Patients with heart failure (HF) and all animal models of HF exhibit an increased sympathetic neural activation, which increases the risk of mortality during HF. The central mechanisms that underlie these abnormalities are poorly understood. We have previously observed that neuronal activation within the paraventricular nucleus (PVN) of the hypothalamus may contribute to elevated neuro-humoral drive. The mechanisms and source of this activation remain to be clearly delineated. Recently we uncovered enhanced excitatory mechanisms that may be mediated by an altered input from higher forebrain areas such as MnPO/SFO and/or ascending noradrenergic input as well as an altered Aldosterone-RAS mechanism involving ACE2. These data, taken together, suggest that altered descending as well as ascending noradrenergic input and an activated Aldosterone-RAS system within the PVN (with interactions between these mechanisms involving nNOS) may be involved in this sympatho-excitation. This proposal tests the hypothesis that activation of MnPO/SFO and ascending noradrenergic mechanisms in combination with the activation of Aldosterone-RAS and inactivation of ACE2 contribute to the increased sympathetic drive in HF We propose to determine 1) which factors, activation of MnPO/SFO, ascending noradrenergic pathways or Alodosterone-RAS mechanisms are primarily responsible for the down-regulation of nNOS in the PVN and subsequent sympatho-excitation in rats with HF and 2) if ExT, which normalizes levels of nNOS and the inhibitory system, also normalizes or reduces the enhanced central activation and the Aldosterone-RAS system. This goal will be accomplished by utilizing a multidisciplinary approach, ranging from studies in intact animals to studies in brain nuclei to individual cells to single molecules. We will use a variety of complementary techniques involving neuroanatomical, immunohistochemical, electrophysiological, molecular, cellular, and Adeno/Lenti viral gene transfer technology. The results will provide significant new information regarding central mechanisms of sympatho-excitation, specifically involvement of the descending and ascending input as well as the Aldosterone-RAS system to the PVN in the increased sympathetic neural activation in the HF state. Understanding the role of these central mechanisms, not studied to date mediating increased sympathetic neural drive will enhance our ability to treat the HF condition and its cardiovascular complications.

Public Health Relevance

A hallmark of chronic heart failure (HF) is increased sympathetic drive. This abnormality increases the risk of mortality during HF. While there has been some progress in elucidating the peripheral mechanisms involved in these abnormalities, the mechanisms thus far identified do not totally account for the elevated neuro-humoral drive during HF. Understanding the role of central mechanisms and the therapeutic value of exercise training will enhance our ability to treat the HF condition and its systemic complications. To date there is growing evidence that exercise training is beneficial however the central mechanisms involved are remain to be elucidated.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL062222-14
Application #
8377967
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2014-08-31
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
14
Fiscal Year
2012
Total Cost
$419,738
Indirect Cost
$137,087
Name
University of Nebraska Medical Center
Department
Type
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Wang, Han-Jun; Rozanski, George J; Zucker, Irving H (2017) Cardiac sympathetic afferent reflex control of cardiac function in normal and chronic heart failure states. J Physiol 595:2519-2534
Becker, Bryan K; Wang, Hanjun; Zucker, Irving H (2017) Central TrkB blockade attenuates ICV angiotensin II-hypertension and sympathetic nerve activity in male Sprague-Dawley rats. Auton Neurosci 205:77-86
Mishra, Paras K; Ying, Wei; Nandi, Shyam Sundar et al. (2017) Diabetic Cardiomyopathy: An Immunometabolic Perspective. Front Endocrinol (Lausanne) 8:72
Sharma, Neeru M; Nandi, Shyam S; Zheng, Hong et al. (2017) A novel role for miR-133a in centrally mediated activation of the renin-angiotensin system in congestive heart failure. Am J Physiol Heart Circ Physiol 312:H968-H979
Sharma, Neeru M; Patel, Kaushik P (2017) Post-translational regulation of neuronal nitric oxide synthase: implications for sympathoexcitatory states. Expert Opin Ther Targets 21:11-22
Schiller, Alicia M; Pellegrino, Peter Ricci; Zucker, Irving H (2017) Eppur Si Muove: The dynamic nature of physiological control of renal blood flow by the renal sympathetic nerves. Auton Neurosci 204:17-24
Schultz, Harold D (2017) Epigenetic influences on carotid body function: a new snag in the road to treating sleep apnoea. J Physiol 595:629-630
Gao, Lie; Zimmerman, Matthew C; Biswal, Shyam et al. (2017) Selective Nrf2 Gene Deletion in the Rostral Ventrolateral Medulla Evokes Hypertension and Sympathoexcitation in Mice. Hypertension 69:1198-1206
Zheng, Hong; Patel, Kaushik P (2017) Integration of renal sensory afferents at the level of the paraventricular nucleus dictating sympathetic outflow. Auton Neurosci 204:57-64
Schiller, Alicia M; Pellegrino, Peter R; Zucker, Irving H (2016) Renal nerves dynamically regulate renal blood flow in conscious, healthy rabbits. Am J Physiol Regul Integr Comp Physiol 310:R156-66

Showing the most recent 10 out of 161 publications