. Right and left ventricular function after chronic pulmonary artery banding in rats assessed with biventricular pressure-volume loops. Am J Physiol Heart Circ Physiol 291: H1580 -H1586, 2006. First published May 5, 2006; doi:10.1152/ajpheart.00286.2006.-In many patients with congenital heart disease, the right ventricle (RV) is subjected to abnormal loading conditions. To better understand the state of compensated RV hypertrophy, which could eventually progress to decompensation, we studied the effects of RV pressure overload in rats. In the present study, we report the biventricular adaptation to 6 wk of pulmonary artery banding (PAB). PAB resulted in an RV pressure overload to ϳ60% of systemic level and a twofold increase in RV mass (P Ͻ 0.01). Systemic hemodynamic parameters were not altered, and overt signs of heart failure were absent. Load-independent measures of ventricular function (end-systolic pressure-volume relation, preload recruitable stroke work relation, maximum first time derivative of pressure divided by end-diastolic volume), assessed by means of pressure-volume (PV) loops, demonstrated a two-to threefold increase in RV contractility under baseline conditions in PAB rats. RV contractility increased in response to dobutamine stimulation (2.5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) both in PAB and sham-operated rats in a similar fashion, indicating preserved RV contractile reserve in PAB rats. Left ventricular (LV) contractility at baseline was unaffected in PAB rats, although LV volume in PAB rats was slightly decreased. LV contractility increased in response to dobutamine (2.5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ), both in PAB and sham rats, whereas the response to a higher dose of dobutamine (5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was blunted in PAB rats. RV pressure overload (6 wk) in rats resulted in a state of compensated RV hypertrophy with preserved RV contractile reserve, whereas LV contractile state at baseline was not affected. Furthermore, this study demonstrates the feasibility of performing biventricular PV-loop measurements in rats. right ventricle; hypertrophy; congenital heart disease; pressure-volume loops RIGHT VENTRICULAR (RV) function is an important determinant of long-term outcome in patients with complex congenital heart disease, chronic pulmonary obstructive diseases, or pulmonary hypertension. In many of these patients, the RV is subjected to (residual) abnormal loading conditions, including pressure overload. Although compensated hypertrophy will develop initially, ultimately RV failure will ensue. The mechanisms underlying the progression from compensated RV hypertrophy to decompensated RV hypertrophy (i.e., RV failure) have not been well defined. As the survival of the patients improves, a better understanding of these mechanisms becomes mandatory to be able to design preventive strategies and to time surgical (re)intervention in these patients.To study the mechanisms underlying the transition from a compensated state of hypertrophy to a decompensated state in patients is very difficult, because invasive data cannot...

Two lipid transfer proteins are active in human plasma, cholesteryl ester transfer protein (CETP), and phospholipid transfer protein (PLTP). Mice by nature do not express CETP. Additional inactivation of the PLTP gene resulted in reduced secretion of VLDL and subsequently in decreased susceptibility to diet-induced atherosclerosis. The aim of this study is to assess possible effects of differences in PLTP expression on VLDL secretion in mice that are proficient in CETP and PLTP. We compared human CETP transgenic (huCETPtg) mice with mice expressing both human lipid transfer proteins (huCETPtg/huPLTPtg). Plasma cholesterol in huCETPtg mice was 1.5-fold higher compared with huCETPtg/huPLTPtg mice ( P Ͻ 0.001). This difference was mostly due to a lower HDL level in the huCETPtg/huPLTPtg mice, which subsequently could lead to the somewhat decreased CETP activity and concentration that was found in huCETPtg/huPLTPtg mice ( P Ͻ 0.05). PLTP activity was 2.8-fold increased in these animals ( P Ͻ 0.001). The human PLTP concentration was 5 g/ml. Moderate overexpression of PLTP resulted in a 1.5-fold higher VLDL secretion compared with huCETPtg mice ( P Ͻ 0.05). The composition of nascent VLDL was similar in both strains. These results indicate that elevated PLTP activity in huCETPtg mice results in an increase in VLDL secretion. In addition, PLTP overexpression decreases plasma HDL cholesterol as well as CETP. Phospholipid transfer protein (PLTP) is an important modulator of plasma HDL levels, size, and composition (1-5). HDL is considered to protect against atherosclerosis by transporting cellular cholesterol from cells in the arterial wall to the liver for further excretion via the bile, as well as by exerting anti-inflammatory and anti-oxidant effects (6-8).The role of PLTP in atherosclerosis was recently evaluated in PLTP deficient mice (5). PLTP deficiency in hyperlipidemic mouse models resulted in decreased atherosclerosis. In vitro experiments with cultured hepatocytes from PLTP deficient mice revealed a defect in VLDL secretion. These effects on VLDL secretion provided an explanation for the decreased atherosclerosis found in PLTP deficient mice (5).Earlier we reported anti-atherogenic properties in mice overexpressing human PLTP (huPLTPtg). Despite lower HDL levels, plasma from these mice is more effective in preventing in vitro accumulation of cholesterol by macrophages and is able to generate more pre ␤ -HDL (3, 9). Studies in mice with adenovirus-mediated overexpression of human PLTP showed similar effects on HDL subclass distribution (10, 11).Thus, depending on the metabolic setting, PLTP may have anti-or pro-atherogenic properties that require further investigation. Presently, we aimed to evaluate whether VLDL secretion is affected by variations in PLTP activity. For this purpose, we crossbred transgenic mice for human CETP (huCETPtg) with huPLTPtg mice (9) and obtained huCETPtg/huPLTPtg mice. These mice provide a unique model to study the role of PLTP in VLDL metabolism in the presence of CETP, whi...

