REVIEW

From Hypertension to Stroke: Mechanisms and Potential

Prevention Strategies
Jian-Guang Yu,1 Rui-Rui Zhou1,2 & Guo-Jun Cai1
1 Department of Pharmacology, Second Military Medical University, Shanghai, China
2 Department of Pharmacy, Shanghai Xuhui District Central Hospital, Shanghai, China

Keywords SUMMARY
arterial baroreflex; hypertension; inflammation;
oxidative stress; stroke prevention. Stroke is a major cause of disability and death worldwide. Prevention aimed at risk fac-
tors of stroke is the most effective strategy to curb the stroke pandemic. Hypertension is
Correspondence one of the most important risk factors for stroke. Despite the substantial evidence of the
Guo-Jun Cai, Department of Pharmacology, benefits of lowering blood pressure, conventional treatment does not normalize the bur-
Second Military Medical University, 325 Guo He den of major cardiovascular events in patients with hypertension. Fully understanding the
Road, Shanghai 200433, China. factors involved in the hypertension-induced stroke helps to develop new strategies for
Tel.: +86-21-8187-1282; stroke prevention. Antihypertensive therapies selected should have positive blood pressure-
Fax: +86-21-6549-3951; independent effects on stroke risk. This review summarizes the factors involved in the
E-mail: cai_gj@yahoo.com hypertension-induced stroke, such as oxidative stress, inflammation, and arterial barore-
flex dysfunction, and potential strategies for its prevention, therefore, provides clues for
clinicians.

doi: 10.1111/j.1755-5949.2011.00264.x

The first two authors contributed equally to this

study.

through the use of appropriate pharmacologic and nonpharma-

Introduction cologic interventions. Hypertension is the most powerful modifi-
Stroke is the primary cause of adult disability and presents a seri- able factor and the second most powerful risk factor, after age, for
ous and growing threat to public health [1]. According to World stroke [14], regardless of geographic location and ethnicity. Ap-
Health Organization figures for 2008, stroke has been the sec- proximately 54% of strokes worldwide can be attributed to hy-
ond leading cause of death in the world, with its proportion from pertension [15]. People with hypertension are 3 to 4 times more
9.7% in 2004 to 12.1% in 2030 [2]. Ischemic stroke was the most likely to suffer a stroke than those without hypertension [16].
frequently occurring type of stroke, accounting for ∼70% of all
stroke events in China and 80–85% in Western countries [3,4].
Apart from death, the greatest burden of stroke on health care Mechanisms Involved in the Pathogenesis
system, is cost of care for long-term physical and mental disability of Hypertension-Induced Stroke
[1,5]. Approximately one-third of stroke victims die within 1 year,
There is a delay between the onset of hypertension and a hyper-
and an equal number of patients are permanently disabled. Strate-
tensive complication. During this long period, a series of changes
gies to reduce the incidence of stroke include prevention of stroke
take place in the cardiovascular system including cerebral circula-
and treatment of patients with acute stroke to reduce death and
tion. These changes, such as vascular remodeling, inflammation,
disability. However, once an attack has occurred, effective treat-
oxidative stress and baroreflex dysfunction, etc., may contribute
ments are limited; thus, prevention is considered the most effec-
to the pathogenesis of stroke in hypertension.
tive strategy to curb the stroke pandemic [6].
Risk factors for stroke are well identified [7,8] and can be classi-
fied into (1) nonmodifiable: age, sex, race, various genetic factors,
Alterations in the Structure of Cerebral
etc; (2) modifiable: hypertension, diabetes, hyperlipidemia, atrial
Blood Vessels
fibrillation, smoking, obesity, etc [9–13]; (3) potentially modifi-
able: alcohol or drug abuse, oral contraceptive use, infection, the Hypertension has profound effects on the structure of cere-
metabolic syndrome, etc. The goal of stroke prevention is to iden- bral blood vessels. Mechanical, neural, and humoral factors all
tify high-risk patients and to target the modifiable risk factors contribute to the changes in composition and structure of the

