Griffiths Philip R, Lolait Stephen J, Pearce Louise E, McBryde Fiona D, Paton Julian F R, O'Carroll Anne-Marie
Laboratories for Integrative Neuroscience and Endocrinology, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Front Physiol. 2018 Oct 24;9:1488. doi: 10.3389/fphys.2018.01488. eCollection 2018.
Dysfunction of the apelinergic system, comprised of the neuropeptide apelin mediating its effects via the G protein-coupled apelin receptor (APJ), may underlie the onset of cardiovascular disease such as hypertension. Apelin expression is increased in the rostral ventrolateral medulla (RVLM) in spontaneously hypertensive rats (SHRs) compared to Wistar-Kyoto (WKY) normotensive rats, however, evidence that the apelinergic system chronically influences mean arterial blood pressure (MABP) under pathophysiological conditions remains to be established. In this study we investigated, in conscious unrestrained rats, whether APJ contributes to MABP and sympathetic vasomotor tone in the progression of two models of hypertension - SHR and -NAME-treated rats - and whether APJ contributes to the development of hypertension in pre-hypertensive SHR. In SHR we showed that APJ gene () expression was elevated in the RVLM, and there was a greater MABP increase following microinjection of [Pyr]apelin-13 to the RVLM of SHR compared to WKY rats. Bilateral microinjection of a lentiviral APJ-specific-shRNA construct into the RVLM of WKY, SHR, and -NAME-treated rats, chronically implanted with radiotelemeters to measure MABP, decreased expression in the RVLM and abolished acute [Pyr]apelin-13-induced increases in MABP. However, chronic knockdown of in the RVLM did not affect MABP in either SHR or -NAME-treated rats. Moreover, knockdown of in the RVLM of prehypertensive SHR did not protect against the development of hypertension. These results show that endogenous apelin, acting via APJ, is not involved in the genesis or maintenance of hypertension in either animal model used in this study.
由神经肽apelin通过G蛋白偶联的apelin受体（APJ）介导其作用所组成的apelinergic系统功能障碍，可能是诸如高血压等心血管疾病发病的基础。与Wistar-Kyoto（WKY）正常血压大鼠相比，自发性高血压大鼠（SHR）的延髓头端腹外侧区（RVLM）中apelin表达增加，然而，在病理生理条件下apelinergic系统对平均动脉血压（MABP）的长期影响的证据仍有待确立。在本研究中，我们在清醒不受约束的大鼠中研究了APJ是否在两种高血压模型——SHR和-NAME处理的大鼠——的进展中对MABP和交感神经血管运动张力有影响，以及APJ是否在高血压前期SHR的高血压发展中起作用。在SHR中，我们发现RVLM中APJ基因（）表达升高，与WKY大鼠相比，向SHR的RVLM微量注射[Pyr]apelin-13后MABP升高幅度更大。将慢病毒APJ特异性-shRNA构建体双侧微量注射到长期植入无线电遥测仪以测量MABP的WKY、SHR和-NAME处理的大鼠的RVLM中，降低了RVLM中的表达，并消除了急性[Pyr]apelin-13诱导的MABP升高。然而，RVLM中 的长期敲低对SHR或-NAME处理的大鼠的MABP均无影响。此外，高血压前期SHR的RVLM中 的敲低并不能预防高血压的发展。这些结果表明，内源性apelin通过APJ起作用，在本研究中使用的两种动物模型中均不参与高血压的发生或维持。
