CARDIOVASCULAR JOURNAL OF AFRICA • Volume 31, No 1, January/February 2020
AFRICA
31
and functional damage in the heart.
2
The accumulation of ROS
activated Nrf2 during exhaustive exercise, but did not produce
a sufficient level of activation to prevent oxidative damage, and
drugs were required to further activate Nrf2. Nrf2 was expressed
at significantly higher levels after the Sal treatment. However, the
expression of Nrf2 mRNA was not affected by Sal, indicating
that Sal did not regulate Nrf2 expression at the transcriptional
or translational level, but instead at the post-translational level.
According to Numazawa, inducers rarely promote the
biosynthesis of Nrf2.
25
The epigenetic regulation of Nrf2 activity
might involve a long-term or basic regulatory mechanism. Sal
may either inhibit Keap1 expression or promote its degradation.
The abundance of Nrf2 was inhibited and its degradation was
reduced, increasing the level of Nrf2 protein. The level of Nrf2
in the nucleus increased significantly as the concentration of Sal
increased. Sal induced nuclear translocation of Nrf2.
Devling
et al.
used an siRNA to antagonise the Keap1
mRNA and its expression decreased significantly. The authors
observed a significant increase in the level of Nrf2 transported
to the nucleus. Moreover, the levels of antioxidant enzymes were
also increased significantly.
26,27
The antioxidant enzyme system downstream of Nrf2 consists
of SOD, CAT and GSH and plays a role in preventing cardiac
remodelling and cardiac function disorders.
28,29
In the control
group, a positive correlation was observed between EDPVR and
GSH, while dP/dt
max
and GSH were positively correlated in the
ES group. Therefore GSH exerted a protective effect on the heart
and improved cardiac function parameters.
The observed decrease in levels of GSH and other enzymes
after exhaustive exercise was due to their function in reversing
ROS levels. The levels of SOD, CAT and GSH all increased with
increasing concentrations of Sal. Sal induced Nrf2 expression
and increased levels of downstream antioxidant enzymes by
increasing the amount of Nrf2 protein and activating its nuclear
translocation.
Conclusion
Sal protected the heart from exhaustive exercise-induced injury,
and it may improve cardiac function and cardiac bioelectricity
in exhausted rats. Sal improved the antioxidant capacity by
activating Nrf2.
This study was supported by grants from the Medical Science Research
Programme of the Chinese Army (CWS12J064), the Medical Technology
Project of the Chinese Army (BWS11J058), the Logistical Science Research
Project of the Chinese Army (CBJ13J002), the National Natural Science
Foundation of China (81870249), and the National Key R&D Programme of
China (2017YFC0908700 and 2017YFC0908703).
References
1.
Wu XN, Zhang Z, Wang JT,
et al
. ECG score changes of PLA officers
and soldiers after a high-intensity exercise in a high altitude training
base and its correlation analysis with SCL-90 rating scale scores.
Med
Pharm J Chin PLA
2016;
1
: 15–18.
2.
Wang YR, Xu P, Wang Y,
et al
. The protection of Salidroside of the
heart against acute exhaustive injury and molecular mechanism in rat.
Oxid Med Cell Longev
2013;
507832
: 1–8.
3.
Ping Z, Zhang LF, Cui YJ,
et al
. The protective effects of salidro-
side from exhaustive exercise-induced heart injury by enhancing the
PGC-1
α
-NRF1/NRF2 pathway and mitochondrial respiratory function
in rats.
Oxid Med Cell Longev
2015;
876825
: 1–9.
4.
Xu P, KangT, Liu HY,
et al
. The effect of nuclear factor erythroid-
2-related factor2 on the changes of cardiac function and electrocar-
diogram in different time after exhausted exercise in rats.
Chin J Appl
Physiol
2016;
2
: 146–151.
5.
Purdom-Dickinson SE, Lin Y, Dedek M,
et al
. Induction of antioxidant
and detoxification response by oxidants in cardiomyoeytes: evidence
from gene expression profiling and activation of Nrf2 transcription
factor.