CNS Neuroscience & Therapeutics 17 (2011) 577–584 

c 2011 Blackwell Publishing Ltd 577

Hypertension and Stroke Prevention
cerebrovascular wall. Hypertension promotes the development of
atherosclerotic plaques in cerebral arteries and arterioles, which
may lead to arterial occlusions and ischemic injury [17–19]. In ad-
dition, hypertension induces lipohyalinosis of penetrating arteries
and arterioles supplying the white matter, resulting in small white
matter infarcts or brain hemorrhage [18].
Hypertension induces hypertrophy and remodeling of smooth
muscle cells in systemic and cerebral arteries, both of which are
aimed at reducing stress on the vessel wall and protecting down-
stream microvessels [20,21]. Under a chronic high intraluminal
pressure, smooth muscle cells undergo hypertrophy, hyperplasia,
or rearrangement and grow inward encroaching into the lumen
of the artery, resulting in narrowing of the vessel lumen, with
increase in the wall thickness or not. Hypertension also leads to
vascular stiffening, resulting in increase in pulse pressure, a good
predictor of stroke [21,22]. Factors contributing to hypertrophy
in cerebral arteries and arterioles include sympathetic perivascu-
lar innervation [23] and mechanical effects of the elevated intra-
luminal pressure on the vascular wall, mediated by growth fac-
tors, oxidative stress and NO [24,25]. Angiotensin II (Ang II) is a
key factor in the mechanisms of cerebrovascular remodeling, with
reactive oxygen species (ROS) involved in it [26]. ROS promote
smooth muscle cell proliferation and initiate remodeling of the ex-
tracellular matrix via activation of matrix metalloproteases [27].
Extracellular matrix proteins, as well as integrin ανβ3, emilin-1,
and elastin-1 [28–30], play a critical role in hypertrophy, remod-
eling, and stiffening. Cerebral arterioles undergoing hypertrophy
or remodeling have reduced stiffening [31]. However, changes in
cerebrovascular wall composition caused by sustained hyperten-
sion may lead to stiffening [32]. Therefore, duration and magni-
tude of the blood pressure (BP) elevation, as well as vessel size are
all important for the alteration in the cerebrovascular wall induced
by hypertension.
Alterations in Cerebral Blood Flow
in Hypertension
Recent studies have shown reductions in cerebral blood flow
(CBF) in selected brain regions [33], which may precede cere-
brovascular symptoms or white matter lesions [34]. The enhance-
ment of CBF induced by brain activation is decreased in hy-
pertensives [35], representing attenuated functional hyperemia
accompanying hypertension. Hypertension alters endothelium-
dependent relaxation of cerebral blood vessels. The increase in
CBF caused by endothelium-dependent vasodilators is attenuated
in hypertensive rats [36]. Furthermore, the CBF reduction, accom-
panying hypertension, might be the result of increased vascular
tone secondary to endothelial dysfunction [37]. Endothelial dys-
function also results in overproduction of NO, which may increase
the permeability of cerebral vessels, resulting in cerebral edema.
Cerebrovascular autoregulation renders CBF independent of
changes in arterial pressure within a certain range (60–150 mmHg
mean arterial pressure), and has myogenic and neurogenic com-
ponents. Experimental and clinical studies have demonstrated that
hypertension leads to a shift of the cerebrovascular autoregula-
tion curve to the right towards higher-pressure values [38]. In-
creased myogenic tone, remodeling and hypertrophy occurring in
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J.-G. Yu et al.
hypertension contribute to the shift in autoregulation by reduc-
ing the vascular lumen and increasing cerebrovascular resistance
[21,37,39]. In addition, endothelial dysfunction might also atten-
uate or abolish myogenic autoregulation. Consequently, higher
perfusion pressures are needed to maintain the adequate CBF in
hypertension to prevent cerebral hypoperfusion, which may be
caused by excessive antihypertensive medication. In hypertension,
intracranial arterial vasculature is dilated, thus resulting in weak-
ened ability for additional vasodilatation in response to ischemic
events and a higher risk for subsequent accidents.
Oxidative Stress
Oxidative stress is a condition in which generation of ROS ex-
ceeds the capacity of the antioxidant defense system. Either excess
generation of ROS, depressed antioxidant capacity, or a combi-
nation of both can result in oxidative stress. Persistent oxidative
stress can deplete antioxidant molecules, inactivate antioxidant
enzymes, and thereby impair antioxidant defense system [40,41].
There is compelling evidence that oxidative stress play a critical
part in the pathogenesis of hypertension, and stroke as a long-term
complication [42,43]. Oxidative stress in the cerebral blood vessels
and brain can cause hypertension, based on the evidence that in-
duction of oxidative stress causes hypertension in normal animals
[44]. ROS is a major mediator of the cerebrovascular dysfunction
induced by Ang II, via activation of NADPH oxidase, in vascula-
ture [45]. The enzyme NADPH oxidase is the main source of ROS
mediating cerebrovascular dysfunction [46], and upregulation of
NADPH oxidase has been demonstrated in various models of hy-
pertension [47,48]. ROS production within BP control regions of
brain contributes to the neurohumoral changes that drive the hy-
pertension [49]. Peroxynitrite is the product of the reaction be-
tween NO and the radical superoxide. It can induce DNA damage
and lipid peroxidation, change protein function [50]. Peroxynitrite
exerts deleterious effects on cerebral blood vessels [51], which can
account for the cerebrovascular dysfunction induced by Ang II.
In addition, hypertension itself can result in oxidative stress in
cerebral blood vessels. This concept is based on the evidence that
ROS production in cerebral vessels is increased in Ang II-induced
hypertension [52,53]. Free radical scavengers could curb the ef-
fects of hypertension on functional hyperemia and endothelium
dependent responses, indicating that the cerebrovascular dysfunc-
tion is mediated by ROS. Therefore, oxidative stress participates in
the structural and functional alterations of cerebral blood vessels
induced by hypertension.
Inflammation in Hypertension
Inflammation is a vital process that leads to changes in vascular
wall integrity, and emerges as a common pathological mechanism
in a variety of vascular diseases, including atherosclerosis and cere-
bral aneurysms [54,55]. Studies have shown that the biomark-
ers of inflammation can predict risk of primary ischemic stroke
[56]. Inflammatory markers such as C-reactive protein (CRP),
interleukin-6 (IL-6), leukocyte elastase, lipoprotein (a), intercellu-
lar adhesion molecule-1 (ICAM-1), and E-selectin are consistently
higher in people prone to develop stroke compared with those
CNS Neuroscience & Therapeutics 17 (2011) 577–584 
c 2011 Blackwell Publishing Ltd
 17555949, 2011, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1755-5949.2011.00264.x by Nat Prov Indonesia, Wiley Online Library on [03/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
J.-G. Yu et al. Hypertension and Stroke Prevention

