The document presents the hypothesis that acupuncture preconditioning at the Neiguan (PC6) acupuncture point protects against myocardial ischemia/reperfusion injury by activating the miR-214/NCX1 pathway. Specifically, it hypothesizes that acupuncture preconditioning upregulates miR-214 expression in the heart, which represses NCX1 mRNA expression and inhibits downstream effectors like BCL2 and CaMKIIδ that mediate cell death pathways and apoptosis. This may represent a non-pharmacological therapeutic approach for activating protective mechanisms against myocardial ischemia/reperfusion injury in coronary heart disease patients.
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ACUPRESSURE HYPOTHESIS
1. HYPOTHESIS
Submit a manuscript: https://www.tmrjournals.com/tmr
doi: 10.12032/TMR20190306109
TMR | July 2019 | vol. 4 | no. 4 | 178
Traditional Chinese Medicine
Acupuncture preconditioning protects against myocardial
ischemia/reperfusion injury mediated apoptosis through
miR-214/NCX1 activation: a hypothesis
Hai-Long Fan1, #, *, Yu-Lan Ren2, #, Li-Zhen Yang1, Fei Wu2
1
Hohhot Hospital of Mongolian Medicine and Traditional Chinese Medicine, Hohhot, China. 2
School of
Acupuncture Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
#
Hai-Long Fan and Yu-Lan Ren are the co-first authors of this paper.
*Corresponding to: Hai-Long Fan, Hohhot Hospital of Mongolian Medicine and Traditional Chinese Medicine, 9
Bao-tou East St, Hohhot, Inner Mongolia, China. E-mail: zjfhl1977@163.com.
Highlights
This review provides evidences for the recommendation of acupuncture preconditioning at Neiguan (PC6) point in
coronary heart disease patients as a non-pharmacological therapeutic method to activate the miR-214/NCX1
pathway.
Traditionality
The concept of acupuncture preconditioning is described in the ancient book of Fan Wang Fang (Eastern Jin
Dynasty of China). It refers to the application of acupuncture before the occurrence of disease or when the disease
is relatively mild. According to the record of the ancient book of Huang Di Nei Jing (Qin Han Period of China, 475
B.C.-221 B.C.), acupuncture at Neiguan (PC6) point can prevent and treat angina pectoris in coronary heart disease
(CHD). The WHO also recommends acupuncture as one of the alternative and complementary therapies for the
prevention and treatment of angina pectoris in CHD.
2. HYPOTHESIS
Submit a manuscript: https://www.tmrjournals.com/tmr
doi: 10.12032/TMR20190306109
TMR | July 2019 | vol. 4 | no. 4 | 179
Abstract
Early reperfusion of ischemic cardiac tissue is usually the best option to improve clinical outcome of angina
pectoris, especially of acute myocardial infarction. However, myocardial reperfusion may cause an abnormal
increase of intracellular Ca2+
-mediated cardiomyocyte death and consequent loss of cardiac function, which is
referred to myocardial ischemia/reperfusion (I/R) injury. Recently, the microRNA-214 (miR-214)/Na+
/Ca2+
exchanger (NCX) 1 co-expression is a key factor in cellular protection against myocardial apoptosis for myocardial
I/R injury. Once activated, miR-214/NCX1 axis can inhibit several Ca2+
downstream signaling effectors that
mediate cell death simultaneously. Studies have shown that acupuncture preconditioning has a protective effect on
myocardial I/R injury, but its mechanism deserves further research. It has been proved that acupuncture
preconditioning for ischemic myocardium successfully inhibit multiple Ca2+
handling related microRNAs that
mediate cell death pathways, and miR-214 is one of its targets. In terms of clinical practice, coronary heart disease
(CHD) patients benefit a lot from this intervention. However, there is barely no study correlating acupuncture
preconditioning to the miR-214/NCX1 co-expression in patients with CHD. This review aims to discuss whether
there is some evidence to justify a recommendation of acupuncture preconditioning in CHD patients as a
non-pharmacological therapeutic method to activate the miR-214/NCX1 co-expression network model.
Keywords: MiR-214/NCX1, Acupuncture preconditioning, Coronary heart disease, Myocardial ischemia,
Reperfusion injury
Concepts:
Acupuncture preconditioning: Acupuncture preconditioning is the method of applying acupuncture on patients
before the symptoms appear. Qi: In traditional Chinese culture, Qi is believed to be a vital force forming part of
any living entity (https://en.wikipedia.org/wiki/Qi). Meridians and collaterals: Meridians and collaterals system
is a concept in traditional Chinese medicine about a path through which the life-energy known as Qi flows
[https://en.wikipedia.org/wiki/Meridian_(Chinese_medicine)]. Neiguan (PC6) point: An acupoint located on
the anterior forearm, two cun above to the wrist crease, between the tendons of palmaris longus and flexor
carpi radialis muscles, along the pericardium meridian (https://en.wikipedia.org/wiki/Nei_guan).
