Current Neurovascular Research (v.14, #2)

The Association of MME microRNA Binding Site Polymorphism with the Risk of Late Onset Alzheimer's Disease in Northern Han Chinese by Chun-Xia Liu, Lin Tan, Fu-Rong Sun, Wei Zhang, Dan Miao, Meng-Shan Tan, Yu Wan, Chen-Chen Tan, Jin-Tai Yu, Lan Tan (90-95).
Background: Although β-amyloid (Aβ) degradation has been normally implicated in the pathogenesis of late-onset Alzheimer's disease (LOAD) through cellular biological studies, the genetic studies linking Aβ degradation and LOAD are still scarce. Neprilysin (NEP), one of the most crucial Aβ-degrading enzymes in AD, is the metalloendopeptidase which particularly participates in the monomeric Aβ species degradation. MicroRNAs (miRNAs) exert post-transcriptional dysregulation and their target sequence on the 3' untranslated regions (3'UTR) may be regulated by single nucleotide polymorphisms (SNPs).

Objective: To investigate the potential risk of common locus within NEP gene (MME) with LOAD in Northern Han Chinese population.

Method: We screened a locus (rs6665) in 3' UTR of NEP gene (MME) which sequence was specially regulated by miRNA-187, and further investigated its possible association with LOAD onset in a large case-control study (984 LOAD patients and 1354 healthy controls) in Northern Han Chinese.

Results: The distribution of rs6665 genotype (P=0.003) and allele A/C (P=0.001) showed significant difference between LOAD and controls (Odds Ratio (OR) =1.255, 95% Confidence Interval (CI) =1.102-1.429). After adjusting for age, gender and Apolipoprotein (ApoE) ε4 status, the minor C allele of rs6665 showed significant association with LOAD in all three genotypic models (Dominant: P=0.003, OR=1.291, 95%CI=1.092-1.526; Recessive: P=0.030, OR =1.425, 95%CI =1.035- 1.961; Additive: P=0.001, OR=1.249,95%CI=1.093-1.427). After stratifying by ApoE ε4 status, rs6665 polymorphism was found to elevate the LOAD risk in ApoE ε4 carriers (P=0.002, OR=1.846, 95%CI=1.264-2.697).

Conclusion: Our study firstly confirmed the association of MME miRNA binding site polymorphism with the risk of LOAD. However, the association results warrant further validation.

In Models of Intracerebral Hemorrhage, Rivaroxaban is Superior to Warfarin to Limit Blood Brain Barrier Disruption and Hematoma Expansion by Shigenobu Sawada, Yoko Ono, Yusuke Egashira, Toshinori Takagi, Kazuhiro Tsuruma, Masamitsu Shimazawa, Toru Iwama, Hideaki Hara (96-103).
Background: Intracerebral hemorrhage (ICH) during oral anticoagulation therapy with an oral vitamin K epoxidase reductase such as warfarin is a life-threatening complication. However, whether direct oral anticoagulants (DOACs) are associated with larger hematoma volume and higher mortality rates remains controversial. We evaluated the hematoma volume and pathophysiology of ICH during anticoagulation with warfarin or rivaroxaban, an orally active direct factor Xa inhibitor.

Method: Mice were orally pretreated with rivaroxaban (10 or 30 mg/kg), warfarin (4 mg/kg), or vehicle. ICH was induced by intrastriatal collagenase-injection. Hematoma volume and neurological deficits 24 h after ICH induction were significantly decreased in the rivaroxaban-pretreated group in comparison with the warfarin-pretreated group. Rivaroxaban did not increase the hematoma volume relative to that observed for vehicle, and improved survival rate 7 days after ICH induction compared with warfarin.

Result: We evaluated blood-brain barrier (BBB) permeability 6 h after ICH induction using Evans blue spectrophotometry. Evans blue extravasation was significantly reduced in the rivaroxaban group compared with the warfarin group. To investigate the mechanism underlying hematoma expansion and BBB permeability, we focused on thrombin, a clot-derived factor and one of the major contributors to ICH-induced brain injury. To investigate the effects of anticoagulant agents on thrombin-induced injuries, human brain endothelial cells were used in membrane permeability assays. Rivaroxaban, but not warfarin, significantly mitigated the thrombin-induced increase in membrane permeability.

Conclusion: These findings indicate that rivaroxaban decreases BBB disruption after ICH, and limits early hematoma expansion in these experimental models compared with warfarin. Our study suggests that rivaroxaban has advantages over warfarin with respect to ICH, an important complication during long-term anticoagulation therapy.

