Eleventh Annual Grant Winners 2010-2011
Title: Mechanisms of Antihypertensive Actions of Angiotensin-Converting Enzyme-2 (ACE2)
Faculty and Students:
Andres Malave Ph.D. (HPD-PHR)
Robert Speth, PhD (HPD-PHR)
Max Zimmerman, BS (FAR)
Benedict Choi, BS (FAR)
This study examines the mechanisms whereby overexpression of angiotensin-converting enzyme-2 (ACE2) in the brain lowers blood pressure in a mouse model of neurogenic hypertension. ACE2 is a recently discovered enzyme that converts the pressor hormone angiotensin II (Ang II) into a depressor hormone, angiotensin 1-7 (Ang 1-7). The receptor for Ang II that causes hypertension is the AT1 subtype. The receptor for Ang 1-7 that reduces blood pressure is the Mas oncogene protein (Mas). Immunohistochemical studies of AT1 and Mas-immunoreactivity in ACE2 overexpressing mice suggests that AT1 receptors are decreased in the nucleus of the solitary tract (NTS, a brain region important for blood pressure homeostasis) while Mas was increased in the NTS and rostroventrolateral medulla (RVLM, another brain region critical for blood pressure regulation). However, it is not known how alterations in the levels of Ang II and Ang 1-7 caused by ACE2 overexpression affects the signaling mediated by the receptors for these angiotensins. Moreover, Western blots of AT1 receptor immunoreactivity show bands with AT1 receptor immunoreactivity in AT1 receptor knock-out mice suggesting that the AT1 receptor antibodies recognize protein(s) other than the AT1 receptor. To resolve these questions about altered AT1 receptor functionality the proposed studies will measure AT1 receptors in the NTS and RVLM using receptor autoradiography. In addition, these studies will examine the expression of AT2 receptors and a novel Ang II binding protein in these brain regions by receptor autoradiography. AT2 receptors have actions that oppose those of the AT1 receptor and the novel Ang II binding protein may also counteract AT1 receptor effects. The findings of this study will provide a better understanding of how the brain controls blood pressure which may lead to development of improved antihypertensive drugs.