J Mol Cell Cardiol
2007;
1
: 159–176.
6.
Silva-Palacios A, Königsberg M, Zazueta C. Nrf2 signaling and redox
homeostasis in the aging heart: A potential target to prevent cardiovas-
cular diseases?
Ageing Res Rev
2016;
26
: 8l–95.
7.
Muthusamy VR, Kannan S, Sadhaasivam K,
et al
. Acute exercise stress
activates Nrf2/ARE signaling and promotes antioxidant mechanisms in
the myocardium.
Free Radic Biol Med
2012;
2
: 366–376.
8.
Safdar A, de Beer J, Tarnopolsky MA. Dysfunctional Nrf2-Keapl redox
signaling in skeletal muscle of the sedentary old.
Free Radic Biol Med
2010;
10
: 1487–1493.
9.
Malauti M, Angeloni C, Garatachea N,
et al
. Sulforaphane treatment
protects skeletal muscle against damage induced by exhaustive exercise
in rats.
J Appl Physiol
2009;
4
: 1028–1036.
10. Dietz BM, Liu D, Hagos GK,
et al
.
Angelica sinesis
and its alkylphthal-
ides induce the detoxification enzyme NAD(P)H: by alkylating Keap1.
Chem Res Toxicol
2008;
21
: 1939–1948.
11. Wakabayashi N, Dinkova-Kostova AT, Holtzclaw WD,
et al
. Protection
against electrophile and oxidant stress by induction of the phase 2
response: fate of cysteines of the Keap1 sensor modified by inducers.
Proc Natl Acad Sci USA
2004;
7
: 2040–2045.
12. Zhang Y, Ahmad KA, Khan FU,
et al
. Chitosan oligosaccharides
prevent doxorubicin-induced oxidative stress and cardiac apoptosis
through activating p38 and JNK MAPK mediated Nrf2/ARE pathway.
Chem Biol Interact
2019;
305
: 54–65.
13. Zipper LM, Mulcahy RT. Erk activation is required for Nrf2 nuclear
localization during pyrrolidine dithiocarbamate induction of glutamate
cysteine ligase modulatory gene expression in Hep G2 cells.
Toxicol Sci
2003;
1
: 124–134.
14. Yang R, Liu A, Ma X,
et al
. Sodium tanshinone IIA sulfonate protects
cardiomyocytes against oxidative stress-mediated apoptosis through
inhibiting JNK activation.
J Cardiovasc Pharmacol
2008;
4
: 396–401.
15. Zhu Y, Zhang YJ, Liu WW,
et a1
. Salidroside suppresses HUVECs cell
injury induced by oxidative stress through activating the Nrf2 signaling
pathway.
Molecules
2016;
8
: 1033.
16. Yuan XY, Pang XW, Zhang GQ,
et al
. Salidroside’s protection against
UVB-mediated oxidative damage and apoptosis is associated with the
upregulation of Nrf2 expression.
Photomed Laser Surg
2017;
1
: 49–56.
17. Chang X, Zhang K, Zhou R,
et al
. Cardioprotective effects of salidro-
side on myocardial ischemia–reperfusion injury in coronary artery
occlusion-induced rats and Langendorff-perfused rat hearts.
Int J
Cardiol
2016;
215
: 532–544.
18. Liu S, Wang YR, Xu P,
et al
. The protection of Salidroside on cardiac
function of repeated exhaustive rat via anti-oxidative stress and MAPKs
signal transduction.
Lat Am J Pharm
2014;
1
: 5–13.
19. Yan J, Zhao W, Thomson JK,
et al.
Stress signaling JNK2 crosstalk with
CaMKII underlies enhanced atrial arrhythmogenesis.
Circ Res
2018;
6
:
821–835.
20. Zhuang L, Li C, Chen Q,
et al.
Fatty acid-binding protein 3 contributes
to ischemic heart injury by regulating cardiac myocyte apoptosis and
MAPK pathways.
Am J Physiol Heart Circ Physiol
2019;
5
: H971–H984.