who are not. Inflammation may also lead to a worse outcome fol-
lowing stroke, resulting from the increase of CRP in response to
IL-6 [57,58]. Additionally, inflammation per se has been identified
as a “novel” risk factor for stroke [6,59,60].
There is increasing evidence supporting the role of vascular
inflammation in the pathogenesis of hypertension [43,61]. Acti-
vation of circulating leukocytes has been observed in hyperten-
sive humans and animals [62,63]. The causal role of inflamma-
tion in the pathogenesis of hypertension is further supported by
the observation that reducing or blocking inflammation leads to
amelioration of hypertension [64,65]. In addition, hypertension-
induced oxidative stress stimulates inflammatory reactions in cere-
bral blood vessels, as a result of production of chemokines, cy-
tokines, and adhesion molecules and proliferation of lymphocytes.
Conversely, inflammation causes oxidative stress, since activated
immune cells have been shown to produce ROS and express Ang
II, resulting in oxidative stress and hypertension [66]. Thus, ox-
idative stress, inflammation, and hypertension are involved in a
self-perpetuating vicious cycle, if without proper treatment, cul-
Figure 1 Mechanisms by which hypertension induces stroke.
minating in stoke as a frequent outcome.

Arterial Baroreflex Dysfunction in Hypertension

Arterial baroreflex is one of the most important physiological
mechanisms controlling BP regulation [67]. Recently, much in-
terest has been focused on the pathological significance of arterial
baroreflex dysfunction. Baroreflex sensitivity (BRS), a marker of
arterial baroreflex function, was found as an important determi-
nant in many cardiovascular diseases [68,69]. We have reported
that arterial baroreflex function plays an important role in the
pathogenesis and prognosis of atherosclerosis, aconitine-induced
arrhythmia and LPS-induced shock in animals [70–72].
Baroreflex can be less sensitive to any given change in BP with
hypertension, due to changes in vascular distensibility and altered
activity in the brainstem portion of the reflex [73]. Reduced BRS
results in vascular changes, arterial stiffness, contributing to a vi-
cious cycle of hypertension and related complications. Baroreflex
impairment has been repeatedly shown to be present in acute is-
chemic and hemorrhagic stroke [74,75]. Not only hypertension
but also arterial baroreflex dysfunction accompanying it, is an im-
portant determinant of stroke [76]. Baroreflex dysfunction and BP
variability may significantly alter cerebral perfusion and boost per-
ihematomal edema after ischemic or hemorrhagic stroke [77,78].
In addition, baroreflex dysfunction significantly increases the lev-
els of the interleukin-1 and IL-6, as well as infarct volume [79]. It
has been shown that baroreflex impairment is independently re-
lated to outcomes after acute ischemic stroke [80] or after intrac-
erebral hemorrhage [75]. In patients, BP variability within short
period (3–72 hours) after acute ischemic stroke is associated with
an increased risk of poor outcome [81,82]. Stroke is significantly
delayed in rats with high BRS than those with low BRS (time to
50% death was 1.47-fold longer than low BRS group, P < 0.01).
Moreover, restoration of BRS by ketanserin can prevent stroke sig-
nificantly in SHR-SP, whether BP was reduced or not [76].
We have recently found that both expression and function of α7
subunit of nicotinic acetylcholine (ACh) receptor (α7-nAChR) de-
creased in aorta of hypertensive rats; hypertension-induced end-
organ damage (EOD) was more severe in α7-nAChR−/− mice than
wild controls; administration of α7-nAChR agonist may lessen
EOD induced by hypertension. As to the determinant effect of
arterial baroreflex on stroke, it might be explained by these ob-
servations: arterial baroreflex dysfunction induces a decrease in
vagal tone; therefore, ACh secreted by vagus declined; thus, anti-
inflammatory effect of ACh mediated by α7-nAChR attenuated as
a result, which not only promotes the ictus but also worsens the
outcome of stroke.
Taken together, there is an intercausal relationship among ox-
idative stress, inflammation, baroreflex dysfunction, and hyper-
tension. If not interrupted, this vicious cycle might culminate in
stroke, as a result of secondary morphological and functional al-
terations of cerebral blood vessels (Figure 1).
Strategies of Stroke Prevention in
Patients with Hypertension
Hypertension is the most important modifiable risk factor for
stroke. In most countries, up to 30% of adults suffer from hy-
pertension [6]. Between 2000 and 2005, the prevalence of adult
hypertension was predicted to have risen by 60%, and to affect a
total of 1.56 billion people worldwide [83]. Moreover, about 54%
of stroke was attributable to hypertension [15]. Thus, it is neces-
sary to identify and treat hypertension and related vascular and
neuronal dysfunction to prevent stroke.
Classic Strategies for BP Control
There is strong evidence that antihypertensive therapy is impor-
tant for prevention of stroke, regardless of age, gender, or eth-
nicity [84–87]. A meta-analysis of nine randomized comparative
trials found that a reduction in systolic BP of just 1 to 3 mmHg
led to a reduction in risk of stroke of 20–30% [88]. However,

