II. Pathobiology of pulmonary arterial hypertension

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Rubin M. Tuder, M. D. Program in Translational Lung Research Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine University of Colorado, School of Medicine PVRI II. Pathobiology of pulmonary arterial hypertension European Cardiology Society, Nice, 2012 Pulmonary Hypertension: Future expectations

Transcript of II. Pathobiology of pulmonary arterial hypertension

Page 1: II. Pathobiology of pulmonary arterial hypertension

Rubin M. Tuder, M. D.

Program in Translational Lung Research

Division of Pulmonary Sciences and Critical Care

Medicine, Department of Medicine

University of Colorado, School of Medicine

PVRI

II. Pathobiology of pulmonary arterial

hypertension

European Cardiology Society, Nice, 2012

Pulmonary Hypertension: Future expectations

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17β estradiol CYP1B1

(Revisited) Key features of cancer

Hanaham and Weinberg, Cell 2010

HIF

Chr 13

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Variability of pulmonary vascular lesions

Stacher et al.,

AJRCCM, 2012

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Where do pulmonary vascular lesions occur?

•Number of pulmonary

Arteries (17 orders)

10^8

Elastic (orders 17-10):

3,000

Muscular (orders 9-5):

800,000

Precapillary (orders 4-1;

25 um):

70 million

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Predominance of PAH in women

Stacher et al., AJRCCM, 2012

Females

Males

Females

Males

Females

Males

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17β estradiol CYP1B1

BMPRII

HPAHSMC IPAH Sert

Overexpressor

Dehydro

epiandrosterone

Overexpression

in cancers

4 and 16-hydroxylation

of estrogen

White, MacLean. Circulation, 2012

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CYP1B1 causes pulmonary hypertension

2,3,4,5-tetramethoxystilbene (TMS)

CYP1B1

White, MacLean. Circulation, 2012

16-OH estrogen

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Morphometric parameters: control vs. PAH

Stacher et al., AJRCCM, 2012

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Conceptual framework for severe PAH:

selection of apoptosis resistance

Normal EC

Trigger

agent

Shear Stress Viral factors Drugs

EC death

(?apoptosis)

Tuder et al. Eur Resp J, 2001

Clonal

Growth

Neoplastic-like

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Hanaham and Weinberg,

Cell 2010

Key features of cancer

TGF-b (BMPR2)

12

As

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(Revisited) Key features of cancer

Hanaham and Weinberg, Cell 2010

HIF

Chr 13

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HIFs and Pulmonary Hypertension

Hypoxic

HIF-1β

GLUT

1 & 3

G

G

G

G

G-6-P

HKII

CA IX

CO₂

HCO

3-

H+

HIF-1α

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PH Endothelial Cells:

Shift to a Glycolytic Pathway

Xu W et al. PNAS 2006

PH ECs have less mitochondria

Normal PAH PAH +NO

Cleveland Clinic: Serpil Erzurum, Weiling Xu, Suzy Comhair,

Raed Dweik, Kewal Asosingh

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IPAH-ECs energetic switch:

Decreased mitochondria

Fijalkowska, Xu, et al. Am J Pathol, 2010

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BMPRII: worse pulmonary vascular remodeling

Stacher et al., AJRCCM, 2012

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Plexiform lesions

Stacher et al., AJRCCM, 2012

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Morphometric parameters and pathological PAH

subphenotypes: plx lesions

Stacher et al., AJRCCM, 2012

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Role of EC APOPTOSIS in the genesis of severe PH

SU5416+CH and MCT Models

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Con D14 D21 D30

p<0.001

p<0.001

% c

aspas

e posi

tive/

per

imet

er

Monocrotaline

Zaiman A et al. AJRCCM, 2008

0

1

2

3

4

5

6

D7 D14 D21 D42

Ac

tiv

e C

as

pa

se

3/V

es

se

l

CH

CH+SU5416

Stewart et al. Faseb Journal, 2001

CH+ SU5416Chronic hypoxia

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Duncan Stewart

0

10

20

30

40

50

60

70

80

90

100P < 0.0003 P < 00005

RS

VP

mm

Hg

Control MCT MCT

+Z-Asp

0

10

20

30

40

50

CH CH+SU5416 Z-Asp+CH+SU5416

Chronic Hypoxia

SU5416

Z-Asp -CH 2

PA

P (

mm

Hg

)

N=12

N=14

N=5

Control

0

10

20

30

40

50

CH CH+SU5416 Z-Asp+CH+SU5416

Chronic Hypoxia

SU5416

Z-Asp -CH 2

PA

P (

mm

Hg

)

N=12

N=14

N=5

Control

Stewart L. Faseb Journal 2001

SU5416+CHMonocrotaline

Role of EC APOPTOSIS in the genesis of severe PH

SU5416+CH and MCT Models

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VEGF receptor blockade: SU5416+CH rat model of human PAH

with endothelial cell proliferation

Abe et al Circulation, 2010; courtesy: Ivan McMurtry

Human IPAH

Rat IPAH-like

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Impact of perivascular inflammation

Stacher et al.,

AJRCCM,

2012

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Schistosomiasis

Egg

Cercariae

S mansoni and S japonicum

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US CDC

200 million people affected by Schistosomiasis

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Schistosomiasis-PAH

Butrous et al. Circulation, 2008; courtesy of Dr. Angela Bandeira

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Courtesy Prof. Zilton Andrade

FACTOR-8

Schistosomiasis-PAH: Pathology

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Purified ova

Cercariae

Infected mouse

Worms

Mouse model of Schisto-PH

3 weeks

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Th2 Peri-Egg Granulomas

Myocyte/Myofibrocyte Macrophage Eosinophil Proliferation

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15

20

25

30

35

-3 -2 -1 0 1 2 3 4 5 6 7

RV

SP

(m

mH

g)

Time (minutes; 0=fasudil administration)

Effect of Acute Fasudil Treatment

Unexposed

IP/IV Exposed

Schisto-PH: combined remodeling and

vasoconstriction (Rho kinase)

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TGF-β RIISmad3

Smad2

+/-

Lack of role for selective loss of either

Smad2 or Smad 3 in hypoxic PH

Hypoxia:

50% 3 weeks

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17β estradiol CYP1B1

(Revisited) Key features of cancer

Hanaham and Weinberg, Cell 2010

HIF

Chr 13

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Acknowledgments

Univ. Colorado: Elvira Stacher (Univ. of Graz), Brian Graham,

James Hunt, Aneta Gandjeva, Carlyne Cool, Steve Groshong

University of Michigan (DTC): Valerie McLaughlin, Marsha

Jessep

Univ. Alabama: William Grizzle

PHBI: Transplant sites: Alleghene University of Medical Sciences (PI: Raymond L. Benza, M.D.);

Baylor College of Medicine (George Noon, M.D.); Cleveland Clinic (PI: Serpil Erzurum, M.D.);

Duke University (PI: Pang-Chieh Jerry Eu, M.D.); Stanford University-UCSF (PI:: Marlene

Rabinovitch, M.D.); University of Alabama (PI: Keith Wille, M.D.; prior PI: Raymond L. Benza,

M.D.); University of California, San Diego (PI: Patricia Thistlethwaite, M.D., Ph.D); Vanderbilt

University (Barbara Meyrick, Ph.D..

CMREF