http://repub.eur.nl/res/aut/41901/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/28709/ 2010-03-01T00:00:00Z Background: Angiotensin (Ang)-(1-7) attenuates the development of heart failure. In addition to its local effects on cardiovascular tissue, Ang-(1-7) also stimulates bone marrow, which harbors cells that might complement the therapeutic effect of Ang-(1-7). We studied the effects of Ang-(1-7) either produced locally in the heart or subcutaneously injected during the development of heart failure induced by myocardial infarction (MI) and explored the role of cardiovascular progenitor cells in promoting the effects of this heptapeptide. Methods and Results: Effects of Ang-(1-7) on bone marrow-derived mononuclear cells in rodents, particularly endothelial progenitor cells, were investigated in vitro and in vivo in rats, in mice deficient for the putative Ang-(1-7) receptor Mas, and in mice overexpressing Ang-(1-7) exclusively in the heart. Three weeks after MI induction through permanent coronary artery occlusion, effects of Ang-(1-7) either produced locally in the heart or injected into the subcutaneous space were investigated. Ang-(1-7) stimulated proliferation of endothelial progenitor cells isolated from sham or infarcted rodents. The stimulation was blunted by A779, a Mas receptor blocker, or by Mas deficiency. Infusion of Ang-(1-7) after MI increased the number of c-kit-and vascular endothelial growth factor-positive cells in infarcted hearts, inhibited cardiac hypertrophy, and improved cardiac function 3 weeks after MI, whereas cardiomyocyte-derived Ang-(1-7) had no effect. Conclusions: Our data suggest circulating rather than cardiac Ang-(1-7) to be beneficial after MI. This beneficial effect correlates with a stimulation of cardiac progenitor cells in vitro and in vivo. This characterizes the heptapeptide as a promising new tool in stimulating cardiovascular regeneration under pathophysiological conditions. http://repub.eur.nl/res/pub/29273/ 2008-12-01T00:00:00Z Pharmacological renin inhibition with aliskiren is an effective antihypertensive drug treatment, but it is currently unknown whether aliskiren is able to attenuate cardiac failure independent of its blood pressure-lowering effects. We investigated the effect of aliskiren on cardiac remodeling, apoptosis, and left ventricular (LV) function after experimental myocardial infarction (MI). C57J/bl6 mice were subjected to coronary artery ligation and were treated for 10 days with vehicle or aliskiren (50 mg/kg per day via an SC osmopump), whereas sham-operated animals served as controls. This dose of aliskiren, which did not affect systemic blood pressure, improved systolic and diastolic LV function, as measured by the assessment of pressure-volume loops after MI. Furthermore, after MI LV dilatation, cardiac hypertrophy and lung weights were decreased in mice treated with aliskiren compared with placebo-treated mice after MI. This was associated with a normalization of the mitogen-activated protein kinase P38 and extracellular signal-regulated kinases 1/2, AKT, and the apoptotic markers bax and bcl-2 (all measured by Western blots), as well as the number of TUNEL-positive cells in histology. LV dilatation, as well as the associated upregulation of gene expression (mRNA abundance) and activity (by zymography) of the cardiac metalloproteinase 9 in the placebo group after MI, was also attenuated in the aliskiren-treated group. Aliskiren improved LV dysfunction after MI in a dose that did not affect blood pressure. This was associated with the amelioration of cardiac remodelling, hypertrophy, and apoptosis. http://repub.eur.nl/res/pub/35648/ 2007-01-01T00:00:00Z BACKGROUND: Strong evidence suggests that mitochondrial malfunction, which leads to disturbed energy metabolism and stimulated apoptosis, is a linchpin in the induction and manifestation of cardiac failure. An adequate exchange of ATP and ADP over the inner mitochondrial membrane by the adenine nucleotide translocase (ANT) is thereby essential to guarantee the cellular energy supply. METHODS AND RESULTS: To explore the effect of an ameliorated mitochondrial ATP/ADP transportation on cardiac dysfunction, we generated transgenic rats overexpressing ANT1 in the heart (ANT rats) and crossed them with renin-overexpressing rats (REN rats) suffering from hypertension-induced cardiac insufficiency. Cardiac-specific ANT1 overexpression resulted in a higher ATP/ADP transportation and elevated activities of respiratory chain complexes. Increased ANT activity in double-transgenic (ANT/REN) animals did not influence excessive hypertension seen in REN rats. Hypertension-induced cardiac hypertrophy in the REN rats was prevented by parallel ANT1 overexpression, however, and left ventricular function remarkably improved. The ANT1 overexpression led to a reduction in fibrosis and an improvement in cardiac tissue architecture. Consequently, the survival rate of ANT/REN rats was enhanced. Further investigations into the cardioprotective mechanism of ANT1 overexpression revealed improved mitochondrial structure and function and significantly reduced apoptosis in ANT/REN rats, shown by lowered cytosolic/mitochondrial cytochrome c ratio, reduced caspase 3 level, and prevented DNA degradation. CONCLUSIONS: Myocardial ANT1 overexpression protects against hypertension-induced cardiac pathology. Thus, the improvement in mitochondrial function may be a basic principle for new strategies in treating heart disease.