CNS Neuroscience & Therapeutics 17 (2011) 577–584 

c 2011 Blackwell Publishing Ltd 579

Hypertension and Stroke Prevention
discontinuation with antihypertensive therapy was associated
with a 28% increase in the risk of stroke [89].
Several categories of antihypertensive drugs, such as thiazide
diuretics, angiotensin-converting enzyme inhibitors (ACEIs), an-
giotensin receptor blockers (ARBs), β-adrenergic receptor block-
ers, and calcium channel blockers (CCBs), reduce the risk of stroke
in hypertensives [90–96], among which CCBs and ARBs have
particularly strong supportive data for a protective effect against
stroke [97,98]. A meta-analysis of two trials provided clear ev-
idence of a reduction of 39% in stroke risk with CCBs versus
placebo [99]. CCBs have also been shown to provide better protec-
tion against stroke than older drugs, such as β-blockers and diuret-
ics [100]. Candesartan-based treatment of hypertension reduced
nonfatal stroke by 27.8% and all stroke by 23.6% compared with
placebo [101]. Compared with older drugs, treatment with ARBs
lessened the incidence of stroke by 26% [102]. There is no differ-
ence in potential to prevent stroke between CCBs and ARBs [103].
In addition to lowering BP, there are BP-independent components
that contribute to the benefit of CCBs and ARBs on stroke [104].
Possible mechanisms for this additional benefit include: reductions
in carotid intima-media thickness, left ventricular mass or central
BP, and improvement in CBF autoregulation [105–107], some of
which are mediated by improvement in nitric oxide production,
decrease in oxidative stress [108], and reduction of inflammation
in cerebral microvessels [109]. Thus, single administration of these
agents or combinations of multiple agents might optimize the
cerebrovascular benefits of antihypertensive treatment for stroke
prevention.
Reducing Oxidative Stress in Hypertension
Theoretically, oxidative stress in hypertension might be corrected
by administration of antioxidants. However, mere administration
of high doses of several antioxidant compounds such as ascorbic
acid, beta carotene, and tocopherol, have shown no benefit or
even increased the risk for stoke. It might be explained by the fact
that oxidative stress in hypertension is not caused by deficiency of
the given antioxidants, thus it cannot be corrected by administra-
tion of such agents. Moreover, traditional antioxidants are nonse-
lective, which neutralize all free radicals including those essential
for normal physiological activities. Thus, administration of sup-
raphysiologic quantities of the traditional antioxidant compounds
would lead to accumulation of their free radical metabolite, which
can actually worsen oxidative stress. Therefore, consumption of
high doses of these agents is not recommended for the prevention
of stroke in hypertensive patients. Specific interventions directed
at the specific underlying mechanism of oxidative stress in hy-
pertension would be most effective [110]. Since Ang II promotes
oxidative stress and hypertension, drugs that interrupt rennin-
angiotensin system (RAS) might be suitable for management of
oxidative stress in certain types of hypertension [111]. As men-
tioned above, for example, CCBs and ARBs can not only lower
BP but also decrease oxidative stress in hypertension. In addition,
consumption of a diet rich in natural antioxidants and other essen-
tial micronutrients, as well as regular exercise and weight control,
also helps to combat oxidative stress [112].
580
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J.-G. Yu et al.
Recently, it has been reported that hydrogen may act as a ther-
