Apelin Gene Transfer Into the Rostral Ventrolateral Medulla Induces Chronic Blood Pressure Elevation in Normotensive Rats

Abstract

Abstract-The peripheral apelin system plays a significant role in cardiovascular homeostasis and in the pathophysiology of cardiovascular diseases. However, the central effect of this neurohormonal system in neural control of cardiovascular function remains poorly understood. Thus, this study was undertaken to evaluate the effect of apelin in the rostral ventrolateral medulla (RVLM) on blood pressure, cardiac function, and sympathetic nerve activity. Apelin mRNA and protein levels were detected with real-time RT-PCR and Western blots, respectively. Expression of apelin was significantly enhanced in the RVLM of spontaneously hypertensive rat (SHR) compared with normotensive Wistar-Kyoto (WKY) rats. To study the functional consequence of upregulated apelin expression, apelin was overexpressed by bilateral microinjection of the AAV2-apelin viral vector into the RVLM of WKY rats. Immunofluorescence staining and Western blots demonstrated that microinjection of AAV2-apelin into the RVLM resulted in a significant increase in apelin expression, which was associated with a chronic elevation in blood pressure and cardiac hypertrophy. In addition, direct microinjection of exogenous apelin-13 (200 pmol in 50 nL) into the RVLM caused a 20 mm Hg elevation in blood pressure and a 24% increase in sympathetic nerve activity. The present study is the first to show that apelin expression is enhanced in the RVLM of SHR versus WKY rats and that overexpression of this gene in the RVLM results in chronic blood pressure elevation and cardiac hypertrophy in normotensive rats. Thus, the apelin system in the RVLM may play a very important role in central blood pressure regulation and in the pathogenesis of hypertension. Key Words: blood pressure Ⅲ hypertension Ⅲ hypertrophy Ⅲ brain Ⅲ sympathetic A pelin is a peptide recently isolated from bovine stomach extracts. 1 It has been identified as the endogenous ligand for the orphan G protein-coupled receptor APJ, 1,2 which is comprised of 7 transmembrane domains and shares a 31% amino acid sequence identity to the angiotensin II type 1 receptor. 3 Despite the degree of homology between these receptors, angiotensin (Ang) II does not bind the APJ receptor, and apelin is the only known ligand for the APJ receptor. 3 Multiple apelin peptides appear to be derived from a 77-aa precursor peptide, including preproapelin apelin-36 (42-77), apelin-17 (61-77), and apelin-13 (65-77). Apelin and APJ are widely distributed in various tissues and are thought to be involved in cardiovascular regulation, 4,5 heart contractility, body fluid homeostasis, 6 control of appetite, and, possibly, immune functions. 7 The role of apelin and APJ in the cardiovascular system is currently the best documented. The accumulated evidence indicates that apelin and its APJ receptor are expressed throughout the cardiovascular system. Both pressor and depressor responses have been described in response to peripheral administration of apelin. 1,5,8 -10 Genetic studies in humans also demonstrate that disruption of the endogenous ...

C1 neurons: the body's EMTs

“…Indeed, abnormal activity within the PVH, the NTS, and the carotid bodies contributes to various forms of hypertension (4,8,192) and heart failure is associated with excessive carotid body activity and changes in the activity of cardiopulmonary and muscle afferents (e.g., 142). A second possible cause of C1 cell hyperactivity, also supported by experimental evidence, may be some change in the local environment of these neurons, perhaps because of microvascular inflammation or glial activation (81,83,89,117,200). For example, endothelial nitric oxide (NO) synthase (eNOS) overexpression in RVLM, which plausibly increases local blood flow causes an espcially large hypotension in spontaneously hypertensive rats of the stroke prone variety (SHRSP) (88), whereas excessive levels of radical oxygen species in the RVLM seem to contribute to hypertension in this strain (89).…”

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“…Likewise, myocardial apelin levels are reduced in patients with ischemic heart failure, and these lower levels are associated with greater mortality rates and less effective cardiac remodelling post-injury (Wang et al 2013). Conversely, spontaneously hypertensive rats exhibit elevated apelin levels in the rostral ventrolateral medulla (RVLM), the region of the brainstem responsible for regulating blood pressure and other autonomic functions (Zhang et al 2009a). Microinjection of apelin into the RVLM caused chronic increases in mean arterial blood pressure (MABP) and cardiac hypertrophy.…”

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