A new endogenous angiotensin, angiotensin-(1-12), has been identified recently. In the periphery, angiotensin-(1-12) has been reported to exert its actions via rapid conversion to angiotensin-II. Therefore, angiotensin-(1-12) has been named as "Proangiotensin-12". The presence of Proangiotensin-12 has been reported in various tissues. Upregulation of different components of renin-angiotensin system in various tissues, including the brain, is well established in cardiovascular diseases, such as hypertension, congestive heart failure and stress. Because Proangiotensin-12 may emerge as an important component of the renin-angiotensin system, it is important to investigate the cardiovascular actions of this new angiotensin. Proangiotensin-12 was identified relatively recently (2006). No information is available about the role Proangiotensin-12 in central regulation of cardiovascular function. Our preliminary studies have demonstrated, for the first time, the presence of Proangiotensin-12 immunoreactive neurons and fibers in the hypothalamic paraventricular nucleus (PVN). The PVN is known to project to the medial subnucleus of the nucleus tractus solitarius (mNTS) and the intermediolateral cell column of the thoraco-lumbar spinal cord (IML). The PVN, mNTS and IML play an important role in the central regulation of cardiovascular function. The overall goal of this project is to characterize and understand the mechanism of cardiovascular actions of Proangiotensin-12 in the PVN, mNTS and IML. A multi-disciplinary approach, involving immunohistochemical, physiological, pharmacological and electrophysiological techniques, will be used to accomplish these aims. The results of the proposed studies are likely to provide useful information regarding the role of this new angiotensin in central cardiovascular regulation based on which future studies can be designed in which prevention and treatment of cardiovascular diseases, such as hypertension, can be attempted. The significance of the proposed studies is high considering that over 61 million Americans suffer from some type of cardiovascular disease which is the leading cause of death in this country.

Public Health Relevance

Proangiotensin-12 is a newly identified angiotensin. Angiotensins have been implicated in cardiovascular diseases like hypertension. Our preliminary studies have demonstrated the presence of Proangioensin-12 in a brain area which is important in the regulation of cardiovascular function. We have also observed that this peptide elicits diverse cardiovascular responses in different brain areas. In this proposal we will investigate the role of Pronagiotensin-12 in the brain regulation of cardiovascular function. This information is likely to be important in understanding the mechanism of some cardiovascular diseases and provide a basis for devising new treatments for these diseases. The proposed studies are important considering that cardiovascular disease is the leading cause of death in this country.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
6R01HL076248-10
Application #
8723590
Study Section
Special Emphasis Panel (ZRG1-VH-B (02))
Program Officer
Maric-Bilkan, Christine
Project Start
2004-03-05
Project End
2014-04-30
Budget Start
2013-07-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$139,336
Indirect Cost
$51,703
Name
Rutgers University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
Kawabe, Tetsuya; Kawabe, Kazumi; Sapru, Hreday N (2014) Cardiovascular effect of angiotensin-(1-12) in the caudal ventrolateral medullary depressor area of the rat. Am J Physiol Heart Circ Physiol 306:H438-49
Chitravanshi, Vineet C; Kawabe, Kazumi; Sapru, Hreday N (2013) Mechanisms of cardiovascular actions of urocortins in the hypothalamic arcuate nucleus of the rat. Am J Physiol Heart Circ Physiol 305:H182-91
Iwasa, Masamitsu; Kawabe, Kazumi; Sapru, Hreday N (2013) Activation of melanocortin receptors in the intermediolateral cell column of the upper thoracic cord elicits tachycardia in the rat. Am J Physiol Heart Circ Physiol 305:H885-93
Sapru, Hreday N (2013) Role of the hypothalamic arcuate nucleus in cardiovascular regulation. Auton Neurosci 175:38-50
Kawabe, Tetsuya; Kawabe, Kazumi; Sapru, Hreday N (2013) Tonic ýý-aminobutyric acid-ergic activity in the hypothalamic arcuate nucleus is attenuated in the spontaneously hypertensive rat. Hypertension 62:281-7
Chitravanshi, Vineet C; Sapru, Hreday N (2011) Cardiovascular responses elicited by a new endogenous angiotensin in the nucleus tractus solitarius of the rat. Am J Physiol Heart Circ Physiol 300:H230-40
Arakawa, Hideki; Chitravanshi, Vineet C; Sapru, Hreday N (2011) The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1-12) and angiotensin II. Am J Physiol Heart Circ Physiol 300:H951-60
Chitravanshi, Vineet C; Sapru, Hreday N (2011) Microinjections of urocortin1 into the nucleus ambiguus of the rat elicit bradycardia. Am J Physiol Heart Circ Physiol 300:H223-9
Kawabe, Tetsuya; Chitravanshi, Vineet C; Nakamura, Takeshi et al. (2009) Mechanism of heart rate responses elicited by chemical stimulation of the hypothalamic paraventricular nucleus in the rat. Brain Res 1248:115-26
Nakamura, Takeshi; Bhatt, Suresh; Sapru, Hreday N (2009) Cardiovascular responses to hypothalamic arcuate nucleus stimulation in the rat: role of sympathetic and vagal efferents. Hypertension 54:1369-75

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