Cerebral Microbleeds Do Not Predict Hemorrhagic Transformation in Acute Ischemic Stroke Patients with Atrial Fibrillation and/or Rheumatic Heart Disease by Junfeng Liu, Deren Wang, Jie Li, Jing Lin, Yao Xiong, Bian Liu, Chenchen Wei, Bo Wu, Zhenxing Ma, Shihong Zhang, Ming Liu (104-109).
Background and Purpose: Cerebral microbleeds (CMBs) are known to be potential risk factors for intracerebral hemorrhage (ICH), but there is controversy on the relationship between CMBs and hemorrhagic transformation (HT) after ischemic stroke. Besides, the question regarding whether the relationship between CMBs and HT can be affected by antithrombotic drugs in acute stage of ischemic stroke has not yet reached a consensus.

Methods: 174 acute ischemic stroke patients with atrial fibrillation (AF) and/or rheumatic heart disease (RHD) were prospectively and consecutively enrolled in the study, of which 160 patients (mean 68.09 A±12.59 years) were finally included in the final analysis (West China Hospital, Sichuan University, n=125; People's Hospital of Deyang City, n=35).We assessed the presence, location and number of CMBs by using susceptibility-weighted imaging (SWI) within 7 days after admission, and the incidence of hemorrhagic transformation was evaluated by magnetic resonance imaging(MRI) during hospitalization. The univariate and multivariate analyses were used to analyze the relationship between CMBs and HT.

Results: CMBs were detected in 90 patients (56.3%). HT was found in 62 (38.8%) patients, among which 43 were hemorrhagic infarction (HI) and 19 were parenchymal haemorrhage (PH). The presence of CMBs was not significantly different among different HT subtypes (no HT, HI and PH; 59.2%, 51.2%, versus 52.6%, P=0.64). There was no relationship between the number/location of CMBs and hemorrhagic transformation subtypes (P=0.38). In the 2 subgroups of patients treated with anticoagulants and antiplatelets after admission, the incidence of HT was not significantly different between patients with and without CMBs (anticoagulants, 13.3% versus 18.2%, P=0.71; antiplatelets, 29.2% versus 40.3%, P= 0.21).

Conclusion: The present study suggests that CMBs do not predict the presence of hemorrhagic transformation in acute ischemic stroke patients with AF and/or RHD. The results were not affected by anticoagulant or antiplatelet agents used in acute stage of ischemic stroke.

Tetramethylpyrazine Facilitates Functional Recovery after Spinal Cord Injury by Inhibiting MMP2, MMP9, and Vascular Endothelial Cell Apoptosis by Jian-Zhong Hu, Xiao-Kai Wang, Yong Cao, Dong-Zhe Li, Tian-Ding Wu, Tao Zhang, Da-Qi Xu, Hong-Bin Lu (110-116).
Background: Spinal cord injury (SCI) is a major public health issue that leads to neurological dysfunctions and morbidities in patients. Tetramethylpyrazine (TMP) plays a neuroprotective role in SCI; however, the underlying mechanism has not been fully elucidated.

Objective: In the present study, we aimed to investigate the mechanisms and therapeutic effects of TMP on SCI.

Methods: A contusion SCI model was established that used a modified Allen's method. In the TMP group, TMP (200 mg/kg) was injected daily for 5 days post-injury, while in the Negative Control (NC) group, an equal volume of normal saline was injected. Hindlimb motor function was evaluated using the Basso, Beattie, Bresnahan (BBB) scale. The effects of TMP on protein levels of the matrix metalloproteinases 2 (MMP2) and 9 (MMP9), Bax and cleaved caspase-3 were determined by western blotting. Apoptotic changes in vascular endothelial cells were evaluated using immunofluorescence and TUNEL staining. Alterations in 3D vessel morphology after treatment with TMP were assessed by synchrotron radiation micro-CT (SRμCT).

Results: TMP treatment significantly improved recovery in hindlimb motor function and attenuated vascular endothelial cell apoptosis in rats with SCI. Additionally, TMP treatment markedly decreased the protein levels of MMP2 and MMP9, pro-apoptotic bax and cleaved caspase-3 while promoting angiogenesis, as evidenced by vessel visualization using SRμCT.

Conclusion: These results indicate that TMP attenuated SCI-induced neurological impairments by the down-regulation of the expression of MMP2 and MMP9 proteins, the inhibition of vascular endothelial cell apoptosis, and the promotion of angiogenesis.

