Aerobic Training‑induced Upregulation of YAP1 and Prevention of Cardiac Pathological Hypertrophy in Male Rats

Arezoo Tabrizi, Rahman Soori, Siroos Choobineh, Majid Gholipour

Abstract


Background: Pathological hypertrophy is one of the negative consequences of cardiac sympathetic hyperactivity. Recent studies have shown that YAP1 plays a critical role in cardiomyocytes
hypertrophy. Considering the preventive role of exercise training in cardiovascular diseases, the
present study was conducted to examine the effect of aerobic exercise training on YAP1 gene
expression and its upstream components.

Methods: Eighteen male Wistar rats were randomly divided
into aerobic training and control groups. Aerobic training was performed one hour/day, five days per
week, for eight weeks, on a treadmill at 65‑75% VO2 max. Pathological hypertrophy was induced
by injecting 3 mg/kg‑1 of isoproterenol for seven days. The left ventricle was separated, and YAP1,
3‑mercaptopyruvate sulfurtransferase (MST), large tumor suppressor (LATS), and mitogen‑activated
protein 4 kinase (MAP4K) gene expressions were assessed and YAP1 protein levels were also
assessed by western blotting. Cell apoptosis was detected by TUNEL assays. The between‑group
differences were evaluated using the T‑test and P value <0.05 was considered statistically significant.

Results: There were no significant between‑group differences in MST gene expression (P = 0.061);
meanwhile, in the training group, LATS and Map4K expressions were suppressed, followed by
a significant increase in YAP1 expression (P < 0.001). Compared to the control group, the left
ventricular weight increased significantly in the training group while the cardiomyocyte apoptosis
decreased.

Conclusions: The results showed that, by reducing LATS, aerobic training‑induced
YAP1 upregulation can help prevent the propagation of cardiomyocyte apoptosis due to pathological
conditions.


Keywords


Aerobic exercise; cardiac hypertrophy; large tumor suppressor; mammalian sterile 20 like kinase; YES associated protein1

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References


Shimizu I, Minamino T. Physiological and pathological cardiac

hypertrophy. J Mol Cell Cardiol 2016;31;97:245‑62.

Maillet M, Van Berlo JH, Molkentin JD. Molecular basis of

physiological heart growth: Fundamental concepts and new

players. Nat Rev Mol Cell Biol 2013;14:38‑48.

Xiao F, Kimura W, Sadek HA. A hippo “AKT” regulates

cardiomyocyte proliferation. Circ Res 2015;116:3‑5.

Gabriel BM, Hamilton DL, Tremblay AM, Wackerhage H. The

Hippo signal transduction network for exercise physiologists.

J Appl Physiol 2016;120:1105‑17.

Sebio A, Lenz HJ. Molecular pathways: Hippo signaling, a

critical tumor suppressor. Clin Cancer Res 2015;21:5002‑7.

Byun J, Del Re DP, Zhai P, Ikeda S, Shirakabe A, Mizushima W,

et al. Yes‑associated protein (YAP) mediates adaptive cardiac

hypertrophy in response to pressure overload. J Biol Chem

;294:3603‑17.

Del Re DP, Yang Y, Nakano N, Cho J, Zhai P, Yamamoto T, et al.

Yes‑associated protein isoform 1 (Yap1) promotes cardiomyocyte

survival and growth to protect against myocardial ischemic

injury. J Biol Chem 2013;288:3977‑88.

Del Re DP. Hippo signaling in the heart–non‑canonical pathways

impact growth, survival and function. Circ J 2016;80:1504‑10.

Del Re DP. The hippo signaling pathway: Implications for heart

regeneration and disease. Clin Transl Med 2015;4:53.

Lin Z, Pu WT. Harnessing hippo in the heart: Hippo/Yap

signaling and applications to heart regeneration and rejuvenation.

Stem Cell Res 2014;13:571‑81.

Lee YI, Cho JY, Kim MH, Kim KB, Lee DJ, Lee KS. Effects of

exercise training on pathological cardiac hypertrophy related gene

expression and apoptosis. Eur J Appl Physiol 2006;97:216‑24.

Arifin WN, Zahiruddin WM. Sample size calculation in animal

studies using resource equation approach. Malays J Med Sci

;24:101‑5.

Fawcett A, Rose M. Guidelines for the housing of mice in

scientific institutions. Animal Welfare Unit, NSW Department

of Primary Industries, West Pennant Hills. Anim Res Rev Pan1

Guideline22 2012;1:1‑143.

Kemi OJ, Haram PM, Loennechen JP, Osnes JB, Skomedal T,

Wisløff U, et al. Moderate vs. high exercise intensity: Differential

effects on aerobic fitness, cardiomyocyte contractility, and

endothelial function. Cardiovasc Res 2005;67:161‑72.

Wisløff U, Helgerud J, Kemi OJ, Ellingsen Ø. Intensity‑controlled

treadmill running in rats: VO2 max and cardiac hypertrophy. Am

J Physiol Heart Circ Physiol 2001;280:H1301‑10.

Siddiqui BS, Ali ST, Tauseef S, Kamal S, Rizwani GH,

Begum S. Isoprenaline: A tool for inducing myocardial infarction

in experimental animals. Int J Pharmac 2016;6:138‑44.

Meng Z, Moroishi T, Guan KL. Mechanisms of Hippo pathway

regulation. Genes Dev 2016;30:1‑7.

Visser S, Yang X. LATS tumor suppressor: A new governor of

cellular homeostasis Cell Cycle 2010;9:3892‑903.

Silva JA Jr, Santana ET, Manchini MT, Antônio EL,

Bocalini DS, Krieger JE, et al. Exercise training can

prevent cardiac hypertrophy induced by sympathetic

hyperactivity with modulation of kallikrein‑kinin pathway and

angiogenesis. PLoS One 2014;9:e91017.

Ventura-Clapier R. Cardiac Hypertrophy, Pathological. In:

Mooren FC, editor. Encyclopedia of Exercise Medicine in Health

and Disease. Berlin, Heidelberg: Springer; 2012. p. 168-71.

Hosseini M, Bambaeichi E, Sarir H, Kargarfard M. Effect of

training with or without Ziziphus jujuba extract on cardiokines

in heart tissue of myocardial infarcted rats. Int J Prev Med

;10:103.

Xia P, Liu Y, Cheng Z. Signaling pathways in cardiac myocyte

apoptosis. Biomed Res Int 2016;2016:9583268.

Windmueller R, Morrisey EE. Hippo and cardiac hypertrophy:

A complex interaction. Circ Res 2015;117:832‑4.

Lin Z, von Gise A, Zhou P, Gu F, Ma Q, Jiang J, et al.

Cardiac‑specific YAP activation improves cardiac function

and survival in an experimental murine MI model. Circ res

;115:354‑63.

Csibi A, Blenis J. Hippo–YAP and mTOR pathways collaborate

to regulate organ size. Nat Cell Biol 2012;14:1244‑5.




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