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Aerobic training induces LVH involving

microRNAs

Edilamar Menezes de Oliveira edilamar@usp.br

Grant FAPESP (2009/18370-3)

Grant CNPq/MCT-2009

Laboratory of Biochemistry and Molecular Biology of the Exercise

School of Physical Education and Sport

University of Sao Paulo - Brazil

Morfolgicas/Funcionais

Diretriz de Reabilitao Cardaca, SBC, 2005 Oliveira & Krieger, 2002

Rno-mir-1

Hemodinmicas

PA de repouso Fluxo Sanguneo Volume plasmtico

Cardiovasculares

FC repouso Melhor Funo Ventricular (VS) Angiognese

HIPERTROFIA

CARDACA FISIOLGICA

Metablicas VO2max Estrutura miofibrilar Sntese e atividade enzimtica

Adaptaes Fisiolgicas ao Treinamento Fsico Aerbio

Fernandes T et al. BJMBR, Sep, 2011

Nadal-Ginard & Madavi, J Clin Invest, 1989.

Heineke & Molkentin Nat Rev, 2006.

Physiological Cardiac Hypertrophy

RV LVRV LVLVRV

SEDENTARY

Eccentric Hypertrophy

AEROBIC TRAINING RESISTANCE TRAINING

Concentric HypertrophyVolume overload

Chamber dilation

Myocyte length >> Myocyte width

No fibrosis

No cardiac dysfunction

Pressure overload

Without chamber dilation

Myocyte width >> Myocyte length

No fibrosis

No cardiac dysfunction

sarcomeres

RV LVRV LVRV LVRV LVLVLVRV LVRV

SEDENTARY

Eccentric Hypertrophy

AEROBIC TRAINING RESISTANCE TRAINING

Concentric HypertrophyVolume overload

Chamber dilation

Myocyte length >> Myocyte width

No fibrosis

No cardiac dysfunction

Pressure overload

Without chamber dilation

Myocyte width >> Myocyte length

No fibrosis

No cardiac dysfunction

sarcomeres

DORN, Hypertension , 2007.

INFLAMA O

APOPTOSE

GLIC LISE

GENES FETAIS

S NTESE DE

PROTE NA

MATRIX

EXTRACELULAR

BIOG NESE

MITOCONDRIA

METABOLISMO

OXIDATIVO

CAPILARIZA O

HIPERTROFIA DE

CARDIOMI CITOS

Some miRNAs are specifically expressed in specific

tissues, such as heart

MicroRNAs are short sequences

non coding protein

regulate specific target genes by

inhibiting translation

MicroRNAs

Descoberta

Lee RC, Feinbaum RL, Ambros V. Cell,1993.

Victor Ambros

Rosalind Lee

Descoberta

Reinhart, B. et al. Nature , 2000.

Lin-14

Lin-28

Lin-41

Lin-42

Daf-12

Descoberta em Humano

Pasquinelli, AE. et al. Nature , 2000.

2002

Correlation between miRNAs e Cncer

2005

Dicer deletion indicating miRNA relevance in

diferent model systems

- Antagomir inhibition of mRNAs in vivo

- First miRNA transgnic mouse

2006 - Correlation between miRNAs and CV disease

MicroRNAs e HC

Van Rooij E. et al. Proc Natl Acad Sci U S A. 2006 .

Eva van Rooij

Eric Olson

Humano

21

7

Constrio artica

Knock in Caucineurina A

Van Rooij E. et al. Proc Natl Acad Sci U S A. 2006 .

Care A. et al. Nature Medicine, 2007.

Gianluigi Condorelli

Van Rooij E. et al. Science, 2007.

O Exerccio Fsico poderia influenciar na expresso de microRNAs no remodelamento

cardaco?

We investigate the role of microRNAs

regulating LV hypertrophy induced by aerobic

training in normotensive rats:

- Classic and the novel cardiac renin angiotensin

system (RAS);

- Angiogenesis;

- Collagen.

Training Protocols

Swimming training 1 (T1): 60 min/day; 1x day;

5x/week;

during 10 weeks

Swimming training 2 (T2): 60 min/day; 1x/ day;

5x/week;

during 8 weeks

9a week: 60 min; 5x/week; 2x/ day

10a week: 60 min; 5x/week; 3x/ day

Oliveira et al., JRAAS, 2009.