Background: Diabetic peripheral neuropathy (DPN) is a common complication of diabetes with a complex pathogenesis. Study has reported that oxidative stress and nitrative stress are all involved in the DPN. However, the mechanism between them is still unclear. In the present study, we investigated whether miR-106a regulated 12/15-Lipoxygenase (12/15-LOX) of oxidative/nitrative stress (OS/NS) in DPN.

Methods: Dorsal root ganglion (DRG) was isolated from 10 healthy mice and 10 DPN mice. DPN mouse model was established by the injection of streptozotocin (STZ), and high glucose was used for inducing the in vitro model of DPN.

Results: In DPN mice, the levels of fasting blood-glucose (FBG) level, Methane Dicarboxylic Aldehyde (MDA) and the Inducible Nitric Oxide Synthase (iNOS) were increased, while the levels of motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV) and superoxide dismutase (SOD) were decreased. MiR-106a level in DRG cells of DPN was decreased. The 12/15-LOX expression and cell apoptosis were increased. DRG cells subjected to high glucose resulted in the same effects as above. MiR-106a was observed to target 12/15-LOX and regulated its expression. MiR-106a overexpression reversed the effect that was induced by high glucose, however, overexpression of 12/15-LOX reversed the effect that was induced by miR-106a overexpression.

Conclusion: MiR-106 may be associated with 12/15-LOX mediated OS/NS in DPN and may be considered as a potential therapeutic target.

Knockdown of C-C Chemokine Receptor 5 (CCR5) is Protective Against Cerebral Ischemia and Reperfusion Injury by Edna Constanza Gómez Victoria, Eliana Cristina de Brito Toscano, Ana Clara de Sousa Cardoso, Daniele Gonçalves da Silva, Aline Silva de Miranda, Lucíola da Silva Barcelos, Michelle Adriane Sugimoto, Lirlândia Pires Sousa, Isabel Vieira de Assis Lima, AntÃ'nio Carlos Pinheiro de Oliveira, Fátima Brant, Fabiana Simao Machado, Mauro Martins Teixeira, AntÃ'nio Lúcio Teixeira, Milene Alvarenga Rachid (125-131).
Background: Stroke is the second leading cause of death and a major cause of disability of adults worldwide. Inflammatory processes are known to contribute to the pathophysiology of cerebral ischemia, especially following reperfusion. Chemokines and their receptors are involved in migration of leukocytes and have been implicated in the pathogenesis of ischemic stroke.

Objective: In the present study, we investigated the effects of C-C chemokine receptor type 5 (CCR5) deficiency on neurological outcome, brain damage and expression of pro-inflammatory chemokines: chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine (CC motif) ligand 3 (CCL3) and chemokine (C-C motif) ligand 5 (CCL5), and the brain-derived neurotrophic factor (BDNF).

Methods: Adult male C57BL/6 (wild-type) (WT) and CCR5 deficient mice were subjected to transient cerebral ischemia induced by 25 min of bilateral common carotid artery occlusion (BCCAO) followed by 24 hours of reperfusion. Mice were divided into four groups: WT sham group, which underwent sham operation; WT ischemic group, which was subjected to transient bilateral common carotid artery occlusion, CCR5-/- sham group, which underwent sham operation, and CCR5-/- ischemic group, which was subjected to transient BCCAO.

Results: In CCR5 deficiency, we observed a significant improvement in the neurological deficits associated with decreased brain infarcted area as evaluated by triphenyltetrazolium chloride (TTC). Moreover, CCR5 deficiency revealed decreased percentage of necrotic cavities areas and frequency of ischemic neurons by histometric analysis. In addition, CCR5-/- ischemic animals showed lower brain levels of the chemokine CXCL1 and higher levels of BDNF by ELISA, compared with WT BCCAo mice.

Conclusion: Taken together, our results suggest a potential neuroprotection in the absence of CCR5 receptor during global brain ischemia and reperfusion injury.

Background: Tanshinone IIA is a key active ingredient of danshen, which is derived from the dried root or rhizome of Salviae miltiorrhizae Bge. The tanshinone IIA has protective effects against the focal cerebral ischemic injury. However, the underlying mechanisms remain unclear.

Methods: An in vitro model of cerebral ischemia was established by subjecting cultures of hippocampal neuronal cells to oxygen-glucose deprivation followed by reperfusion (OGD/R). The probes of 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester (CMH2DCFDA) and 5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine,iodide (JC-1) were used to determine the mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) production. Western-blot was used to detect the expression of proteins in HT-22 cells.

