Anuka E.,Hebrew University of Jerusalem |
Yivgi-Ohana N.,Hebrew University of Jerusalem |
Eimerl S.,Hebrew University of Jerusalem |
Garfinkel B.,Hebrew University of Jerusalem |
And 7 more authors.
Molecular Endocrinology | Year: 2013
Steroidogenic acute regulatory protein (StAR) is indispensable for steroid hormone synthesis in the adrenal cortex and the gonadal tissues. This study reveals that StAR is also expressed at high levels in nonsteroidogenic cardiac fibroblasts confined to the left ventricle of mouse heart examined 3 days after permanent ligation of the left anterior descending coronary artery. Unlike StAR, CYP11A1 and 3β-hydroxysteroid dehydrogenase proteins were not observed in the postinfarction heart, suggesting an apparent lack of de novo cardiac steroidogenesis. Work with primary cultures of rat heart cells revealed that StAR is induced in fibroblasts responding to proapoptotic treatments with hydrogen peroxide or the kinase inhibitor staurosporine (STS). Such induction of StAR in culture was noted before spontaneous differentiation of the fibroblasts to myofibroblasts. STS induction of StAR in the cardiac fibroblasts conferred a marked resistance to apoptotic cell death. Consistent with that finding, down-regulation of StAR by RNA interference proportionally increased the number of STS-treated apoptotic cells. StAR down-regulation also resulted in a marked increase of BAX activation in the mitochondria, an event known to associate with the onset of apoptosis. Last, STS treatment of HeLa cells showed that apoptotic demise characterized by mitochondrial fission, cytochrome c release, and nuclear fragmentation is arrested in individual HeLa cells overexpressing StAR. Collectively, our in vivo and ex vivo evidence suggests that postinfarction expression of nonsteroidogenic StAR in cardiac fibroblasts has novel antiapoptotic activity, allowing myofibroblast precursor cells to survive the traumatized event, probably to differentiate and function in tissue repair at the infarction site. © 2013 by The Endocrine Society. Source
Barzelay A.,Tel Aviv Sourasky Medical Center |
Hochhauser E.,The Cardiac Research Laboratory |
Entin-Meer M.,Tel Aviv Sourasky Medical Center |
Chepurko Y.,The Cardiac Research Laboratory |
And 9 more authors.
Atherosclerosis | Year: 2012
Objective: The LIM-homeobox transcription factor Isl1 plays a crucial role during heart embryogenesis and later on gives rise to adult resident cardiac stem cells. In this study, we aimed to discover new extra cardiac populations of Isl1 stem cells. We then investigated endogenous Isl1 kinetics after myocardial infarction (MI), and the effect of intra-myocardial gene transfer of naked DNA encoding Isl1 on functional recovery after MI. Methods: We used the transgenic mice Isl1/cre/Z/EG for lineage tracing of extra cardiac Isl1 stem cells. Non transgenic mice were used to study Isl1 kinetics post-MI by RT-PCR and FACS analysis. MI was induced in non transgenic mice by permanent ligation of the left anterior descending coronary artery (LAD). Naked DNA encoding Isl1 was injected to the peri-infarct region. Evaluation of cardiac performance was conducted by echocardiogram. Analysis of myocardial fibrosis and number of vessels was performed on histological cryosections. Results and conclusions: Isl1 gives rise to subpopulations of progenitors in both the bone marrow and spleen, and is re-expressed in the spleen and left ventricle following MI. Intramyocardial gene transfer of Isl1 to the border zone of the infarcted hearts resulted in partial salvage of left ventricular function, enhanced vascularization, and reduced myocardial fibrosis.The Isl1 gene appears to be an attractive reparative target for future management of myocardial dysfunction. © 2012 Elsevier Ireland Ltd. Source