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ABSTRACT: S100A1, a small EF-hand Ca(2+)-binding protein with intracellular and extracellular functions, is predominantly expressed in cardiac muscle where it plays a crucial role as a modulator of Ca(2+) homeostasis, energy metabolism and contractile performance. Essentially, its beneficial effects on heart function have been attributed to its direct interaction with, and effects on, sarcoplasmic reticulum calcium handling proteins sarco(endo) plasmic reticulum Ca(2+) ATPase and the ryanodine receptor. Downregulated levels of S100A1 in cardiomyocytes postmyocardial infarction have been linked to diminished cardiac reserve and contribute to the development of heart failure. Interestingly, S100A1 expression has recently been described in endothelial cells where it is downregulated in heart failure and has been shown to modulate intracellular Ca(2+) levels and nitric oxide production. Absence of the Ca(2+) sensor protein in endothelial cells is associated with endothelial dysfunction and hypertension. Thus, S100A1 is emerging as a potential therapeutic target for diverse cardiovascular conditions.
The Canadian journal of cardiology 03/2010; 26 Suppl A:9A-12A. · 3.36 Impact Factor
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Lukas Brander,
Christer Sinderby,
François Lecomte,
Howard Leong-Poi,
David Bell,
Jennifer Beck,
James N Tsoporis,
Rosanna Vaschetto,
Marcus J Schultz, Thomas G Parker,
Jesús Villar,
Haibo Zhang,
Arthur S Slutsky
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ABSTRACT: To determine if neurally adjusted ventilatory assist (NAVA) that delivers pressure in proportion to diaphragm electrical activity is as protective to acutely injured lungs (ALI) and non-pulmonary organs as volume controlled (VC), low tidal volume (Vt), high positive end-expiratory pressure (PEEP) ventilation.
Prospective, randomized, laboratory animal study.
Twenty-seven male New Zealand white rabbits.
Anesthetized rabbits with hydrochloric acid-induced ALI were randomized (n = 9 per group) to 5.5 h NAVA (non-paralyzed), VC (paralyzed; Vt 6-ml/kg), or VC (paralyzed; Vt 15-ml/kg). PEEP was adjusted to hemodynamic goals in NAVA and VC6-ml/kg, and was 1 cmH2O in VC15-ml/kg.
PaO2/FiO2; lung wet-to-dry ratio; lung histology; interleukin-8 (IL-8) concentrations in broncho-alveolar-lavage (BAL) fluid, plasma, and non-pulmonary organs; plasminogen activator inhibitor type-1 and tissue factor in BAL fluid and plasma; non-pulmonary organ apoptosis rate; creatinine clearance; echocardiography. PEEP was similar in NAVA and VC6-ml/kg. During NAVA, Vt was lower (3.1 +/- 0.9 ml/kg), whereas PaO2/ FiO2, respiratory rate, and PaCO2 were higher compared to VC6-ml/kg (p<0.05 for all). Variables assessing ventilator-induced lung injury (VILI), IL-8 levels, non-pulmonary organ apoptosis rate, and kidney as well as cardiac performance were similar in NAVA compared to VC6-ml/kg. VILI and non-pulmonary organ dysfunction was attenuated in both groups compared to VC15-ml/kg.
In anesthetized rabbits with early experimental ALI, NAVA is as effective as VC6-ml/kg in preventing VILI, in attenuating excessive systemic and remote organ inflammation, and in preserving cardiac and kidney function.
European Journal of Intensive Care Medicine 09/2009; 35(11):1979-89. · 5.17 Impact Factor
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Mei Sun,
Manyin Chen,
Fayez Dawood,
Urszula Zurawska,
Jeff Y Li, Thomas Parker,
Zamaneh Kassiri,
Lorrie A Kirshenbaum,
Malcolm Arnold,
Rama Khokha,
Peter P Liu
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ABSTRACT: Pressure overload is accompanied by cardiac myocyte apoptosis, hypertrophy, and inflammatory/fibrogenic responses that lead to ventricular remodeling and heart failure. Despite incomplete understanding of how this process is regulated, the upregulation of tumor necrosis factor (TNF)-alpha after aortic banding in the myocardium is known. In the present study, we tested our hypothesis that TNF-alpha regulates the cardiac inflammatory response, extracellular matrix homeostasis, and ventricular hypertrophy in response to mechanical overload and contributes to ventricular dysfunction.
C57/BL wild-type mice and TNF-knockout (TNF-/-) mice underwent descending aortic banding or sham operation. Compared with sham-operated mice, wild-type mice with aortic banding showed a significant increase in cardiac TNF-alpha levels, which coincided with myocyte apoptosis, inflammatory response, and cardiac hypertrophy in week 2 and a significant elevation in matrix metalloproteinase-9 activity and impaired cardiac function in weeks 2 and 6. Compared with wild-type mice with aortic banding, TNF-/- mice with aortic banding showed attenuated cardiac apoptosis, hypertrophy, inflammatory response, and reparative fibrosis. These mice also showed reduced cardiac matrix metalloproteinase-9 activity and improved cardiac function.
Findings from the present study have suggested that TNF-alpha contributes to adverse left ventricular remodeling during pressure overload through regulation of cardiac repair and remodeling, leading to ventricular dysfunction.
Circulation 04/2007; 115(11):1398-407. · 14.74 Impact Factor
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ABSTRACT: The goal of this study was to compare the effects of the vasopeptidase inhibitor omapatrilat and the angiotensin-converting enzyme inhibitor (ACEI) captopril in the postmyocardial infarction (MI) rat model. BACKGROUND; The cardioprotective effects of ACEIs after MI are thought to be partially due to an increase in bradykinin (BK). Vasopeptidase inhibitors inhibit both ACE and neutral endopeptidase (NEP), further reduce BK metabolism and increase natriuretic peptides, which may result in better cardioprotective effects than with ACEIs after MI.
Myocardial infarction was induced in 514 Wistar male rats by ligation of the anterior coronary artery. Rats surviving 4 h after MI (n = 282) were assigned to omapatrilat (40 or 80 mg/kg/day), captopril (160 mg/kg/day) or no treatment. After 56 days, neurohumoral, hemodynamic, ventricular remodeling, morphometry, immunohistochemistry and cardiac cytokine expression were measured.
Omapatrilat and captopril resulted in similarly improved survival, cardiac hemodynamics and reduced cardiac fibrosis and hypertrophy after MI. The pattern of left ventricular (LV) remodeling differed, omapatrilat causing less attenuation of the rightward shift of the LV pressure-volume relation at lower filling pressures than captopril. Both interventions reduced messenger ribonucleic acid expression of the profibrotic cytokine transforming growth factor-beta(1); neither effected the anti-inflammatory cytokine interleukin-10, and only captopril reduced the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Expression of TNF-alpha was in cardiomyocytes. Both medications reduced circulating endothelin-1, angiotensin II and catecholamines, but only omapatrilat increased atrial natriuretic peptides.
This study indicates that both omapatrilat and captopril markedly improve post-MI survival, cardiac function and cardiac remodeling in the rat. It would appear that the addition of NEP inhibition to those of ACEIs does not result in significant further benefit after MI.
Journal of the American College of Cardiology 06/2002; 39(10):1692-8. · 14.16 Impact Factor