Abbreviations:
CHD, Coronary heart disease; I/R, Ischemia/reperfusion; miR-214, MicroRNA-214; IPC, Ischemic
preconditioning; TCM, Traditional Chinese medicine; NCX, Na+
/Ca2+
exchanger; BCL2, B-cell
leukemia/lymphoma 2; CaMK, Calmodulin-dependent protein kinase; miRNAs, MicroRNA.
Acknowledgments:
This study is supported fiancially by the Natural Science Foundation of Inner Mongolia Autonomous Region in
China (Grant No.2018MS08043), the National Natural Science Foundation of China (Grant No.81573885),
Project of Huhhot Science and Technology (Grant No.2018-Sociology-1-3) and Research Project of Health and
Family Planning Commission of Inner Mongolia in China (Grant No.201703145). The funders will not have
any impact on the trial and the publication of the results.
Competing interests:
The authors report no conflicts of interest.
Citation:
Hai-Long Fan, Yu-Lan Ren, Li-Zhen Yang, et al. Acupuncture preconditioning protects against myocardial
ischemia/reperfusion injury mediated apoptosis through miR-214/NCX1 activation: a hypothesis. Traditional
Medicine Research, 2019, 4 (4): 178-183.
Executive Editor: Cui-Hong Zhu.
Submitted: 23 January 2019, Accepted: 23 February 2019, Online: 17 March 2019.
3. HYPOTHESIS
Submit a manuscript: https://www.tmrjournals.com/tmr
doi: 10.12032/TMR20190306109
TMR | July 2019 | vol. 4 | no. 4 | 180
Background
Myocardial ischemia, the main mechanism of angina
pectoris, usually causes the symptoms of severe chest
pain and discomfort in the left anterior chest or
adjacent areas among coronary heart disease (CHD)
patients [1]. It is believed that the most effective
treatment to improve ischemic cardiac tisse after acute
myocardial infarction is early reperfusion. However, in
the process of myocaridial reperfusion, the number of
intracellular Ca2+
may be probably increased
abnormally, which may cause the death of
cardiomyocytes and consequent loss of cardiac
function, or myocardial ischemia/reperfusion (I/R)
injury. Myocardial I/R injury, caused by myocardial
ischemia, cardiac surgery or circulatory arrest, may
finally rise up to adverse cardiovascular outcomes [2].
MicroRNA-214 (miR-214) was recorded to be able to
protect cardiomyocytes from I/R injury by the
inhibition of the mRNA that encodes Na+
/Ca2+
exchanger (NCX) 1 and consequently controls Ca2+
overload-mediated cell death [3]. These findings reveal
a significant role for the miR-214/NCX1 mRNA
co-expression network model as a regulator of
cardiomyocyte Ca2+
balance and survival during
myocardial I/R injury.
Among several strategies that are being studied to
modulate miR-214, acupuncture preconditioning could
represent a new non-pharmacological approach of
early intervention and prevention of CHD for
modulating gene expression of the anti-apoptosis
signaling [4-10]. The concept of acupuncture
preconditioning is described in the ancient book Fan
Wang Fang (Eastern Jin Dynasty of China). It refers to
the application of acupuncture in advance to stimulate
the Qi (Qi is believed to be a vital force forming part
of any living entity) of meridians and collaterals
(Meridians and collaterals system is a concept in
traditional Chinese medicine about a path through
which the life-energy known as Qi flows) before the
occurrence of disease or when the disease is relatively
mild, so as to enhance the body's disease resistance,
prevent the occurrence of disease, and alleviate the
damage degree of subsequent disease. Acupuncture
preconditioning follows the principles of disease
prevention in the ancient book Huang Di Nei Jing (Qin
Han Period of China, 475 B.C.-221 B.C.).
However, there are no available data regarding the
relationship between acupuncture preconditioning and
modulation of the miR-214/NCX1mRNA
co-expression in myocardial I/R injury. This paper will
try to present evidence for the miR-214/NCX1mRNA
co-expression after acupuncture preconditioning and
argue how this interaction may represent an crucial
link in the puzzle of myocardial I/R injury.