Training Protocols

Swimming training 1 (T1): 60 min/day; 1x day;

5x/week;

during 10 weeks

Swimming training 2 (T2): 60 min/day; 1x/ day;

5x/week;

during 8 weeks

9a week: 60 min; 5x/week; 2x/ day

10a week: 60 min; 5x/week; 3x/ day

Oliveira et al., JRAAS, 2009.

Moderate-volume training Moderate Cardiac Hypertrophy

Training Protocols

Swimming training 1 (T1): 60 min/day; 1x day;

5x/week;

during 10 weeks

Swimming training 2 (T2): 60 min/day; 1x/ day;

5x/week;

during 8 weeks

9a week: 60 min; 5x/week; 2x/ day

10a week: 60 min; 5x/week; 3x/ day

Oliveira et al., JRAAS, 2009.

Moderate-volume training Moderate Cardiac Hypertrophy

High-volume training Robust Cardiac Hypertrophy

High performance, like an atleta

Oliveira et al., JRAAS, 2009.

Swimming training System

Workload: caudal dumbbells weighting 5% of corresponding body

weight

Exercise training markers

* p

A CB C T1 T2

0

30

60

90

120

150

ECO (mg/g) LV/BW (mg/g) Myocyte Diameter (m)

Card

iac

Hyp

ert

rop

hy

(% o

f c

on

tro

l) *

* * **

** *

S T1 T2

S T1 T2

Cardiac Hypertrophy

Soci, UPR et al., Physiological Genomics 43: 665-673, 2011

y = 17,26x + 25,48

R = 0.680018

P

p

microRNA Array (349 miRNAs)

87 microRNAs were

differentially expressed with

exercise training

- 10.000 20.000 30.000 40.000 50.000 60.000

miRNA

- 2.000 4.000 6.000 8.000 10.000

miRNA

P2 P1 SC

* p

miRNAs differentially expressed in the

LV with Exercise training.

Increased by T1

SC

Decreased by T1

Largest decreased by T2

Largest increased by T2

miRs, 1, 133a e 133b Expression

* p

We investigate the role of microRNAs

regulating LV hypertrophy induced by aerobic

training in normotensive rats:

- Classic and the novel cardiac renin angiotensin

system (RAS);

- Angiogenesis;

- Collagen.

Fernandes, et al., Hypertension, 58: 182-189, 2011

Fernandes, et al., Hypertension, 58: 182-189, 2011

Fernandes, et al., Hypertension, 58: 182-189, 2011

Cardiac ACE - Ang II axis

Cardiac ACE-2 - Ang (1-7) axis

Fernandes, et al., Hypertension, 58: 182-189, 2011

Cardiac ACE-2 - Ang (1-7) axis

Fernandes, et al., Hypertension, 58: 182-189, 2011

These results suggest that this nonclassic cardiac RAS

counteracts the classic RAS

Fernandes, et al., Hypertension, 58: 182-189, 2011

This modulation might increase blood and oxygen transport to the

exercising cardiac muscle to facilitate high performance

miR-143

VASODILATION

VASOCONSTRICTION

ACE-2

CH

miR-27a

miR-27b

ACE

microRNA and

Physiological Hypertrophy

Ang (1-7)

Ang II

We investigate the role of microRNAs

regulating LV hypertrophy induced by aerobic

training in normotensive rats:

- Classic and the novel cardiac renin angiotensin

system (RAS);

- Angiogenesis;

- Collagen.

- 5.000 10.000 15.000 20.000 25.000

rno-let-7f

rno-miR-126

rno-let-7b

rno-miR-221

rno-miR-222

rno-miR-27b

rno-miR-378

rno-miR-214

Expresso gnica (Unidades Arbitrrias)

SC

P1

P2

microRNAs Angiognicos

Silva-Jr ND et al., Medicine & Science in Sports & Exercise (em reviso)

Representao esquemtica da ao do miR-126 em vias angiognicas mediadas por VEGF

Silva-Jr ND et al., Medicine & Science in Sports & Exercise (em reviso)

0

50

100

150

200

250

SC P1 P2

*

*

SC

P1

P2

Exp

ress

o r

elati

va d

o V

EG

F n

o V

E

por

wes

tern

blo

ttin

g(%

do c

on

trole

)

microRNA e Angiognese Cardaca

Silva-Jr ND et al., Medicine & Science in Sports & Exercise (em reviso)

microRNA-126 no VE

0

20

40

60

80

100

120

140

160

180

200

SC P1 P2

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