Right ventricular (RV) hypertrophy is an important problem in congenital heart disease. We determined the alterations in phenotype that occur in the initial phase of RV hypertrophy and their possible correlations with the degree of hypertrophy. Therefore, we performed a differential proteomic profiling study on RV hypertrophy using an animal model of pulmonary artery banding (PAB) in parallel with hemodynamic characterization. The RV homogenates were subfractionated in myofilament and cytoplasmic proteins, which subsequently were separated by two-dimensional gel electrophoresis (2-DE), excised, and analyzed by mass spectrometry (MS). The cytoplasmic fraction showed expression changes in metabolic proteins, indicative of a shift from fatty acid to glucose as a substrate for energy supply. Up-regulation of three HSP-27s (1.9-, 1.7-, and 3.5-fold) indicated an altered stress response in RV hypertrophy. Detailed analysis by immunoblotting and MS showed that two of these HSP-27s were at least phosphorylated on Ser15. The myofilament fraction showed up-regulation of desmin and alpha-B-crystallin (1.4-and 1.3-fold, respectively). This alteration in desmin was confirmed by 1-DE immunoblots. Certain differentially expressed proteins, such as HSP-27, showed a significant correlation with the RV weight to the body weight ratio in the PAB rats, suggesting an association with the degree of hypertrophy.

Excessive adventitial neovascularization is one of the hallmarks of atherosclerotic plaque progression and is associated with an increased plaque burden by facilitating leukocyte influx and perivascular inflammation. Statins act atheroprotective by reducing plasma cholesterol levels and by quenching inflammation, but recent studies suggest that they may also affect neovascularization. In this study, we aimed to investigate this notion in apoE(-/-) mice. Advanced carotid artery lesions were induced by perivascular collar placement in mice on western type diet or diet supplemented with atorvastatin (0.003%, w/w). Atorvastatin treatment did not affect diet induced body weight gain and did not lower plasma total cholesterol levels. Plaque size at 8 weeks after collar placement was significantly reduced in atorvastatin treated mice compared to control mice, while also necrotic core size was significantly lower in atorvastatin treated mice. Interestingly, atorvastatin treatment reduced the number of perivascular CD31(+) neovessels by almost 40%. Furthermore, endothelial proliferation was significantly inhibited by atorvastatin treatment in vitro. In conclusion, atorvastatin treatment inhibits plaque development in ApoE deficient mice independent of plasma total cholesterol levels. Given the profound inhibition of adventitial neovascularization, we propose that statins may partly exert their protective effects by modulating this process, identifying yet another atheroprotective mechanism for statins.

our data indicate that chymase inhibition can inhibit pro-atherogenic and plaque destabilizing effects which are associated with perivascular mast cell activation. Our study thus identifies pharmacological chymase inhibition as a potential therapeutic modality for atherosclerotic plaque stabilization.

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The key components to the molecular understanding of the pathophysiology of various forms of heart failure involve global and/or large-scale identifications of proteins, their patterns of expression, posttranslational modifications, and functional characterization. Particularly, proteins involved in the induction of cardiac (mal)adaptive hypertrophic growth, interstitial fibrosis, and contractile dysfunction are of interest. In general, with the accumulation of vast amounts of DNA sequences in databases, researchers have become aware that merely having complete sequences of genomes and transcriptional changes for thousands of genes simultaneously will not be sufficient to elucidate, in molecular terms, the etiology and pathophysiology of cardiovascular disease. In the last decade, a new technology called proteomics has become available that allows biological and (patho)physiological questions to be approached exclusively from the protein perspective. Proteomics may enable us to map the entire complement of proteins expressed by the heart at any time and condition. This approach creates the unique possibility to identify, by differential analysis, protein alterations associated with the etiology of heart disease and its progression, outcome, and response to therapy. To illustrate the true power of proteomics, most of the currently available methodologies are first reviewed, including their limitations. This review also deals with the current status and the perspectives of proteomics applications in research on heart failure in general. Furthermore, examples of our recent data on global protein profiling of the pressure-overloaded rat right ventricle and of endothelin-1-stimulated cultures of neonatal rat cardiac myocytes are provided. The last section is devoted to the continuous advances in proteomic technologies, including protein separation methods, mass spectrometric instrumentation, computational analysis, and bioinformatic tools, together with integrative databases.

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