demonstrated that this substance may determine the expression of the cardiac genome (oncogenes).

Comparative effects of indapamide and hydrochlorothiazide on cardiac hypertrophy and vascular smooth-muscle phenotype in the stroke-prone, spontaneously hypertensive rat

The effects of two diuretics, indapamide (3 mg/kg/day) and hydrochlorothiazide (20 mg/kg/day), were analyzed over a 44-day period on the cardiovascular hypertrophy of stroke-prone spontaneously hypertensive rats (SHR-SP). Untreated SHR-SP developed severe hypertension and cardiac hypertrophy when compared to normotensive Wistar-Kyoto (WKY) rats after 8 weeks on 1% sodium chloride. In diuretic-treated animals, systolic blood pressure was moderately decreased by the end of the treatment when compared with untreated SHR-SP (- 13 and - 18%. respectively, p < 0.05). Morphometric analysis of myocyte cross-sectional areas evidenced that indapamide was the most effective in preventing myocyte hypertrophy ( −33%, p < 0.0001). Small coronary artery wall thickness was efficiently prevented in the two treated groups, but medial hypertrophy was prevented by hydrochlorothiazide only. Among markers of smooth-muscle cell phenotype (contractile or extracellular matrix proteins) EIIIA-fibronectin (FN), one FN cellular isoform, was shown to be the most sensitive marker by an immunohistochemical technic. Medial expression of EIIIA-FN, which was characteristic of SHR-SP coronary arteries, was prevented by the two treatments. The two diuretic treatments, despite similar effects on blood pressure and smooth-muscle phenotype, prevent SHR-SP cardiovascular hypertrophy with a drug-specific efficiency.

Adaptational changes of sarcomere and sarcolemma during chronic cardiac overloading in rats and in humans.

In response to increasing demand, the cardiac muscle has developed several adaptational mechanisms. Gene expression is modified in a quantitative and a qualitative way since the heart hypertrophies and since its structure changes to improve the efficiency of the contraction. The sarcomere modifications are both species-and tissue-specific. An isoenzymic shift of myosin from high adenosine triphosphatase (ATPase) activity form V-1 to low activity form V-3 occurs in all conditions in which V-1 is initially predominant, i.e., in rat (and also rabbit) ventricles and the atria of other species, including humans. It was not observed in conditions in which V-3 was predominant, as in human ventricles (and also in those of cats and pigs). Another shift from creatine kinase (CK) monomer M to CK B, the form that predominates in the fetal heart, is also observed. The sarcolemma is also modified, at least in rats. The digitalis receptor was characterized by studying the inotropic effect of the drug on an isolated heart preparation and on a purified preparation of sarcolemma with a high Na+, K+-ATPase activity by binding [3H]ouabain and ouabain-induced inhibition of the enzymatic activity. In hypertrophied heart, both the recovery of normal contractility after ouabain infusion and the release of previously bound ouabain were slowed, as for fetal hearts. Changes in other inotropic receptors have also been reported. From a practical point of view, this means that screening of new inotropic agents has to be done on hypertrophied hearts and not, as usual, on normal tissue.

Cell Interactions with Extracellular Matrix during Perinatal Development of Myocardium

Cardiac morphogenesis is dependent on the coordinated and programmed expression of cell surface receptors that can mediate interactions of cells with extracellular matrix (ECM) components, which in turn promote either cell adhesion or migration and determine the phenotype. Besides, the role of the membrane receptors as anchoring proteins for cytoskeleton appears prominent, the complex being implicated in different intracellular signaling cascades. A broad range of cellular processes involved in ontogenesis including, cell proliferation, growth and differentiation depend on cytokines but also on the nature of ECM components, ECM-activated receptors, induced alterations in cytoskeleton elements and transducing signals.

Growth factors and the cardiac extra-cellular matrix

The extracellular matrix (ECM) provides physical support to the tissue and plays an important role in the regulation of cellular function. It is a complex mesh of fibrillar collagens types I III, and V which associate directly with cells via membrane receptors or indirectly through basement membrane components such as fibronectin (FN), laminin, collagen type IV and proteoglycans [1]. Laminin, FN and collagen type IV contain specific sequences (RDG and YGSR sequences) which interact with integrins that are integral membrane proteins, thereby establishing a tight connection between the cells and ECM [2]. FN itself is present in both ECM and basal membrane, and either originates from the plasma (pFN) by exsudation at local sites or is synthetised locally by the tissular cells (cFN) [2]. Different isoforms of cFN originate from a single primary transcript by alternative splicing which is regulated during development [3,4,5] and pathological situations [4,6].