Results: The results of cell proliferative assays showed that the tanshinone IIA attenuated OGD/Rmediated neuronal cell death, with the evidence of increased cell viability. In addition, OGD/R exposure led to increase the levels of intracellular reactive oxygen species (ROS), which were significantly suppressed by tanshinone IIA treatment. Furthermore, tanshinone IIA treatment inhibited elevations in MMP and autophagy following exposure to OGD/R. Additionally, OGD/R promoted cell death with concomitant inhibiting phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of Rapamycin (mTOR) pathway, which was reversed by tanshinone IIA.

Conclusion: These results suggest that the tanshinone IIA protects against OGD/R-mediated cell death in HT-22 cells, in part, due to activating PI3K/Akt/mTOR pathway.

Young Stroke Patients Treated with Intravenous Thrombolysis have a More Favorable Outcome and Mortality Compared with Older Patients by Jijun Shi, Yongjun Cao, Shoujiang You, Zhichao Huang, Xia Zhang, Huihui Liu, Chun-Feng Liu (141-148).
Background: Previous clinical studies suggest that intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator benefits stroke patients, but the efficacy of IVT in young stroke patients is not well-studied in China.

Objective: We compared the safety and efficacy of IVT with recombinant tissue plasminogen activator between Chinese young stroke patients (18-50 years old) and older patients (51-80 years old).

Method: We analyzed data from the Soochow Stroke Registry for 373 stroke patients (18-50 years, n=74 vs. 51-80 years, n=299) who received IVT between May 2009 and January 2016. Main outcomes included symptomatic intracerebral hemorrhage (sICH) within 7 days, and mortality and favorable outcome (modified Rankin scale 0-2) at 3 months. Associations between baseline characteristics and outcomes for the two groups were analyzed by logistic regression.

Results: Favorable outcome at 3 months was significantly higher in young adults (adjusted odds ratio 2.09; 95% confidence interval 1.09-3.99, p=0.026). The incidence of sICH and mortality was low for young adults compared with older patients, but there were no statistically significant differences between the two groups. Multivariable analysis showed that baseline National Institutes of Health Stroke Score was associated with favorable outcome (p=0.026) in young adults.

Conclusion: Our analysis indicated that young stroke patients treated with IVT had a more favorable outcome without an increased risk of sICH and mortality compared with older patients. We conclude that IVT is safe and at least as beneficial for Chinese young adults with acute ischemic stroke compared with older patients.

Prolonged Perfusion Predicts Recurrent Ischemic Stroke but not Transient Ischemic Attack in Patients with Symptomatic Intracranial Stenosis by Linfang Lan, Xinyi Leng, Vincent Ip, Thomas Leung, Yannie Soo, Jill Abrigo, Ka Sing Wong (149-157).
Background: Intracranial arterial stenosis (ICAS) is the dominant cause for ischemic stroke worldwide, with hemodynamic compromise as a crucial contributor. Prolonged perfusion is commonly observed in ICAS patients on CT perfusion (CTP) maps, while the clinical significance of this perfusion pattern has not been elucidated.

Method: Patients having symptomatic ICAS of 50-99% stenosis with sustained downstream cerebral blood flow (CBF) were enrolled in this study. Prolonged perfusion was defined as increased mean transit time (MTT) in vascular territories of the target ICAS on CTP maps. The primary clinical outcome was recurrence of ipsilateral ischemic stroke, and secondary outcome was any ipsilateral ischemic events at 2 years follow-up.

Results: Of the 95 patients (median age 61y; 70% males) with symptomatic ICAS, 29 patients (30.5%) had prolonged perfusion. Such delayed perfusion was persistent in a majority of patients according to the 1-year imaging follow-up. The prolongation of cerebral perfusion was associated with subsequent risk for ipsilateral ischemic stroke (HR 7.01; 95% CI 1.86-26.46; p = 0.004), but not for any ipsilateral ischemic events (HR 1.52; 95% CI 0.63-3.68; p = 0.348). Further comparison of perfusion measures showed lower CBF (p = 0.034) and higher MTT (p = 0.064) in patients with recurrent ischemic stroke, but not in those with recurrent transient ischemic attack (TIA). Among patients with recurrent stroke, a majority had multiple infarcts along the borderzone regions.