apeutic antioxidant by selectively reducing cytotoxic oxygen rad-
icals [113]. Ohsawa et al. showed that hydrogen selectively scav-
enge the toxic hydroxyl radical, through specifically quenching
the hydroxyl radical while preserving other reactive oxygen and
nitrogen species important in signaling. In rodents subjected to
focal cerebral ischemia-reperfusion, inhaled 2% hydrogen lim-
ited the infarct volume, if given before the reperfusion phase of
injury. Most recently, inhalation of hydrogen, as well as injec-
tion of hydrogen saline has been proved to have antioxidant and
antiapoptotic properties that afford neuroprotection in neonatal
hypoxia–ischemia rat models [114,115]. Moreover, hydrogen has
been proved to possess antiinflammatory property, which is also
mediated by neutralizing of hydroxyl radical [116]. Thus, we can
expect that hydrogen might be a promising strategy for prevention
of stroke in hypertensives.
Reducing Inflammation in Hypertension
It is well accepted that inflammation is an essential mechanism
for EOD in hypertension. However, traditional antiinflammatory
drugs could not be used for controlling inflammation and reduc-
ing organ damage in hypertension. Considering the proinflamma-
tory effects of Ang II, antihypertensive approaches using agents
affecting components of RAS, are beneficial because of their po-
tential antiinflammatory properties [117–119]. It has been well
know that ARBs such as telmisartan and olmesartan, exert antiin-
flammatory effect during antihypertensive treatment, by reduc-
ing levels of hsCRP, IL-6, tumor necrosis factor-α (TNF-α) and
monocyte chemotactic protein-1 (MCP-1) [120]. Furthermore,
prestroke therapy with ACEIs appears to lessen stroke severity in
patients [121]. ACEIs such as enalapril, have been found to reduce
inflammatory process, through reduction of ICAM-1, E-selectin,
and MCP-1 [122,123]. Captopril shows an antiatherosclerotic ef-
fect, and ramipril decreases inflammatory infiltrates in experimen-
tal models [124,125]. Apart from angiotensin-converting enzyme,
chymase in mast cells is also involved in conversion of Ang I to
Ang II. Chymase is considered to be responsible for >80% of tissue
Ang II formation in the human heart and >60% of that in arteries
[126]. Therefore, chymase has been implicated in the pathogene-
sis of cardiovascular diseases, including atherosclerosis and hyper-
tension [127,128]. Recently, it was reported that homocysteine
may increase mast cell chymase expression and activity through
the mechanism of oxidative stress [129,130]. Indirect inhibition
of chymase through inhibition of mast cell by ketotifen reduces
splanchnic inflammatory response in a portal hypertension model
in rats [131]. Furthermore, inhibition of chymase with Y-40079
significantly abolished leukocyte rolling and adhesion in postis-
chemic small intestine [132]. Thus, inhibitors of chymase might
also be potential strategy for stroke prevention.
Moreover, statins such as rosuvastatin may reduce IL-6 and
TNF-α in hypertensives [133]. Prestroke therapy with statins ap-
pears to lessen stroke severity [134–136] and cessation of pre-
stroke statin therapy at the time of stroke appears deleterious
[137]. Peroxisome proliferator-activated receptor agonists such as
pioglitazone, may also interfere with the inflammatory process in
hypertension through reduction of CRP, ICAM-1, and vascular
CNS Neuroscience & Therapeutics 17 (2011) 577–584 
c 2011 Blackwell Publishing Ltd
 17555949, 2011, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1755-5949.2011.00264.x by Nat Prov Indonesia, Wiley Online Library on [03/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
J.-G. Yu et al. Hypertension and Stroke Prevention

