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AKT2 Promotes Bone Marrow Cell-Mediated Aortic Protection in Mice

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Presentation on theme: "AKT2 Promotes Bone Marrow Cell-Mediated Aortic Protection in Mice"— Presentation transcript:

1 AKT2 Promotes Bone Marrow Cell-Mediated Aortic Protection in Mice
Sili Zou, MD, PhD, Pingping Ren, MD, PhD, Lin Zhang, MS, Alon R. Azares, BS, Sui Zhang, MD, PhD, Joseph S. Coselli, MD, Ying H. Shen, MD, PhD, Scott A. LeMaire, MD  The Annals of Thoracic Surgery  Volume 101, Issue 6, Pages (June 2016) DOI: /j.athoracsur Copyright © 2016 The Society of Thoracic Surgeons Terms and Conditions

2 Fig 1 Increased susceptibility to aortic aneurysm and dissection (AAD) development in mice with Akt2-deficient bone marrow cells (BMCs). (A) Schematic illustration of the study design. Wild-type (WT) mice were irradiated (IR) and were then administered green fluorescent protein (GFP+) BMCs from either WT mice (GFP+ WT BMCs) or Akt2-/- mice (GFP+ Akt2-/- BMCs). Four weeks later, the mice were either unchallenged with saline or challenged with continuous angiotensin II (Ang II) infusion for 4 weeks. (BMT = bone marrow transplant.) (B) The BM reconstitution rate in GFP+ chimeric mice was 98%. (C) Representative aortas show the development of AAD in challenged Akt2-/- BMT mice but not in challenged WT BMT mice. (D) Comparison of aortic diameters among unchallenged WT BMT mice, challenged WT BMT mice, and challenged Akt2-/- BMT mice. (Arch [dark gray]; Asc = ascending [black]; Desc = descending [gray]; IR = infrarenal [white]; SR = suprarenal [light gray]. (E) None of the challenged WT BMT mice (0 of 14) had AAD, but 64% (9 of 14) of the challenged Akt2-/- BMT mice had AAD. The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2016 The Society of Thoracic Surgeons Terms and Conditions

3 Fig 2 Increased aortic damage in mice with Akt2-deficient bone marrow (BM) cells. Representative images of (A) hematoxylin and eosin staining and (B) elastic fiber staining in unchallenged or challenged wild-type (WT) BM transplant (BMT) mice, challenged Akt2-/- BMT mice, and 2 challenged Akt2-/- BMT mice with aneurysm and dissection (AAD). The insets show higher magnification views of the regions indicated. (C) Quantitative analysis of aortic medial thickness in groups of mice shown in A and B and in challenged Akt2-/- BMT mice without (w/o) AAD. The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2016 The Society of Thoracic Surgeons Terms and Conditions

4 Fig 3 Reduced bone marrow (BM) cell recruitment in the aortic wall of mice with Akt2-deficient BM cells. (A) Representative immunofluorescence images and (B) quantitative analysis showing the recruitment of BM-derived (green fluorescent protein [GFP+]) cells in challenged or unchallenged wild-type (WT) BM transplant (BMT) mice and challenged Akt2-/- BMT mice with or without (w/o) aortic aneurysm and dissection (AAD). (DAPI = 4′,6-diamidino-2-phenylindole.) The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2016 The Society of Thoracic Surgeons Terms and Conditions

5 Fig 4 Reduced induction of bone marrow (BM) cell–derived pericytes/vascular progenitors in the aortic wall of mice with Akt2-deficient BM cells. (A) Representative immunofluorescence images. Insets show higher magnification views of the regions indicated. Quantitative analysis showing induction of (B) total (neuron-glial antigen 2 [NG2+]), (C) BM-derived (green fluorescent protein [GFP+]NG2+), and (D) resident (GFP-NG2+) pericytes in the aortic wall of unchallenged or challenged wild-type (WT) BM transplant (BMT) mice and challenged Akt2-/- BMT mice with or without (w/o) aortic aneurysm and dissection (AAD). (E) Activation of NG2+ cells in BM-derived cells (GFP+NG2+ cells/GFP+ cells) is also shown. (DAPI = 4′,6-diamidino-2-phenylindole.) The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2016 The Society of Thoracic Surgeons Terms and Conditions

6 Fig 5 Reduced induction of fibroblasts in the aortic wall of mice with Akt2-deficient bone marrow (BM) cells. (A) Representative immunofluorescence images. The insets show higher magnification views of the regions indicated. Quantitative analysis showing induction of (B) total (fibroblast-specific protein 1 [FSP1+]), (C) BM-derived (green fluorescent protein [GFP+]FSP1+), and (D) resident (GFP-FSP1+) fibroblasts in the aortic wall of unchallenged or challenged wild-type (WT) BM transplant (BMT) mice and challenged Akt2-/- BMT mice with or without (w/o) aneurysm and dissection (AAD). (E) Activation of fibroblasts in BM-derived cells (GFP+ FSP1+ cells/GFP+ cells) is also shown. (DAPI = 4′,6-diamidino-2-phenylindole.) The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2016 The Society of Thoracic Surgeons Terms and Conditions

7 Fig 6 Increased induction of macrophages in the aortic wall of mice with Akt2-deficient bone marrow (BM) cells. (A) Representative immunofluorescence images. The insets show higher magnification views of the regions indicated. Quantitative analysis showing induction of (B) total (CD68+), (C) BM-derived (GFP+CD68+), and (D) resident (GFP-CD68+) macrophages in the aortic wall of unchallenged or challenged wild-type (WT) BM transplant (BMT) mice and challenged Akt2-/- BMT mice with or without (w/o) aortic aneurysm and dissection (AAD). (DAPI = 4′,6-diamidino-2-phenylindole.) The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2016 The Society of Thoracic Surgeons Terms and Conditions

8 Fig 7 Critical role of Akt2 in bone marrow cell (BMC)-mediated aortic cell survival. (A) Representative images. (DAPI = DAPI = 4′,6-diamidino-2-phenylindole; TUNEL = terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling.) (B) Quantitative data from TUNEL analysis showing more apoptotic cells in the aortic wall of challenged Akt2-/- bone marrow transplant (BMT) mice than in that of challenged wild-type (WT) BMT mice. (C, D) Smooth muscle cells (SMCs) cocultured with either WT BMCs or Akt2-/- BMCs were treated with hydrogen peroxide. The protective effect of WT BMCs on SMCs was significantly diminished in SMCs cocultured with Akt2-/- BMCs. (Solid bars = unchallenged; open bars = hydrogen peroxide treated, 0.3 mM.) The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2016 The Society of Thoracic Surgeons Terms and Conditions

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