Talya Razin1, Naomi Melamed-Book2, Jasmin Argaman3, Iris Galin4, Yosef Lowy5, Eli Anuka6, Nili Naftali-Shani7, Michal Kandel-Kfir8, Benjamin P Garfinkel9, Shlomi Brielle10, Zvi Granot11, Ron N Apte12, Simon J Conway13, Jeffery D Molkentin14, Yehuda Kamari15, Jonathan Leor16, Joseph Orly17. 1. Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel. Electronic address: talya.razin@mail.huji.ac.il. 2. Bio-Imaging Unit, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel. Electronic address: book@mail.huji.ac.il. 3. Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel. 4. Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel. Electronic address: Iris.Galin@mail.huji.ac.il. 5. Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel. Electronic address: yosef.levi1@mail.huji.ac.il. 6. Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel. Electronic address: eli.anuka@mail.huji.ac.il. 7. Neufeld Cardiac Research Institute, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Tamman Cardiovascular Research Institute, and Sheba Center of Regenerative Medicine, Stem Cells and Tissue Engineering, Sheba Medical Center, Tel-Hashomer, Israel. Electronic address: Nili.Naftali-shani@sheba.health.gov.il. 8. Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel, Sackler Faculty of Medicine, Tel-Aviv University, Israel. Electronic address: Michal.KandelKfir-@sheba.health.gov.il. 9. Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel. Electronic address: bgarfinkel@hsph.harvard.edu. 10. Department of Cell and Developmental Biology, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel. Electronic address: shlomi.brielle@mail.huji.ac.il. 11. Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University Medical School, 91120 Jerusalem, Israel. Electronic address: zvikag@ekmd.huji.ac.il. 12. Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University, Beer-Sheva, Israel. Electronic address: rapte@bgu.ac.il. 13. Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, IN 46202, United States. Electronic address: siconway@iu.edu. 14. Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH, United States. Electronic address: Jeff.Molkentin@cchmc.org. 15. Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel, Sackler Faculty of Medicine, Tel-Aviv University, Israel. Electronic address: yehuda.kamari@sheba.health.gov.il. 16. Neufeld Cardiac Research Institute, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Tamman Cardiovascular Research Institute, and Sheba Center of Regenerative Medicine, Stem Cells and Tissue Engineering, Sheba Medical Center, Tel-Hashomer, Israel. Electronic address: jonathan.leor@sheba.health.gov.il. 17. Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel. Electronic address: orly@vms.huji.ac.il.
Abstract
AIMS: One unaddressed aspect of healing after myocardial infarction (MI) is how non-myocyte cells that survived the ischemic injury, keep withstanding additional cellular damage by stress forms typically arising during the post-infarction inflammation. Here we aimed to determine if cell survival is conferred by expression of a mitochondrial protein novel to the cardiac proteome, known as steroidogenic acute regulatory protein, (StAR/STARD1). Further studies aimed to unravel the regulation and role of the non-steroidogenic cardiac StAR after MI. METHODS AND RESULTS: Following permanent ligation of the left anterior descending coronary artery in mouse heart, timeline western blot analyses showed that StAR expression corresponds to the inflammatory response to MI. Following the identification of StAR in mitochondria of cardiac fibroblasts in culture, confocal microscopy immunohistochemistry (IHC) identified StAR expression in left ventricular (LV) activated interstitial fibroblasts, adventitial fibroblasts and endothelial cells. Further work with the primary fibroblasts model revealed that interleukin-1α (IL-1α) signaling via NF-κB and p38 MAPK pathways efficiently upregulates the expression of the Star gene products. At the functional level, IL-1α primed fibroblasts were protected against apoptosis when exposed to cisplatin mimicry of in vivo apoptotic stress; yet, the protective impact of IL-1α was lost upon siRNA mediated StAR downregulation. At the physiological level, StAR expression was nullified during post-MI inflammation in a mouse model with global IL-1α deficiency, concomitantly resulting in a 4-fold elevation of apoptotic fibroblasts. Serial echocardiography and IHC studies of mice examined 24 days after MI revealed aggravation of LV dysfunction, LV dilatation, anterior wall thinning and adverse tissue remodeling when compared with loxP control hearts. CONCLUSIONS: This study calls attention to overlooked aspects of cellular responses evolved under the stress conditions associated with the default inflammatory response to MI. Our observations suggest that LV IL-1α is cardioprotective, and at least one mechanism of this action is mediated by induction of StAR expression in border zone fibroblasts, which renders them apoptosis resistant. This acquired survival feature also has long-term ramifications on the heart recovery by diminishing adverse remodeling and improving the heart function after MI.
AIMS: One unaddressed aspect of healing after myocardial infarction (MI) is how non-myocyte cells that survived the ischemic injury, keep withstanding additional cellular damage by stress forms typically arising during the post-infarction inflammation. Here we aimed to determine if cell survival is conferred by expression of a mitochondrial protein novel to the cardiac proteome, known as steroidogenic acute regulatory protein, (StAR/STARD1). Further studies aimed to unravel the regulation and role of the non-steroidogenic cardiac StAR after MI. METHODS AND RESULTS: Following permanent ligation of the left anterior descending coronary artery in mouse heart, timeline western blot analyses showed that StAR expression corresponds to the inflammatory response to MI. Following the identification of StAR in mitochondria of cardiac fibroblasts in culture, confocal microscopy immunohistochemistry (IHC) identified StAR expression in left ventricular (LV) activated interstitial fibroblasts, adventitial fibroblasts and endothelial cells. Further work with the primary fibroblasts model revealed that interleukin-1α (IL-1α) signaling via NF-κB and p38 MAPK pathways efficiently upregulates the expression of the Star gene products. At the functional level, IL-1α primed fibroblasts were protected against apoptosis when exposed to cisplatin mimicry of in vivo apoptotic stress; yet, the protective impact of IL-1α was lost upon siRNA mediated StAR downregulation. At the physiological level, StAR expression was nullified during post-MI inflammation in a mouse model with global IL-1α deficiency, concomitantly resulting in a 4-fold elevation of apoptotic fibroblasts. Serial echocardiography and IHC studies of mice examined 24 days after MI revealed aggravation of LV dysfunction, LV dilatation, anterior wall thinning and adverse tissue remodeling when compared with loxP control hearts. CONCLUSIONS: This study calls attention to overlooked aspects of cellular responses evolved under the stress conditions associated with the default inflammatory response to MI. Our observations suggest that LV IL-1α is cardioprotective, and at least one mechanism of this action is mediated by induction of StAR expression in border zone fibroblasts, which renders them apoptosis resistant. This acquired survival feature also has long-term ramifications on the heart recovery by diminishing adverse remodeling and improving the heart function after MI.