Inflammatory Crossroads between atherosclerosis and

metabolic disease

Davos, Cardiology Update 2011

Christian M. Matter, MD

Cardiovascular Research

Institute of Physiology, Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich and

Cardiology, Cardiovascular Center, University Hospital, Zurich

Cardiovascular Risk Factors

GeneticsHypercholesterolemia

Diabetes Hypertension

SmokingObesity

Inflammation

Atherogenesis - Inflammation

Inflammation: Obesity, T2DM, Atherosclerosis

Wellen & Hotamisligil, JCI 2003

Epidemic of T2DM (and obesity)

Hossain et al NEJM 2007

Obesity – Inflammation – Atherosclerosis

Matter & Handschin, Circulation 2007

Hotamisligil, Nature 2006

Inflammation – Obesity – Diabetes – Athero

SIRT1 – from Yeast to Men

Guarente, Cell 2008

SIRT1, a conserved deacetylase

Resveratrol activates SIRT1

Koo & Montminy, Cell 2006

SIRT1 Effects

Finkel, Nature 2009

SIRT1 – Role in Atherosclerosis?

inflammationNF-kB ↓

endothelial functioneNOS↑

Effects onSIRT1 of plaque

formation?

Mφ/lipid metabolismLXR↑PPARγ ↓

Published:

Decreased SIRT1 expression in atherosclerosis

Stein et al, EHJ 2010

SIRT1 deletion increases atherosclerosis

Stein et al, EHJ 2010

Potential causes: SIRT1 – Atherosclerosis

Chol Uptake- SRA- CD36- Lox-1

SIRT1 decreases foam cells

Stein et al, EHJ 2010

SIRT1 decreases LOX-1 – via NFkB

Stein et al, EHJ 2010

SIRT1 deficiency enhances plaque inflammation

Stein et al, Aging 2010

SIRT1 decreases endothelial activation

Stein et al, Aging 2010

Summary: SIRT1 – Atherosclerosis

SIRT1 reduces TF activity and thrombosis

Breitenstein & Stein et al, CVR 2010

laser beam-induced

thrombosis model

Summary

Atherosclerosis, obesity, T2DM, share inflammatory mediators

SIRT1: Protects from obesity, T2DM.

SIRT1 may inhibit atherothrombosis:

Anti-atherosclerotic via NFkB

LOX-1 (macroph) and ROS (EC)

Anti-thrombotic via tissue factor

Inhibition of SIRT1 may offer attractive protective therapies for atherosclerosis, obesity, and T2DM....

Perspective: SIRT1 activators

Stein & Matter, Cell Cycle 2011

THANKS !

Cardiovascular Research, University of Zurich

Thomas F. Lüscher

Tobias von Lukowicz, Pia K. Schuler, Romeo Ricci, Uelkan Kilic,

Christine Lohmann, Nicola Schäfer, Chad Brokopp, Sokrates Stein,

Stephan Winnik, Roland Klingenberg, Margot Crucet, Matthias Hasun

Zurich Center for Integrative Human Physiology (ZIHP)

Alfred Buck, Bruno Weber, Philipp A. Kaufmann

Arnold von Eckardstein, Dario Neri

Max Gassmann, François Verrey, Carsten Wagner

Marc Y. Donath, Christoph Handschin

Michael O. Hottiger, Paul O. Hassa; Ernst Beinder, Andreas Zisch

University of Geneva

Brenda Kwak, François Mach

University of Ottawa

Michael McBurney

University Lausanne, EPFL

Walter Wahli, Johan Auwerx

Sirtris, Boston

Jennifer Cermak, George Vlasuk

Goteborg University

Jan Borén

Kantonsspital Baden

Jürg H. Beer

Lack of JNK2 diminishes endothelial dysfunction

Osto, Matter et al, Circulation 2008

Hypercholesterolemia (HCD)-induced endothelial dysfunction

Osto, Matter et al, Circulation 2008

Lack of JNK-2 decreases vascular ROS

Some SIRT1 (non-histone) substrates

Protein Paper Function

eNOS Mattagajasingh, PNAS (2007)Nisoli, Science (2005)

Endothelial nitric oxide synthase

Foxo3a Motta, Cell (2003) Forkhead-induced apoptosis

Ku70 (via PCAF/GCN5) Cohen, Mol Cell (2004) Bax-induced apoptosis

LXR Li, Mol Cell (2007) Highly expressed in liver, adipose, intestine and Mφ

MyoD (via PCAF/GCN5) Fulco, Mol Cell (2003) Muscle cell differentiation

NF-κB Yeung, EMBO (2004) Survival x apoptosis

p300 Motta, Cell (2004) Forkhead-induced apoptosis

p53 Luo, Cell (2001) & Vaziri, Cell (2001) Apoptosis

PCAF (PCAF/GCN5) Fulco, Mol Cell (2003)Cohen, Mol Cell (2004)

Muscle cell differentiationBax-induced apoptosis

PGC-1α Rodgers, Nature (2005) Transcriptional coactivator of eg. FOXO1, ERRα and PPARα

PPARγ Picard, Nature (2004) Induces adipogenesis

TAFI68 Muth, EMBO (2001) Subunit of the TATA box-binding protein (TBP)-containing factor TIF-IB/SL1

UCP2 Bordone, PloS Biol (2006) Regulation of insulin secretion in pancreatic beta cells

Macrophages and atherosclerosis

Libby, Nature 2002

Wellen & Hotamisligil, JCI 2005

Similarities: Macrophages – adipocytes

Stress-activated MAPK signaling modules

Davis, Cell 2000

JNK2 is required for atherosclerosis

JNK2 – role in atherogenesis, SR-A (pharmacological & genetic approach)

JNK1 – a bridge to metabolic stress

Ricci et al, Science 2004

Lack of JNK2 increases SR-A expression

Decreased foam cell formation in ApoE-/- JNK2-/- macrophages Increased Dil-acLDL binding Increased SR-A expression Decreased P-Ser

Ricci et al, Science 2004

Calorie restriction prolongs life in many species

Saccharomyces cerevisiae (yeast): Jiang, FASEB J, 2000

Drosophila melanogaster (fly): Mair, Science, 2003

Caenorhabditis elegans (nematode): Lakowski, PNAS, 1998

Daphnia longispina (crustacean): Ingle, J. Exp. Zool., 1937

Frontinella pyramitela (spider): Austad, Exp. Gerontol., 1989

Mus musculus (mice): Weindruch, Science, 1982

Macaca mulatta (rhesus mokey): Mattison, Interdiscip. Top. Gerontol., 2007

Metabolic Syndrome – Caloric Restriction

Guarente, Nature 2006

SIRT1 – a NAD+-dependent protein deacetylase

Sirt1 metabolic sensor of NAD/NADH levelsDeacetylation inhibits transcription

Michan & Sinclair, Biochem J, 2007

SIRT1 activation may reduce athero-thrombosis