Stromal Cell-Derived Factor-1 Is Cardioprotective After Myocardial Infarction

Gladstone Institute of Cardiovascular Disease, 1650 Owens St, San Francisco, CA 94158, USA.
Circulation (Impact Factor: 14.43). 05/2008; 117(17):2224-31. DOI: 10.1161/CIRCULATIONAHA.107.694992
Source: PubMed


Heart disease is a leading cause of mortality throughout the world. Tissue damage from vascular occlusive events results in the replacement of contractile myocardium by nonfunctional scar tissue. The potential of new technologies to regenerate damaged myocardium is significant, although cell-based therapies must overcome several technical barriers. One possible cell-independent alternative is the direct administration of small proteins to damaged myocardium.
Here we show that the secreted signaling protein stromal cell-derived factor-1alpha (SDF-1alpha), which activates the cell-survival factor protein kinase B (PKB/Akt) via the G protein-coupled receptor CXCR4, protected tissue after an acute ischemic event in mice and activated Akt within endothelial cells and myocytes of the heart. Significantly better cardiac function than in control mice was evident as early as 24 hours after infarction as well as at 3, 14, and 28 days after infarction. Prolonged survival of hypoxic myocardium was followed by an increase in levels of vascular endothelial growth factor protein and neoangiogenesis. Consistent with improved cardiac function, mice exposed to SDF-1alpha demonstrated significantly decreased scar formation than control mice.
These findings suggest that SDF-1alpha may serve a tissue-protective and regenerative role for solid organs suffering a hypoxic insult.

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Available from: Jason E Fish, Oct 04, 2015
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    • "It acts as the unique ligand for its receptor CXCR4 and the SDF-1–CXCR4 axis is up-regulated in both experimental and clinical studies of myocardial infarction (Zaruba & Franz, 2010). SDF-1α–CXCR4 has been utilised to target stem cells to ischaemic tissue, thereby improving left ventricular (LV) dimensions and function (Misao et al., 2006; Sasaki et al., 2007; Saxena et al., 2008; Tang et al., 2010). Importantly, the SDF-1α–CXCR4 signalling axis exerts these effects via a Gα1 dependent mechanism and activation of phosphoinositide 3 kinase (PI3K), mitogen activated protein kinase (MAPK), and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signalling. "
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    ABSTRACT: Alleviating myocardial injury associated with ST elevation myocardial infarction is central to improving the global burden of coronary heart disease. The chemokine stromal cell-derived factor 1α (SDF-1α) has dual potential benefit in this regard. Firstly, SDF-1α is up-regulated in experimental and clinical studies of acute myocardial infarction (AMI) and regulates stem cell migration to sites of injury. SDF-1α delivery to the myocardium after AMI is associated with improved stem cell homing, angiogenesis, and left ventricular function in animal models, and improvements in heart failure and quality of life in humans. Secondly, SDF-1α may have a role in remote ischaemic conditioning (RIC), the phenomenon whereby non-lethal ischaemia-reperfusion applied to an organ or tissue remote from the heart protects the myocardium from lethal ischaemia-reperfusion injury (IRI). SDF-1α is increased in the serum of rats subjected to RIC and protects against myocardial IRI in ex vivo studies. Despite these potential pleiotropic effects, a limitation of SDF-1α is its short plasma half-life due to cleavage by dipeptidyl peptidase-4 (DPP-4). However, DPP-4 inhibitors increase the half-life of SDF-1α by preventing its degradation and are also protective against lethal IRI. In summary, SDF-1 potentially delivers a 'two-pronged' defence of the myocardium: acutely protecting it from IRI while simultaneously stimulating repair by recruiting stem cells to the site of injury. In this article we examine the evidence for acute and chronic cardioprotective roles of SDF-1α and discuss potential therapeutic manipulations of this mechanism with DPP-4 inhibitors to protect against lethal tissue injury in the clinical setting.
    Pharmacology [?] Therapeutics 04/2014; 143(3). DOI:10.1016/j.pharmthera.2014.03.009 · 9.72 Impact Factor
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    • "This favourable effect is due likely to preservation of myocardial tissue rather than through recruitment of stem cells. In fact, SDF1 has been shown to promote cell survival in a variety of cells including CMCs [104]. "
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    ABSTRACT: Although the adult mammalian heart was once believed to be a post-mitotic organ without any capacity for regeneration, recent findings have challenged this dogma. A modified view assigns to the mammalian heart a measurable capacity for regeneration throughout life. The ultimate goals of the cardiac regeneration field have been pursued by multiple strategies, including understanding the developmental biology of cardiomyocytes and cardiac stem and progenitor cells, applying chemical genetics, and engineering biomaterials and delivery methods that facilitate cell transplantation. Successful stimulation of endogenous regenerative capacity in injured adult mammalian hearts can benefit from studies of natural cardiac regeneration.
    Stem cell reviews 08/2013; 9(6). DOI:10.1007/s12015-013-9461-4 · 2.77 Impact Factor
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    • "Cardioprotective SDF-1α/CXCL12 activates the cell-survival factor protein kinase B (PKB/Akt) via Cxcr4 and protects ischemic myocardium. This decreases scar size and mediates neovascularization in mice and rats [24, 34]. The interaction between SDF-1α/CXCL12 and Cxcr4 has been increasingly exploited in an effort to enhance the efficacy of stem cell therapy after MI [42, 51]. "
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    ABSTRACT: Modern life styles have made cardiovascular disease the leading cause of morbidity and mortality worldwide. Although current treatments substantially ameliorate patients' prognosis after MI, they cannot restore the affected tissue or entirely re-establish organ function. Therefore, the main goal of modern cardiology should be to design strategies to reduce myocardial necrosis and optimize cardiac repair following MI. Cell-based therapy was considered a novel and potentially new strategy in regenerative medicine; however, its clinical implementation has not yielded the expected results. Chemokines seem to increase the efficiency of cell-therapy and may represent a reliable method to be exploited in the future. This review surveys current knowledge of cell therapy and highlights key insights into the role of chemokines in stem cell engraftment in infarcted myocardium and their possible clinical implications.
    Current Stem Cell Research & Therapy 04/2013; 8(4). DOI:10.2174/1574888X11308040003 · 2.21 Impact Factor
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