No abstract

The development of right heart failure (RHF) is characterized by alterations of right ventricle (RV) structure and function, but the mechanisms of RHF remain still unknown. Thus, understanding the RHF is essential for improved therapies. Therefore, identification by quantitative proteomics of targets specific to RHF may have therapeutic benefits to identify novel potential therapeutic targets. The objective of this study was to analyze the molecular mechanisms changing RV function in the diseased RHF and thus, to identify novel potential therapeutic targets. For this, we have performed differential proteomic analysis of whole RV proteins using two experimental rat models of RHF. Differential protein expression was observed for hundred twenty six RV proteins including proteins involved in structural constituent of cytoskeleton, motor activity, structural molecule activity, cytoskeleton protein binding and microtubule binding. Interestingly, further analysis of down-regulated proteins, reveals that both protein and gene expressions of proteasome subunits were drastically decreased in RHF, which was accompanied by an increase of ubiquitinated proteins. Interestingly, the proteasomal activities chymotrypsin and caspase-like were decreased whereas trypsin-like activity was maintained. In conclusion, this study revealed the involvement of ubiquitin-proteasome system (UPS) in RHF. Three deregulated mechanisms were discovered: (1) decreased gene and protein expressions of proteasome subunits, (2) decreased specific activity of proteasome; and (3) a specific accumulation of ubiquitinated proteins. This modulation of UPS of RV may provide a novel therapeutic avenue for restoration of cardiac function in the diseased RHF.

Tetrahydrobiopterin (BH4), which fosters the formation of and stabilizes endothelial NO synthase (eNOS) as an active dimer, tightly regulates eNOS coupling / uncoupling. Moreover, studies conducted in genetically-modified models demonstrate that BH4 pulmonary deficiency is a key determinant in the pathogenesis of pulmonary hypertension. The present study thus investigates biopterin metabolism and eNOS expression, as well as the effect of sepiapterin (a precursor of BH4) and eNOS gene deletion, in a mice model of hypoxic pulmonary hypertension. In lungs, chronic hypoxia increased BH4 levels and eNOS expression, without modifying dihydrobiopterin (BH2, the oxidation product of BH4) levels, GTP cyclohydrolase-1 or dihydrofolate reductase expression (two key enzymes regulating BH4 availability). In intrapulmonary arteries, chronic hypoxia also increased expression of eNOS, but did not induce destabilisation of eNOS dimers into monomers. In hypoxic mice, sepiapterin prevented increase in right ventricular systolic pressure and right ventricular hypertrophy, whereas it modified neither remodelling nor alteration in vasomotor responses (hyper-responsiveness to phenylephrine, decrease in endothelium-dependent relaxation to acetylcholine) in intrapulmonary arteries. Finally, deletion of eNOS gene partially prevented hypoxia-induced increase in right ventricular systolic pressure, right ventricular hypertrophy and remodelling of intrapulmonary arteries. Collectively, these data demonstrate the absence of BH4/BH2 changes and eNOS dimer destabilisation, which may induce eNOS uncoupling during hypoxia-induced pulmonary hypertension. Thus, even though eNOS gene deletion and sepiapterin treatment exert protective effects on hypoxia-induced pulmonary vascular remodelling, increase on right ventricular pressure and / or right ventricular hypertrophy, these effects appear unrelated to biopterin-dependent eNOS uncoupling within pulmonary vasculature of hypoxic wild-type mice.

SUMMARY Eighteen patients with chronic aortic insufficiency were evaluated hemodynamically and angiographically 8 months after aortic valve replacement. Both the pulmonary artery diastolic pressure and the left ventricular end-diastolic volume decreased significantly (p < 0.001), but the mean ejection fraction and the cardiac output remained identically lowered, though some individual cases showed improvement. The relative reduction in end-diastolic volume correlated only with the preoperative ejection (p < 0.05) and regurgitation fractions (p < 0.02).In the 10 patients whose left ventricular volume remained high or ejection fraction low, a second evaluation was performed 27 months after surgery. The left ventricular end-diastolic volume was significantly lowered (from 151 to 120 mI/m2, p < 0.05) back to normal in five cases. The systolic and diastolic ventricular shape returned to normal. Cardiac index and ejection fraction were unchanged.These results show a marked improvement a few months after aortic valve replacement, with a further improvement several months later, as shown mainly by the decrease of left ventricular end-diastolic volume and the return to normal of left ventricular cavity shape. However, in most cases, the ejection fraction remained at its preoperative value, suggesting that surgery should be performed early, before myocardial deterioration appears.AORTIC REGURGITATION produces no clinical symptoms at first1' 2 because the left ventricle is initially the only cardiac chamber involved and can compensate for the regurgitation. During this time, the total cardiac volume increases slowly, pulmonary pressures remain normal, and left ventricular function shows no evidence of change. The alteration in left ventricular function is, however, a major factor in the postoperative prognosis.37The best time for valve replacement is difficult to determine, despite precise clinical, hemodynamic and angiographic data, because the relative risks involved in the consequences of prolonged aortic regurgitation, and those inherent in surgery and prosthetic valves, are not easy to determine.Evaluation of the results of valve replacement in relation to the pre-and postoperative hemodynamic and angiographic findings has only been undertaken in a few studies that, for the most part, involved few patients.8"-' The aim of the present study was to determine which preoperative factors have a prognostic value, to assess the reversibility of the left ventricular changes and to ascertain the optimal time for valve replacement. 18-65 years), suffering from an isolated, marked, long-standing aortic regurgitation. Its etiology was rheumatic in 10 cases, infective endocarditis in six and unknown in the other two. No patient had associated coronary disease and coronary arteriography, systematically performed in the 15 patients over 40 years old, was normal. Eleven patients were in functional class I or II of the New York Heart Association and seven were in class III or IV. Seventeen showed an increase in heart size on a standar...