Science - USA (2018-12-21)

larger myocardium mass (Fig. 6F), higher end
diastolic volume (EDV) (Fig. 6H) and end systolic
volume (ESV) (Fig. 6I), and lower ejection frac-
tion (Fig. 6G) in JP2DNLS-KI mice than in wild-type
littermates. These findings suggest that JP2NT
functions as an endogenous cardiac protector
against pathological challenges.

Discussion

Our study provides compelling evidence suggest-
ing that an E-C coupling structural protein can

also act as a transcriptional regulator. We have

shown that regulated cleavage of JP2 converts it

from a structural proteinto a nuclear transcrip-

tional regulator via an NLS and an ARR con-

tained within JP2NT. JP2NT is enriched in the

promoter region of genes in cardiomyocytes and

primarily acts as a transcriptional repressor of

genes implicated in cell growth and differentia-

tion, hypertrophy, inflammation, and fibrosis,

with evidence for a specific interaction with

the transcription factor MEF2. Cardiac-specific

transgenic overexpression of JP2NT attenuates

pressure overload induced development of heart

failure, identifying JP2NT generation as a self-

protective homeostatic mechanism that safe-

guards against the deleterious effects of cardiac

stress. These discoveries reveal a signaling path-

way that transduces membrane stresses into

transcriptome changes in the setting of E-C un-

coupling after cardiac stress.

JP2 was initially discovered as a structural

protein with dual membrane-anchoring domains

Guoet al.,Science 362 , eaan3303 (2018) 21 December 2018 8of9

4.0

6.0

8.0

10.0

12.0

14.0

16.0

18.0

Ejection Fraction (EF) HW/BW Ratio (mg/g)

Baseline

**

---

TAB

Control JP2NT-OE Control JP2NT-OE

Baseline TAB

Control JP2NT-OE Control JP2NT-OE

Baseline TAB

Control JP2NT-OE Control JP2NT-OE

0.0

0.2

0.4

0.6

0.8

1.0

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

LW/BW Ratio (mg/g)

ACB

EGF

-4.5 -2.5 -0.5

IGF1

FGF2

VEGF

ERK1/2

TGF-β

CREB1

E HIF1A

Z-score

F

0.0

50.0

100.0

150.0

200.0

Mass (mg)

WT WT

Baseline TAB

JP2

ΔNLS

-KI

JP2

ΔNLS

-KI

• 
  

WT WT

Baseline TAB

JP2

ΔNLS

-KI

JP2

ΔNLS

-KI

0.0

25.0

50.0

75.0

100.0

EF

• 
  

G

WT WT

Baseline TAB

JP2

ΔNLS

-KI

JP2

ΔNLS

-KI

0.0

30.0

60.0

90.0

120.0

EDV (um)

• 
  

H

JP2

ΔNLS

-KI

JP2

ΔNLS

WT -KI WT

Baseline TAB

0

15

30

45.0

60.0

ESV(um)

• 
  

I

-log

(p value) 10

Significant

False

True

20

15

10

5

0

-8 -4 0 4

Coefficient

D

Fig. 6. JP2NT overexpression protects against pressure overload-
induced hypertrophy and heart failure.(A) Cardiac specific over-
expression of JP2NT (JP2NT-OE) preserved cardiac ejection fraction (EF)
in mice 3 weeks after transverse aortic banding (TAB). (B) JP2NT
overexpression attenuated TAB-induced cardiac hypertrophy as evidenced
by a decreased heart weight/body weight (HW/BW) ratio. (C) Lung
weight/body weight (LW/BW) ratio is significantly reduced in JP2NT-OE
mice after TAB;n= 5, 5, 22, 13 for each group respectively. (D) Volcano

plot of the effect of JP2NT overexpression on TAB-induced transcriptional

remodeling. JP2NT-OE significantly changed the transcriptional response

to TAB. Red dots indicate the transcripts whose response to TAB was

significantly changed by JP2NT-OE. (E) IPA pathway enrichment analysis

of significantly altered transcripts in JP2NT-OE mice after TAB as

compared to littermate controls. (FtoI) Echocardiogram measurement of

heart mass (F), ejection fraction (G), EDV (H), and ESV (I) in WT and

JP2DNLS-KI mice under baseline or TAB condition.

RESEARCH | RESEARCH ARTICLE

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