Tomasz J Guzik. Diabetes, perivascular adipose tissue and inflammation.

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1 Tomasz J Guzik Diabetes, perivascular adipose tissue and inflammation. Translational Research Laboratory Department of Internal and Agricutural Medicine Jagiellonian University School of Medicine Cracow, Poland Yudkin et al, The Lancet,

2 Metabolic syndrome Vascular dysfunction Inflammation Schachinger, Circulation, 2 Blake, Ridker, Circulation, 23 Cardio-vascular disease

3 Adipocytokines Pro-inflammatory: Leptin Resistin Visfatin Anti-inflammatory: Adiponectin secreted frizzled-related protein 5 (Sfrp5) Classical cytokines IL-6 TNF-alpha RANTES MCP-1 MCP-2 Chemerin IL-1

4 Vasorelaxation (% of pre-constriction) Superoxide production LGCL (RLU/sec/mg dw) Adipocytokines and vascular function Leptin acutely impairs endothelial function Role of oxygen free radicals Endothelial function Superoxide production ACh [-log] % 2% 4% Leptin 2ng/ml 6 4 control Leptin 6% 8% 1% - p<.1 vs control - p<.5 vs leptin Leptin+ MnTPAB (5uM) Control 2 native +L-NAME endo - n=8-1

5 Endothelial function (ACh induced vasorelaxation) Endothelial function (ACh induced vasorelaxation) Relationship between plasma leptin levels and endothelial function in humans BMI>29 Plasma leptin levels (ng/ml) Plasma leptin levels (ng/ml)

6 % of CD4+ cells Pro-inflammatory effects of adipocytokines Leptin Resistin Guzik, J Physiol Pharmacol, sham 1 Leptin 5 p<.5 vs ctr CD69+ CD25+

7 Vaso-protective effects of Adiponectin Causes vasorelaxation Prevents endothelium-leukocyte interactions Fesus, Gollasch et al, Cardiovasc Res, 27 Ouedraogo, Scalia, J Clin Invest, 27

8 Why is perivascular inflammation important Adipose tissue Advances in Clinical Practice Inflammation Diabetes (T2DM) Metabolic syndrome Vascular dysfunction/ Atheroma

9 Macrophage as a key player in adipose tissue

10 Peripheral blood monocyte subpopulations Multivariate analysis of relationships to clinical risk factors for atherosclerosis n=15 patients

11 Finding the T in the fat Nat Rev Immunol, 21 obese Non-obese T cells Wu et al. Circulation. 27;115:

12 T cells can modify adipocyte differentiation in culture Adipocytes Preadipocytes + T cells Preadipocytes + T cells (highly activated Wu et al. Circulation. 27;115:

T-cell macrophage interaction in the adipose tissue inflammation in obesity T cell infiltration precedes that of macrophages in diet induced obesity Macrophage T

13 T-cell macrophage interaction in the adipose tissue inflammation in obesity T cell infiltration precedes that of macrophages in diet induced obesity Macrophage T cells (CD8+) T cells (CD4+) T reg Presence of CD8 T cells affects characteristics of macrophage dependent inflammation Nishimura et al. Nature Medicine 15, (29)

14 T regulatory cells are decreased in adipose tissue in several models of obesity Feuerer et al. Nature Medicine 15, (29)

15 Immunotherapy of insulin resistance Block TNF Reduced insulin resistance Hotamisigil, et al. Science, 1996 T cell depletion with selective increase of CD4+Foxp3+ T cell prevent insulin resistance in obesity Winer et al, Nature Medicine 15, (29

16 T cell subpopulations in obesity Lumeng, Maillard, Saltiel, Nature Medicine 15, (29)

17 Dual / Triple? Role of adipose tissue in relation to vascular disease OBESITY HEALTH CVdisase without obesity

Systolic blood pressure (mmhg) Andothelium dependent Relaxation (%) Angiotensin II induced vascular dysfunction and hypertension 14 day infusion of angiotensin

18 Systolic blood pressure (mmhg) Andothelium dependent Relaxation (%) Angiotensin II induced vascular dysfunction and hypertension 14 day infusion of angiotensin II.7 mg/kg per day or buffer (sham) Blood pressure 2 4 Vascular function Ang II Ang II infusion ACh (-Log M) 6 sham 5

19 Control Hypertension

20 Perivascular fat (AU) (pixels of fat/total vascular pixels) Perivascular fat increases with Angiotensin II infusion while visceral epidydymal fat is reduced Cells per mg (x1 4 ) Epidydymal fat (mg) Perivascular fat Amount Epidydymal fat sham Ang II sham Ang II 4 Cellularity sham Ang II sham Ang II

Perivascular adipose tissue Perilipin staining expression 5 4 3 2 1

21 Perivascular adipose tissue Perilipin staining expression Tressel S, Jo H; Emory University, unpublished Vascular Epidy dymal

