Ivana Bulatovic

Karolinska University Hospital, Tukholma, Stockholm, Sweden

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Publications (4)29.25 Total impact

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    ABSTRACT: Generation of new cardiomyocytes is critical for cardiac repair following myocardial injury, but which kind of stimuli is most important for cardiomyocyte regeneration is still unclear. Here we explore if apoptotic stimuli, manifested through caspase activation, influences cardiac progenitor up-regulation and cardiomyocyte differentiation. Using mouse embryonic stem cells as a cellular model, we show that sublethal activation of caspases increases the yield of cardiomyocytes while concurrently promoting the proliferation and differentiation of c-Kit+/α-actininlow cardiac progenitor cells. A broad-spectrum caspase inhibitor blocked these effects. In addition, the caspase inhibitor reversed the mRNA expression of genes expressed in cardiomyocytes and their precursors. Our study demonstrates that sublethal caspase-activation has an important role in cardiomyocyte differentiation and may have significant implications for promoting cardiac regeneration after myocardial injury involving exogenous or endogenous cell sources.
    PLoS ONE 03/2015; 10(3):e0120176. DOI:10.1371/journal.pone.0120176 · 3.53 Impact Factor
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    ABSTRACT: Rationale: The ability of a cell to independently regulate nuclear and cytosolic Ca(2+) signalling is currently attributed to the differential distribution of IP3R channel isoforms in the nucleoplasmic versus the endoplasmic reticulum. In cardiac myocytes, T-tubules confer the necessary compartmentation of Ca(2+) signals that allows sarcomere contraction in response to plasma membrane depolarization, but whether there is a similar structure tunneling extracellular stimulation to control nuclear Ca(2+) signals locally has not been explored. Objective: To study the role of perinuclear sarcolemma in selective nuclear Ca(2+) signalling. Methods and Results: We report here that IGF-1 triggers a fast and independent nuclear Ca(2+) signal in neonatal rat cardiac myocytes, human embryonic cardiac myocytes and adult rat cardiac myocytes. This fast and localized response is achieved by activation of IGF-1R signalling complexes present in perinuclear invaginations of the plasma membrane. The perinuclear IGF-1R pool connects extracellular stimulation to local activation of nuclear Ca(2+)-signalling and transcriptional up-regulation through the perinuclear hydrolysis of PIP(2), IP(3) production, nuclear Ca(2+) release and activation of the transcription factor MEF2C. Genetically engineered Ca(2+) buffers -parvalbumin- with cytosolic or nuclear localization demonstrated that the nuclear Ca(2+) handling system is physically and functionally segregated from the cytosolic Ca(2+) signalling machinery. Conclusions: These data reveal the existence of an IP(3)-dependent nuclear Ca(2+) toolkit located in direct apposition to the cell surface, which allows the local control of rapid and independent activation of nuclear Ca(2+) signalling in response to an extracellular ligand.
    Circulation Research 11/2012; 112(2). DOI:10.1161/CIRCRESAHA.112.273839 · 11.09 Impact Factor
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    ABSTRACT: Rationale: The ability of a cell to independently regulate nuclear and cytosolic Ca(2+) signalling is currently attributed to the differential distribution of IP3R channel isoforms in the nucleoplasmic versus the endoplasmic reticulum. In cardiac myocytes, T-tubules confer the necessary compartmentation of Ca(2+) signals that allows sarcomere contraction in response to plasma membrane depolarization, but whether there is a similar structure tunneling extracellular stimulation to control nuclear Ca(2+) signals locally has not been explored. Objective: To study the role of perinuclear sarcolemma in selective nuclear Ca(2+) signalling. Methods and Results: We report here that IGF-1 triggers a fast and independent nuclear Ca(2+) signal in neonatal rat cardiac myocytes, human embryonic cardiac myocytes and adult rat cardiac myocytes. This fast and localized response is achieved by activation of IGF-1R signalling complexes present in perinuclear invaginations of the plasma membrane. The perinuclear IGF-1R pool connects extracellular stimulation to local activation of nuclear Ca(2+)-signalling and transcriptional up-regulation through the perinuclear hydrolysis of PIP(2), IP(3) production, nuclear Ca(2+) release and activation of the transcription factor MEF2C. Genetically engineered Ca(2+) buffers -parvalbumin- with cytosolic or nuclear localization demonstrated that the nuclear Ca(2+) handling system is physically and functionally segregated from the cytosolic Ca(2+) signalling machinery. Conclusions: These data reveal the existence of an IP(3)-dependent nuclear Ca(2+) toolkit located in direct apposition to the cell surface, which allows the local control of rapid and independent activation of nuclear Ca(2+) signalling in response to an extracellular ligand.
    Circulation Research 11/2012; · 11.09 Impact Factor
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    ABSTRACT: To explore how cardiac regeneration and cell turnover adapts to disease, different forms of stress were studied for their effects on the cardiac progenitor cell markers c-Kit and Isl1, the early cardiomyocyte marker Nkx2.5, and mast cells. Adult female rats were examined during pregnancy, after myocardial infarction and ischemia-reperfusion injury with/out insulin like growth factor-1(IGF-1) and hepatocyte growth factor (HGF). Different cardiac sub-domains were analyzed at one and two weeks post-intervention, both at the mRNA and protein levels. While pregnancy and myocardial infarction up-regulated Nkx2.5 and c-Kit (adjusted for mast cell activation), ischemia-reperfusion injury induced the strongest up-regulation which occurred globally throughout the entire heart and not just around the site of injury. This response seems to be partly mediated by increased endogenous production of IGF-1 and HGF. Contrary to c-Kit, Isl1 was not up-regulated by pregnancy or myocardial infarction while ischemia-reperfusion injury induced not a global but a focal up-regulation in the outflow tract and also in the peri-ischemic region, correlating with the up-regulation of endogenous IGF-1. The addition of IGF-1 and HGF did boost the endogenous expression of IGF and HGF correlating to focal up-regulation of Isl1. c-Kit expression was not further influenced by the exogenous growth factors. This indicates that there is a spatial mismatch between on one hand c-Kit and Nkx2.5 expression and on the other hand Isl1 expression. In conclusion, ischemia-reperfusion injury was the strongest stimulus with both global and focal cardiomyocyte progenitor cell marker up-regulations, correlating to the endogenous up-regulation of the growth factors IGF-1 and HGF. Also pregnancy induced a general up-regulation of c-Kit and early Nkx2.5+ cardiomyocytes throughout the heart. Utilization of these pathways could provide new strategies for the treatment of cardiac disease.
    PLoS ONE 05/2012; 7(5):e36804. DOI:10.1371/journal.pone.0036804 · 3.53 Impact Factor