title: HASF is a stem cell paracrine factor that activates PKC epsilon mediated cytoprotection.
abstract: Despite advances in the treatment of acute tissue ischemia significant challenges remain in effective cytoprotection from ischemic cell death. It has been documented that injected stem cells, such as mesenchymal stem cells (MSCs), can confer protection to ischemic tissue through the release of paracrine factors. The study of these factors is essential for understanding tissue repair and the development of new therapeutic approaches for regenerative medicine. We have recently shown that a novel factor secreted by MSCs, which we called HASF (Hypoxia and Akt induced Stem cell Factor), promotes cardiomyocyte proliferation. In this study we show that HASF has a cytoprotective effect on ischemia induced cardiomyocyte death. We assessed whether HASF could potentially be used as a therapeutic agent to prevent the damage associated with myocardial infarction. In vitro treatment of cardiomyocytes with HASF protein resulted in decreased apoptosis; TUNEL positive nuclei were fewer in number, and caspase activation and mitochondrial pore opening were inhibited. Purified HASF protein was injected into the heart immediately following myocardial infarction. Heart function was found to be comparable to sham operated animals one month following injury and fibrosis was significantly reduced. In vivo and in vitro HASF activated protein kinase C ε (PKCε). Inhibition of PKCε blocked the HASF effect on apoptosis. Furthermore, the beneficial effects of HASF were lost in mice lacking PKCε. Collectively these results identify HASF as a protein of significant therapeutic potential, acting in part through PKCε.
authors.affiliation: Duke Cardiovascular Research Center, Duke University Medical Center, NC 27710, USA; Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, NC 27710, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Duke Cardiovascular Research Center, Duke University Medical Center, NC 27710, USA; Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, NC 27710, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.affiliation: Duke Cardiovascular Research Center, Duke University Medical Center, NC 27710, USA; Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, NC 27710, USA.
authors.forename: Farideh
authors.initials: F
authors.lastname: Beigi
authors.affiliation: Duke Cardiovascular Research Center, Duke University Medical Center, NC 27710, USA; Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, NC 27710, USA.
authors.forename: Conrad P
authors.initials: CP
authors.lastname: Hodgkinson
authors.affiliation: Duke Cardiovascular Research Center, Duke University Medical Center, NC 27710, USA; Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, NC 27710, USA.
authors.forename: Heberty T
authors.initials: HT
authors.lastname: Facundo
authors.affiliation: Duke Cardiovascular Research Center, Duke University Medical Center, NC 27710, USA; Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, NC 27710, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Duke Cardiovascular Research Center, Duke University Medical Center, NC 27710, USA; Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, NC 27710, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Espinoza-Derout
authors.affiliation: Duke Cardiovascular Research Center, Duke University Medical Center, NC 27710, USA; Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, NC 27710, USA.
authors.forename: Xiyou
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Duke Cardiovascular Research Center, Duke University Medical Center, NC 27710, USA; Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, NC 27710, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Pratt
authors.affiliation: Duke Cardiovascular Research Center, Duke University Medical Center, NC 27710, USA; Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, NC 27710, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Mirotsou
authors.affiliation: Duke Cardiovascular Research Center, Duke University Medical Center, NC 27710, USA; Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, NC 27710, USA. Electronic address: victor.dzau@duke.edu.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Dzau
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects; D019610:Cytoprotection; D005786:Gene Expression Regulation; D006801:Humans; D020287:In Situ Nick-End Labeling; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019899:Paracrine Communication / Q000235:genetics; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C532315:GoPro49 protein, mouse; D008565:Membrane Proteins; D051744:Protein Kinase C-epsilon
keywords: Cytoprotection; Ischemia; Mesenchymal stem cell; PKC epsilon; Paracrine