Hypothesis
We hypothesize that by evoking miRNA-214 in the
heart, the cardioprotective roles of acupuncture
preconditioning at Neiguan (PC6) point (an acupoint
located on the anterior forearm, two cun above to the
wrist crease, between the tendons of palmaris longus
and flexor carpi radialis muscles, along the
pericardium meridian) are attributed to the repression
of NCX1 mRNA expression, to the inhibition of NCX1
and some Ca2+
downstream effector proteins [B-cell
leukemia/lymphoma 2 (BCL2) and calmodulin-
dependent protein kinase (CaMK) IIδ] that regulate
cell death pathways, and to a cardioprotective role for
I/R injury; acupuncture preconditioning at Neiguan
(PC6) point may be a non-pharmacological option of
early intervention and prevention of CHD for
activating the miRNA-214/NCX1 mRNA
co-expression network model and blocking myocardial
apoptosis for myocardial I/R injury.
Hypothesis evaluation
MiRNA-214/NCX1 mRNA co-expression network
and myocardial I/R injury
The role of Ca2+
, a core of cardiac contraction and
signaling networks, in the regulation of pathological
cardiac growth and remodeling is crucial, yet the
overload of intracellular Ca2+
often occurs when
cardiomyocyte suffer from ischemic injury and other
stresses [11, 12], and is accompanied by increasing
expression of both proapoptotic BCL2 family members
[11] and CaMK [13]; these changes lead to cardiac
contractile dysfunction and ultimately cell death thanks
to the signals transducted through the effector proteins
in the Ca2+
downstream singnaling pathway [11-14]. A
series of proteins (eg. the LTCC-SERCA2 pump and
NCX1) modulate Ca2+
handling [3]. NCX, particularly,
is considered to be the main route for Ca2+
influx
during I/R injury [14, 15]. Blocking NCX-mediated
Ca2+
influx can offer good myocardial protection [16,
17].
Furthermore, accumulating evidence suggests that
many microRNAs (miRNAs) are associated with I/R
injury [18-23]. It’s reported that miRNAs may plays
key roles in the regulation of cellular processes of
cardiac remodeling and disease, including myocyte
hypertrophy [24-28] as well as apoptosis [18-20, 29].
MiRNAs are a class of endogenous and non-coding
short-length RNAs (17-25 nt). And they may mediate
target mRNAs to reduce or inhibit protein translation
[30]. It has been studied that it is in this way that
miRNAs act an essential part in the several cardiac
functions [31]. MiR-214 can protect cardiac myocytes
[3, 4], the expression of which was dramatically
depressed in myocardial I/R injury [5]. As outlined
above, miR-214 knocked-out mice suffered depletion
4. HYPOTHESIS
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doi: 10.12032/TMR20190306109
TMR | July 2019 | vol. 4 | no. 4 | 181
of cardiac contractility, excessive fibrosis, and
increased apoptosis in answer to I/R injury [3].
MiR-214 was found contributing to the repression of
mRNA that encodes NCX1, which regulating of Ca2+
influx, as well as the repression of Ca2+
downstream
signaling effectors (BCL2, CaMKIIδ) that mediate cell
death [3]. These findings show the importantance of
the miR-214/ NCX1 mRNA co-expression network
model to regulate cardiomyocyte Ca2+
balance and
survival during myocardial I/R injury (Figure 1).
Figure 1 A miRNA-214/NCX1 mRNA co-expression
network model for blocking myocardial apoptosis
I/R, Ischemia/reperfusion; NCX1, Na+
/Ca2+
exchanger
1; BCL2, B-cell leukemia/lymphoma 2; CaMKII δ ,
Calmodulin-dependent protein kinase II δ.
Acupuncture preconditioning and myocardial I/R
injury
In 1986, Murry [32] identified myocardial ischemic
preconditioning (IPC) for the first time; the term refers
to cardiac muscle with an enhanced tolerance for
subsequent lethal I/R injury after repeated brief I/R
injuries. For early intervention and prevention of CHD,
myocardial IPC provides a compelling new strategy:
an activated, endogenous protective mechanism for the
heart to improve damage resistance of myocardial
ischemia and anoxia, with the least damage to ischemic
tissue cells. The theory behind myocardial IPC is
similar to that of prevention in traditional Chinese
medicine (TCM). A detailed interpretation of
acupuncture preconditioning was described in the
ancient book Zhen Jiu Ju Ying written by Gao Wu in
the Ming Dynasty of China, which referred the
acupuncture maniupulation applied to patients with
sub-health or sickness might stimulate Qi, enhance
disease resistance and alleviate stress. According to the
record of antient book Huang Di Nei Jing (Qin Han
Period of China, 475 B.C.-221 B.C.), the clinical
prevention and control of angina pectoris in CHD by
acupuncture at Neiguan (PC6) point can be traced back
to 3,000 years ago. Additional detailed applications of
a cardioprotective effect of Neiguan (PC6) point were
described in other TCM classics, such as the Zhen Jiu
Zi Sheng Jing in 1220 A.D., the Zhen Jiu Ju Ying in
1537 A.D. and the Zhen Jiu Da Cheng in 1601 A.D.
Besides, the World Health Organization reported:
“Acupuncture: Review and Analysis of Reports on
Controlled Clinical Trials in 2002,” recommended
acupuncture as one of the alternative and
complementary therapies for early intervention,
prevention and treatment of angina pectoris in CHD.