Conclusion: In patients with symptomatic ICAS, persistent prolonged cerebral perfusion might contribute to the relapse of ischemic stroke, but not TIA.

Atomoxetine Protects Against NMDA Receptor-mediated Hippocampal Neuronal Death Following Transient Global Cerebral Ischemia by Joon Ha Park, Yang Hee Kim, Ji Hyeon Ahn, Soo Young Choi, Seongkweon Hong, Sung Koo Kim, Il Jun Kang, Young-Myeong Kim, Tae-Kyeong Lee, Moo-Ho Won, Choong-Hyun Lee (158-168).
Background: Atomoxetine has been widely used for the treatment of attention-deficit/ hyperactivity disorder. ATX has additional abilities such as antagonistic effects on the N-methyl-Daspartate receptors (NMDARs) and benefit effects in some animal models of neurological disorders. However, there were few studies regarding protective effects and related mechanisms of ATX against cerebral ischemic insults.

Objective: The objective of this study is to investigate neuroprotection of ATX pretreatment and its mechanisms in the hippocampal cornu ammonis 1 (CA1) region following transient global cerebral ischemia in gerbils.

Method: Gerbils were subjected to transient global cerebral ischemia induced by the occlusion of common carotid arteries for 5 min. Thirty mg/kg of ATX was administrated intraperitoneally once daily for 3 days before ischemic surgery. To examine neuroprotective effects of ATX, we carried out neuronal nuclear antigen immunohistochemistry and Fluoro-Jade B histofluorescence staining. In addition, immunoreactivities of NMDAR1, NMDAR2A/B, B-cell lymphoma 2 (Bcl-2) and Bcl-2- associated X protein (Bax) are closely related with neuroexcitotoxicity.

Results: ATX pretreatment reduced ischemia-induced hyperactivity and protected CA1 pyramidal neurons from ischemia. Pretreatment with ATX significantly attenuated ischemia-induced increases of NMDAR1 and NMDAR2A/B immunoreactivities in the CA1 pyramidal neurons at early time following ischemia. In addition, significant ischemia-induced alterations of Bcl-2 and Bax immunoreactivities were not observed in the ATX-treated group following ischemia.

Conclusion: These results show that pretreatment with ATX protected against ischemic neuronal via inhibition of ischemia-induced excitotoxicity at early time following transient global cerebral ischemia.

Prognostic Parameters for Symptomatic Intracranial Hemorrhage after Intravenous Thrombolysis in Acute Ischemic Stroke in an Asian Population by Thanin Lokeskrawee, Sombat Muengtaweepongsa, Jayanton Patumanond, Somsak Tiamkao, Thanoot Thamangraksat, Phanyarat Phankhian, Polchai Pleumpanupatand, Paworamon Sribussara, Teeraparp Kitjavijit, Anake Supap, Weerawan Rattanaphibool, Jariya Prisiri (169-176).
Background: Symptomatic intracranial hemorrhage (sICH) is a major complication after intravenous thrombolysis leading to severe disability and death. The incidence was higher in Asian than in western countries. Prognostic factors across ethnicities are presumably different. Studies in Asian populations are limited.

Method: Clinical data from January 2008 to September 2016 in one provincial and four regional hospitals in the northern part of Thailand were retrospectively reviewed. Patients were those with acute ischemic stroke, to whom recombinant tissue plasminogen activator (rt-PA) had been prescribed. They were classified into 3 groups; no intracranial hemorrhage (no ICH), asymptomatic intracranial hemorrhage (asICH) and symptomatic intracranial hemorrhage (sICH), based on clinical and brain imaging (computed tomography or CT). Prognostic parameters were investigated using a multi-level, multivariable ordinal logistic model.

Results: After exclusion of ineligible patients, the remaining 1,172 patients were classified into no ICH (n=923, 78.8%), asICH (n=154, 13.1%) and sICH (n=95, 8.1%). Independent prognostic parameters for intracranial hemorrhage were the National Institutes of Health Stroke Scale (NIHSS) >20 (OR, 3.51; 95% CI, 2.18-5.65; p<0.001), NIHSS >10 (OR, 2.02; 95% CI, 1.42-2.87; p<0.001), use of nicardipine during rt-PA (OR, 1.61; 95% CI, 1.09-2.40; p=0.018), systolic blood pressure (SBP) prior to thrombolysis ≥ 140 mmHg (OR, 1.47; 95% CI, 1.06-2.04; p=0.021), and platelet count <250,000 cell/mm3 (OR, 1.45; 95% CI, 1.04-2.01; p=0.029).