22 <FITC-A> Immune cell infiltration in different compartments of adipose tissue perivascular AT VAT SAT Gr1 13% B cell 25% Other 13% NK 9 T cell 18% Macrophage 18% DC 4% B cell 9% NK 8% DC 6% Gr1 8% Othe r T cell 13% Macrophage 54% B cell 17% NK 1% DC 6% Gr1 6% T cell 11% Macrophage 5% T cell Macrophage CD45 CD11b CD3 <APC-A> I-A b

cells in AT (cells/mg) 4 3 T cells Macrophages sham Ang II 4 3 2 2 1 1 pvascat viscat sqat

23 T cells in AT (cells/mg) B cells in AT (cells/mg) T cell infiltration in vascat, viscat ans SqAT in Angiotensin II dependent hypertension I-Ab/CD11b+ cells in AT (cells/mg) I-Ab/CD11c+ cells in AT (cells/mg) 4 3 T cells Macrophages sham Ang II pvascat viscat sqat pvascat viscat sqat 4 B cells 4 CD11c+ cells pvascat viscat SQAT pvascat viscat SQAT

24 Aortic CD3 mrna copy number/milion 18s Ang II induced hypertension leads to vascular T cell infiltration in the peripheral fat Sham Ang II CD3 16 Real time PCR TcR Sham Ang II Guzik et al J Exp Med, 27 24

25 Adiponectin levels following angiotensin II infusion perivascular AT VAT SAT sham Ang II sham Ang II sham Ang

26 IL-17 Selected inflammatory genes expression in adipose tissue depots following angiotensin II infusion perivascular AT VAT SAT TNF-alpha

27 2 1 Selected inflammatory gene expression in adipose tissue depots following angiotensin II infusion perivascular AT VAT SAT sham Ang 2 1 sham Ang sham Ang sham Ang sham Ang sham Ang

28 T cell infiltration into perivascular AT following angiotensin II infusion Role of RANTES sham Ang II

Cell number/aorta (x1 4 ) Cell number/aorta (x1 5 ) WT T cell infiltration into peri-aortic wall in Angiotensin II induced hypertension Role of vascular

29 Cell number/aorta (x1 4 ) Cell number/aorta (x1 5 ) WT T cell infiltration into peri-aortic wall in Angiotensin II induced hypertension Role of vascular RANTES CD45 T cells 25.7 Total Leukocytes (CD45) 2 1 SSC CD45 CD45 CD3 WT RANTES -/- RANTES -/- 13 T cells (CD3) 6 sham Ang II 4 SSC CD45 CD45 CD3 2 WT RANTES -/-

30 Tail cuff BP [mmhg] Does loss of RANTES affect blood pressure/vascular dysfunction? Blood pressure Vascular function baseline Ang II [ACh] log M C57BL/6 ANGII RANTES-/- ANGII RANTES-/- C57BL/6 9 C57BL/6 RANTES -/ [SNP] log M

Med, 1999 Hypertension non-atherosclerotic model NO PGI 2 CNP EDHF

31 Role of inflammation in the pathogenesis of vascular dysfunction Atherosclerosis Cytokines, CRP etc ICAM-1 VCAM-1 Herrera V; Nat Med, 1999 Hypertension non-atherosclerotic model NO PGI 2 CNP EDHF ET PGH 2 O 2 - TXA 2 APPROPRIATE VASCULAR FUNCTION VASCULAR DYSFUNCTION

32 Role of inflammation in the pathogenesis of vascular dysfunction Inflammation comes from perivascular fat Adipokines NO PGI 2 CNP EDHF Cytokines ICAM-1 VCAM-1 ET PGH 2 O 2 - TXA 2 APPROPRIATE VASCULAR FUNCTION VASCULAR DYSFUNCTION Adventitia/Perivascular Adipose tissue

33 HEALTH Dual / Triple? Role of PVAT CVdisase without obesity OBESITY ADRF Adiponectin typical visceral WAT Leptin ROS Resistin Adiponectin Inflammation Change of typical AT phenotype chemokine release Vaso-protective enos signalling vasorelaxation anti-inlammatory Leukocyte rolling Adhesion molecule expression Vascular dysfunction Inflammatory cell reservoir Cytokine rerlease Incl. TNF-a

34 Collaborators Jagiellonian University School of Medicine Krakow, Poland Richard Korbut Agnieszka Kawczynska-Drozdz Tomasz Mikolajczyk Dominik Ludew Grzegorz Osmenda Ryszard Nosalski Karol Urbanski Pawel Matusik Emory University School of Medicine Atlanta GA David G Harrison Klaudia Budzyn Heinrich Lob Ayaz Rahman Louise McCann Stanford University, Department of Immunollogy Cornelia Weyand Jorg Goronzy

Adipose Tissue as an Endocrine Organ. Abdel Moniem Ibrahim, MD Professor of Physiology Cairo University

Adipose Tissue as an Endocrine Organ Abdel Moniem Ibrahim, MD Professor of Physiology Cairo University Functions of Adipose Tissue Adipose tissue expresses and secretes a variety of bioactive peptides,