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Michael Autieri , PhD

Associate Professor, Physiology

Telephone:  215-707-1751

Fax:  215-707-5737

Office: MRB 810

Email: mautieri@temple.edu

Department of Physiology

Cardiovascular Research Center

PhD, Hahnemann University, Philadelphia, PA

 

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Increased intimal hyperplasia in AIF-1 transgenic mouse. Wild type (A) and transgenic mice in which AIF-1 expression is driven by the smooth muscle cell specific SM22a promoter (B) were subject to carotid artery ligation injury. Note increased neointima in AIF-1 Tg mouse.

The broad focus of my research program is the identification and characterization of proteins that play a role in progression of neointimal hyperplasia subsequent to arterial injury, including proliferative, inflammatory, and anti-inflammatory proteins. Our specific goal is to understand the molecular mechanisms of vascular smooth muscle cell activation leading to neointimal hyperplasia. We have two major areas of investigation currently NIH- funded or pending NIH funding. One is AIF-1, which is a pro-inflammatory signal transduction protein, and the other is IL-19, an anti-inflammatory, vasculoprotective cytokine.

Title: The role of Allograft Inflammatory Factor-1 in VSMC activation and vascular restenosis.
We have identified a protein termed Allograft Inflammatory Factor-1 (AIF-1), which is a cytoplasmic, calcium-binding protein. We have determined that AIF-1 expression is predictive of development of clinical transplant vasculopathy. Expression of AIF-1 in injured carotid artery significantly exacerbates reduction of lumen diameter and recruits bone marrow cells to the adventitia. Knock-down of AIF-1 abrogates neointimal hyperplasia. Expression of AIF-1 in human VSMC increases migration, proliferation, induces expression of G-CSF, and activates the Rac1 GTPase. AIF-1 contains several signaling domains, binds to and polymerizes actin, and interacts with signaling proteins. Our data support our central hypothesis that AIF-1 is an inflammation-responsive scaffold protein that plays a key role in regulation of VSMC activation and development of neointimal hyperplasia. Our immediate goals are to 1- determine a cause and effect relationship between AIF-1 expression and neointimal hyperplasia in vivo, and 2- characterize the cellular pathways and molecular mechanisms responsible for AIF-1 activity in VSMC. We currently utilize an AIF-1 VSMC specific transgenic mouse, in tandem with ex vivo molecular and cellular biological analysis for many of our studies. We have taken this project from an unidentified band on a differential display gel through identification of a novel gene to cellular and molecular characterization up to generation of a transgenic and pending conditional knock out mouse. Characterization of AIF-1 function will clarify our understanding of inflammation-mediated signal transduction leading to VSMC pathobiology and vascular-immune cell cross talk.

Title: Expression and direct suppressive effects of anti-inflammatory cytokines on VSMC and vascular restenosis.
Our overall hypothesis is that IL-19 plays a protective role in the vascular response to injury by at least one of two processes: 1- direct inhibitory effects on VSMC activation, and 2- attenuation of the inflammatory response. IL-19 is a recently described member of the IL-10 family of anti-inflammatory cytokines. IL-19 expression is ascribed to be restricted to hematopoetic and inflammatory cells, where it has an anti-inflammatory effect. Nothing has been reported on the mechanism(s) of IL-19 effects, either in immune or vascular cells. We have preliminary data showing; IL-19 is not expressed in quiescent vascular smooth muscle cells (VSMC) or normal arteries, but is induced in VSMC by inflammatory cytokines and in arteries by injury; IL-19 is anti-proliferative for cultured, human coronary artery VSMC, and induces phosphorylation of STAT-3 in these cells; IL-19 pre-treatment inhibits inflammation-stimulated activation of ERK1/2 and p38; inhibits inflammation-stimulated expression of proliferative and inflammatory genes including, but not limited to, IL-8, COX2, CRP, ICAM-1, cyclins, and c-fos; induces expression of the suppressor of cytokine signaling 5 (SOCS5), but inhibits expression and translocation of HuR, a transcription factor which regulates stability of inflammatory and proliferative gene mRNA. IL-19 adenoviral gene transfer significantly reduces neointimal formation in balloon angioplasty-injured rat carotid arteries. Although a great deal of attention has been given to the role and effects of pro inflammatory cytokines, little has been reported on the potential protective effects of anti-inflammatory cytokines on the vascular response to injury with respect to direct effects on VSMC pathophysiology. The overall goals of this project are designed to characterize the mechanism of IL-19 suppressive effects on VSMC and development of intimal hyperplasia; and define a role for IL-19 in vascular-immune cell communication. We propose that IL-19 is a novel factor central to both of these processes.