Conclusion: Patients with these parameters should be closely monitored. Information should be provided to the patients and their relatives.

TREM2 and the Progression of Alzheimer's Disease by Li Gao, Teng Jiang, Xiaoying Yao, Ling Yu, Xiaolan Yang, Yansheng Li (177-183).
Alzheimer's disease (AD) is the most common form of dementia, which has been currently considered as a genetically complex disorder caused by a combination of environmental and genetic risk factors. Previous studies have reported that triggering receptor expressed on myeloid cells 2 (TREM2) gene represents a promising candidate gene for AD susceptibility and progression. Interestingly, recent findings further suggested that the association between TREM2 variants and AD risk was quite diverse among different ethnicities and populations. As a member of immunoglobulin superfamily, TREM2 protein suppresses inflammatory responses, mediates phagocytic pathways, and contributes to the homeostasis of neuroimmunity in the central nervous system. Emerging evidence has indicated that TREM2 was involved in AD-related neuropathology including amyloid-β deposition, tau hyperphosphorylation, neuroinflammation, and neuronal and synaptic losses in AD animal models, but the precise underlying mechanisms have not been fully characterized yet. Here, we reviewed the new epidemiological findings regarding the association of TREM2 with AD. Meanwhile, we summarized the recent updates about the biological functions of TREM2 and its role in AD pathogenesis. In addition, we also explored the potential TREM2- targeting therapies for AD treatment.

Background: Transient receptor potential (TRP) channels are a superfamily of ion channels termed after the trp gene in Drosophila that are diverse in structure and control a wide range of biological functions including cell development and growth, thermal regulation, and vascular physiology. Of significant interest is the transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor, also known as the capsaicin receptor and the vanilloid receptor 1, that is a non-selective cation channel sensitive to a host of external stimuli including capsaicin and camphor, venoms, acid/basic pH changes, and temperature.

Methods: Given the multiple modalities that TRPV1 receptors impact in the body, we examined and discussed the role of these receptors in vasomotor control, metabolic disorders, cellular injury, oxidative stress, apoptosis, autophagy, and neurodegenerative disorders and their overlap with other signal transduction pathways that impact trophic factors.

Results: Surprisingly, TRPV1 receptors do not rely entirely upon calcium signaling to affect cellular biology, but also have a close relationship with the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and protein kinase B (Akt) that have roles in pain sensitivity, stem cell development, cellular survival, and cellular metabolism. These pathways with TRPV1 converge in the signaling of growth factors with recent work highlighting a relationship with erythropoietin (EPO). Angiogenesis and endothelial tube formation controlled by EPO requires, in part, the activation of TRPV1 receptors in conjunction with Akt and AMPK pathways.

Conclusion: TRPV1 receptors could prove to become vital to target disorders of vascular origin and neurodegeneration. Broader and currently unrealized implementations for both EPO and TRPV1 receptors can be envisioned for for the development of novel therapeutic strategies in multiple systems of the body.

Clinical Significance of the Sympathetic Nervous System in the Development and Progression of Pulmonary Arterial Hypertension by Ru-Xia Liu, Qian Luo, Hui Qiao, Juan Yu, Qian-Long Zhang, Peng Wang, Yong-Gang Cao, Chang-Lin Jiang, Li-Hui Qu (190-198).
Background: Pulmonary arterial hypertension (PAH) is defined as a complex disease of clinically characterized by elevated pulmonary pressure eventually resulting in right heart failure and premature death. To date, PAH still remains a life-threatening disease. Published evidence suggests that patients with PAH present profound sympathetic nervous system abnormalities and sympathetic activity has been shown to be increased. The mechanism of PAH is still complex and poorly understood.

Results: Some data have showed that adrenoceptors are involved in the process of the pathology and have different functions in the progression of PAH followed by heart failure. Alpha-adrenergic receptors mediate most excitatory effects and induce growth of smooth muscle cells and adventitial fibroblasts via complex cellular and molecular mechanisms. However, beta-adrenergic receptor mainly detected in endothelial layer commonly exerts relaxation effects on pulmonary artery. In addition, G protein-coupled receptor kinase 2, the primary G protein-coupled receptor kinase expressed in the heart, has been shown to be increased, resulting in the distinctive loss of inotropic reserve and functional capacity of the failing heart according to the activation of sympathetic nervous system.

Conclusion: Here, we summarize the relevant available studies describing the roles of sympathetic nervous system in the progression of PAH.