cell adhesion molecule-1 levels [138]. Recently, α7-nAChR has
been proved to be an essential regulator of inflammation [139],
selective activation of α7-nAChR inhibits inflammatory cytokine
production in macrophages and monocytes, and in several models
of inflammatory disease in vivo [140–142]. Therefore, selective ag-
onists of α7-nAChR may be considered to inhibit inflammation in
hypertension.
Restoration of Impaired Arterial Baroreflex
Function in Hypertension
Arterial baroreflex function can be positively influenced by cer-
tain drugs, especially β-blockers [143]. A recent report showed
that β-blockers could lessen severity of stroke in ischemic stroke
patients [144], and pretreatment with β-blockers reduced infarct
volume in experimental ischemia models [145]. It has been re-
ported that β-blockers can also reduce brain edema in either an-
imals or patients with traumatic brain injury [146,147]. However
the benefit of β-blockers in acute human stroke remains contro-
versial [148,149].
Ketanserin, a new type of antihypertensive drug, is a selec-
tive 5-HT2A receptor antagonist with additional α1-adrenoceptor-
blocking properties. In our previous studies, it was found that
ketanserin significantly improve BRS in hypertensive rats [150].
Ketanserin reduced the incidence of fatal strokes, through amelio-
ration of BRS besides reduction of BP [76,151]. Other drugs, such
as clonidine, moxonidine, mecobalamin, and folic acid, also im-
proved BRS [152–155]. Baroreceptor stimulation has been used
in patients with drug-resistant hypertension [156]. It has been
shown that vagus nerve stimulation reduces infarct size in rat
focal cerebral ischemia [157]. Therefore, baroreflex modulation
through drugs or electrical stimulation might be a potential strat-
egy for stroke prevention.
Conclusions
Stroke is a major public health concern, and hypertension is one of
the most important risk factors. We have provided a brief overview
of factors involved in the hypertension-induced stroke and recent
developments in its prevention. However, hypertension is often
accompanied by many other systemic diseases, which also increase
the risk for stroke. Combination treatment of these diseases be-
sides hypertension-related status, as well as a healthy life style may
lead to more effective prevention of stroke.
Acknowledgments
This work was supported by grants from the National Basic Re-
search Program of China (973 Program, 2009CB521901) and
the National Natural Science Foundation of China (30730106,
30900529, 30973525).
Conflict of Interest
The authors have no conflict of interest.

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