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Recent Medically Related Publications, Obtained from PubMed (Click on PubMed ID to view abstract)

19901155. Hinoki A, Kimura K, Higuchi S, Eguchi K, Takaguri A, Ishimaru K, Frank GD, Gerthoffer WT, Sommerville LJ, Autieri MV, Eguchi S, p21-Activated Kinase 1 Participates in Vascular Remodeling In Vitro and In Vivo. Inter-American Society of Hypertension. Hypertension :()2009 Nov 9

19601851. Cuneo AA, Autieri MV, Expression and function of anti-inflammatory interleukins: the other side of the vascular response to injury. Curr Vasc Pharmacol 7:3(267-76)2009 Jul

19095998. Suzuki H, Kimura K, Shirai H, Eguchi K, Higuchi S, Hinoki A, Ishimaru K, Brailoiu E, Dhanasekaran DN, Stemmle LN, Fields TA, Frank GD, Autieri MV, Eguchi S, Endothelial nitric oxide synthase inhibits G12/13 and rho-kinase activated by the angiotensin II type-1 receptor: implication in vascular migration. Arterioscler Thromb Vasc Biol 29:2(217-24)2009 Feb

18779232. Sommerville LJ, Xing C, Kelemen SE, Eguchi S, Autieri MV, Inhibition of allograft inflammatory factor-1 expression reduces development of neointimal hyperplasia and p38 kinase activity. Cardiovasc Res 81:1(206-15)2009 Jan 1

18669613. Tian Y, Sommerville LJ, Cuneo A, Kelemen SE, Autieri MV, Expression and suppressive effects of interleukin-19 on vascular smooth muscle cell pathophysiology and development of intimal hyperplasia. Am J Pathol 173:3(901-9)2008 Sep

17991871. Sommerville LJ, Kelemen SE, Autieri MV, Increased smooth muscle cell activation and neointima formation in response to injury in AIF-1 transgenic mice. Arterioscler Thromb Vasc Biol 28:1(47-53)2008 Jan

16291819. Tian Y, Kelemen SE, Autieri MV, Inhibition of AIF-1 expression by constitutive siRNA expression reduces macrophage migration, proliferation, and signal transduction initiated by atherogenic stimuli. Am J Physiol Cell Physiol 290:4(C1083-91)2006 Apr

16049345. Kelemen SE, Autieri MV, Expression of allograft inflammatory factor-1 in T lymphocytes: a role in T-lymphocyte activation and proliferative arteriopathies. Am J Pathol 167:2(619-26)2005 Aug

15922740. Autieri MV, Chen X, The ability of AIF-1 to activate human vascular smooth muscle cells is lost by mutations in the EF-hand calcium-binding region. Exp Cell Res 307:1(204-11)2005 Jul 1

15737749. Kelemen SF, Eisen HJ, Autieri MV, Expression of the FAST-1 transcription factor in coronary artery transplant vasculopathy and activated vascular smooth muscle cells. J Heart Lung Transplant 24:3(246-50)2005 Mar

15385271. Chen X, Kelemen SE, Autieri MV, Expression of granulocyte colony-stimulating factor is induced in injured rat carotid arteries and mediates vascular smooth muscle cell migration. Am J Physiol Cell Physiol 288:1(C81-8)2005 Jan

15320847. Autieri MV, Allograft-induced proliferation of vascular smooth muscle cells: potential targets for treating transplant vasculopathy. Curr Vasc Pharmacol 1:1(1-9)2003 Mar

15257047. Autieri MV, Kelemen SE, Gaughan JP, Eisen HJ, Early growth responsive gene (Egr)-1 expression correlates with cardiac allograft rejection. Transplantation 78:1(107-11)2004 Jul 15

15117732. Chen X, Kelemen SE, Autieri MV, AIF-1 expression modulates proliferation of human vascular smooth muscle cells by autocrine expression of G-CSF. Arterioscler Thromb Vasc Biol 24:7(1217-22)2004 Jul

15098065. Autieri MV, Antiproliferative effects of immunosuppressant drugs on vascular smooth muscle cells: an additional advantage for attenuating transplant vasculopathy. Drug News Perspect 17:2(110-6)2004 Mar

15010287. Autieri MV, Inducible expression of the signal transduction protein 14-3-3gamma in injured arteries and stimulated human vascular smooth muscle cells. Exp Mol Pathol 76:2(99-107)2004 Apr

12819813. Autieri MV, Regulating the regulators: transcription factors as targets for attenuating proliferative arteriopathies. Drug News Perspect 16:3(149-58)2003 Apr

12714565. Autieri MV, Kelemen SE, Wendt KW, AIF-1 is an actin-polymerizing and Rac1-activating protein that promotes vascular smooth muscle cell migration. Circ Res 92:10(1107-14)2003 May 30

12390951. Autieri MV, Kelemen S, Thomas BA, Feller ED, Goldman BI, Eisen HJ, Allograft inflammatory factor-1 expression correlates with cardiac rejection and development of cardiac allograft vasculopathy. Circulation 106:17(2218-23)2002 Oct 22

11557666. Autieri MV, Carbone CM, Overexpression of allograft inflammatory factor-1 promotes proliferation of vascular smooth muscle cells by cell cycle deregulation. Arterioscler Thromb Vasc Biol 21:9(1421-6)2001 Sep

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Dr. Autieri Lab is located MRB 809     215-707-2060  

Postdoctoral Fellows         

 Khatuna Gabunia         khatuna.gabunia@temple.edu                                                                                

Graduate Students

Anthony A. Cuneo          cuneoa@temple.edu

Laura Sommerville        ls1257@temple.edu

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Sheri Kelmen

Lab Manager - Autieri Lab

T:  215-707-3170

F:  215-707-5737

Email address: sheri.kelemen@temple.edu

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