Recent animal studies indicate that acupuncture
preconditioning at Neiguan (PC6) point has a
cardioprotective effect on ischemia-reperfusion in the
myocardium [33]. Methods of preparing acupuncture
preconditioning for myocardial I/R injury rats model
are ligating anterior descending branch of the left
coronary artery for 40 min and re-perfusing the artery
for 60 min. The myocardial I/R injury rats model in an
acupuncture preconditioning group were pretreated
with acupuncture applied at bilateral Neiguan (PC6)
point for 20 min once a day for 5 consecutive days
before ischemia. The Neiguan (PC6) point of rats is
located on the point in the midline and 3mm above the
tranverse crease of forelimbs.
Acupuncture preconditioning and miRNA-214/
NCX1 mRNA co-expression network
Studies in laboratory animals have shown [7-8, 10,
33-35] that myocardial protective effects of
acupuncture preconditioning at Neiguan (PC6) point
for myocardial I/R injury [8-10] are analogous to IPC,
but the mechanism behind the effects remains unclear.
Several possibilities exist, including the repression of
oxygen-free radicals, release of endogenous active
substances (e.g. adenosine), up-regulation of
Ca2+
-ATPase mRNA and Na+
-K+
-ATPase mRNA,
decrease of Ca2 +
content in the myocardial cell, or
stimulation of the BCL2 protein that represses cell
death [36]. Acupuncture preconditioning at Neiguan
(PC6) point promotes the expression of miR-214 in
myocardial I/R injury [4, 6]. MiR-214 repression
directly targets on NCX1 [3]. Tests showed that the
relevant protein levels of NCX1 and CaMK IIδ were
also decreased in cells of myocardial I/R injury treated
with acupuncture preconditioning at Neiguan (PC6)
point [6]. The miR-214 binding sites are in the 3ʹ-UTR
of NCX1 mRNA. The present findings indicate that
acupuncture preconditioning at Neiguan (PC6) point
mediates many target mRNAs related to Ca2+
handling
[36]. Here, we focus on the relationship between
acupuncture preconditioning at Neiguan (PC6) point
and modulation of the miR-214/NCX1 mRNA
5. HYPOTHESIS
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doi: 10.12032/TMR20190306109
TMR | July 2019 | vol. 4 | no. 4 | 182
co-expression in myocardial I/R injury. These findings
reveal a pivotal role for the miR-214/NCX1 mRNA
co-expression network model as a regulator of
cardiomyocyte Ca2+
homeostasis and survival during
myocardial I/R injury. We show that the essential
mechanism is that by evoking miRNA-214 in the heart,
acupuncture preconditioning at Neiguan (PC6) point
regulates NCX1 mRNA expression, and inhibits the
expression of NCX1 and several Ca2+
downstream
signaling effectors (BCL2, CaMKIIδ) that mediate cell
death pathways to play a cardioprotective role for
myocardial I/R injury. The mechanism of acupuncture
preconditioning that influences the miRNA-214/
NCX1 mRNA co-expression network model may
prevent and treat myocardial I/R injury (Figure 2).
Figue 2 A miRNA-214/NCX1 mRNA co-expression
network model for blocking myocardial apoptosis:
a novel hypothesis for acupuncture’s protective
mechanism against myocardial I/R injury
I/R, Ischemia/reperfusion; NCX1, Na+
/Ca2+
exchanger
1; BCL2, B-cell leukemia/lymphoma 2; CaMKII δ ,
Calmodulin-dependent protein kinase II δ.
Consequences of the hypothesis and discussion
Our hypothesis suggests that acupuncture
preconditioning at Neiguan (PC6) point may be a
non-pharmacological option of early intervention and
prevention of CHD for activating the miRNA-214
/NCX1 mRNA co-expression network model and
blocking myocardial apoptosis for myocardial I/R
injury. Acupuncture preconditioning at Neiguan (PC6)
point appears to have myocardial protective effects. If
our hypothesis is confirmed by further studies, the
scientific evidence will support acupuncture
preconditioning for myocardial I/R injury by acupoint
selection along the meridian. We hope that our paper
stimulates research on this topic, which may have
important clinical and public health implications.
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