Contribution of Apelin-17 to Collateral Circulation Following Cerebral Ischemic Stroke
- 162 Downloads
Apelin, an essential mediator of homeostasis, is crucially involved in cardiovascular diseases, including ischemic stroke. However, the functional roles of apelin-17 in cerebral collateral circulation and ischemic stroke protection are unknown. Here, we investigated the association between plasma apelin-17 levels and collateral circulation in patients with ischemic stroke and examined the mechanism undergirding the effects of apelin-17 on cerebral artery contraction and ischemic stroke protection in an animal model. Plasma nitric oxide (NO), apelin-17, and apelin-36 levels were assessed by enzyme-linked immunosorbent assays in ischemic stroke patients with good or poor collateral circulation and in healthy participants. Additionally, the effects of apelin-17 on rat basilar artery contractions (in vitro) and cerebral ischemia (in vivo) were determined using vessel tension measurements and nuclear magnetic resonance, respectively. Patients with good collateral circulation had significantly higher plasma apelin-17 and apelin-36 levels than both patients with poor collateral circulation and healthy participants and plasma NO levels significantly higher than those in healthy participants. In vitro, apelin-17 pretreatment markedly attenuated U46619-induced rat basilar artery contractions in an endothelium-dependent manner. Additionally, NO production or guanylyl cyclase inhibitors abolished the apelin-17 effect on U46619-induced vascular contraction. Intravenous pretreatment of rats with apelin-17 markedly reduced cerebral infarct volume at 24 h after middle cerebral artery occlusion. Plasma apelin-17 levels in ischemic stroke patients were positively associated with enhanced collateral circulation, which our animal study data suggested may have resulted from an apelin-17-induced cerebral artery dilation mediated through the NO–cGMP pathway.
KeywordsStroke Apelin-17 Cerebral collateral circulation Basilar artery Endothelium Nitric oxide Cerebral ischemic protection
The authors would like to thank Lei Zhan for editing the English text in a draft of this manuscript.
The present study was supported by grants from the National Key Research and Development Program of China (2016YFC1300600); Natural Science Foundation of China (Grant No. 81371284, 81570403, 81600286); Overseas Scholars Start Fund from Department of Human Resources and Social Security of Anhui Province; Outstanding Young Investigator of Anhui Medical University; Anhui Provincial Natural Science Foundation (Grant Nos. 1708085MH187, 1508085QH164).
Compliance with Ethical Standards
Research Involving Animals
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Informed consent was obtained from all individual participants included in the study.
Conflict of Interest
The authors declare that they have no conflict of interest.
- 6.Schramm P, Schellinger PD, Fiebach JB, Heiland S, Jansen O, Knauth M, et al. Comparison of ct and ct angiography source images with diffusion-weighted imaging in patients with acute stroke within 6 hours after onset. Stroke. 2002;33:2426–32. https://doi.org/10.1161/01.STR.0000032244.03134.37.CrossRefGoogle Scholar
- 7.Fischer U, Arnold M, Nedeltchev K, Brekenfeld C, Ballinari P, Remonda L, et al. Nihss score and arteriographic findings in acute ischemic stroke. Stroke. 2005;36(10):2121–5. https://doi.org/10.1161/01.STR.0000182099.04994.fc.CrossRefGoogle Scholar
- 14.Wang W, McKinnie SM, Farhan M, Paul M, McDonald T, McLean B, et al. Angiotensin-converting enzyme 2 metabolizes and partially inactivates pyr-apelin-13 and apelin-17: physiological effects in the cardiovascular system. Hypertension. 2016;68:365–77. https://doi.org/10.1161/HYPERTENSIONAHA.115.06892.CrossRefGoogle Scholar
- 17.Pisarenko OI, Lankin VZ, Konovalova GG, Serebryakova LI, Shulzhenko VS, Timoshin AA, et al. Apelin-12 and its structural analog enhance antioxidant defense in experimental myocardial ischemia and reperfusion. Mol Cell Biochem. 2014;391(1–2):241–50. https://doi.org/10.1007/s11010-014-2008-4.CrossRefGoogle Scholar
- 18.Berry MF, Pirolli TJ, Jayasankar V, Burdick J, Morine KJ, Gardner TJ, et al. Apelin has in vivo inotropic effects on normal and failing hearts. Circulation 2004; 110(11 suppl 1):II187–93. doi: https://doi.org/10.1161/01.CIR.0000138382.57325.5c, II-187, II-193.
- 28.Maguire JJ, Kleinz MJ, Pitkin SL, Davenport AP. [pyr1]apelin-13 identified as the predominant apelin isoform in the human heart: vasoactive mechanisms and inotropic action in disease. Hypertension. 2009;54:598–604. https://doi.org/10.1161/HYPERTENSIONAHA.109.134619.CrossRefGoogle Scholar
- 29.Zhang YH. Nitric oxide signalling and neuronal nitric oxide synthase in the heart under stress. F1000Research 2017; 6:742. doi: https://doi.org/10.12688/f1000research.10128.1.
- 34.Vandael DH, Mahapatra S, Calorio C, Marcantoni A, Carbone E. Cav1.3 and cav1.2 channels of adrenal chromaffin cells: emerging views on camp/cgmp-mediated phosphorylation and role in pacemaking. Biochim Biophys Acta. 2013;1828(7):1608–18. https://doi.org/10.1016/j.bbamem.2012.11.013.CrossRefGoogle Scholar