Heart failure with impaired systolic function (HF) is a common malady of the aging population, with dire personal and socioeconomic consequences. The past 2 decades have seen little progress in the development of new pharmaceutical agents to treat HF. A major factor contributing to the progression of HF and adverse outcomes is exaggerated sympathetic nervous system activity. Current pharmacological treatments for HF target the peripheral effects of this augmented sympathetic nerve activity, but not the central nervous system source. Recent studies in my laboratory have implicated the extracellular signal- regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway as an obligatory step leading to sympathetic excitation by many of the neurochemicals (i.e., angiotensin II, aldosterone, pro-inflammatory cytokines) that are known to be upregulated in key cardiovascular regulatory regions of the HF brain ? effectively acting as a final common pathway for these excitatory agonists. Working with a rat model of ischemia-induced HF that closely mimics systolic HF in humans, we found that reducing brain ERK1/2 activity in these regions ? and in particular in the hypothalamic paraventricular nucleus which is a source of presympathetic neurons ? reduces sympathetic nerve activity and ameliorates the peripheral manifestations of HF. In addition, our preliminary studies suggest that this molecular pathway is amenable to treatment with peripherally administered drug-loaded microparticle preparations. The present proposal will address both basic mechanistic and potential therapeutic aspects of this molecular pathway. The mechanistic studies will focus specifically on the role of ERK1/2 signaling in the hypothalamic paraventricular nucleus, a locus of presympathetic neurons known to contribute to augmented sympathetic nerve activity in HF. We will examine the role of the epidermal growth factor receptor as a putative ?gateway? to the ERK1/2 signaling pathway by multiple excitatory agonists, the effect of ERK1/2 signaling on transcription factors that upregulate the expression of excitatory agonists, the effect of ERK1/2 signaling on a potassium channel mechanisms that may increase the excitability of presympathetic neurons. The therapeutic studies will explore the possibility that an advanced drug delivery system that facilitates passage of drug across the blood brain barrier can reduce brain ERK1/2 signaling and thereby reduce sympathetic nerve activity to improve peripheral manifestations of HF and survival in HF - a critical translational issue. We anticipate that these studies will lead to better understanding of the role of brain ERK1/2 signaling in sympathetic excitation and will lay the groundwork for the development of novel pharmacological approaches to the treatment of HF.

Public Health Relevance

Excitatory neurochemical mediators increase in cardiovascular regions of the brain in systolic heart failure and cause an increase in sympathetic nervous system activity, a harbinger of adverse outcomes. We have recently identified the extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein kinase signaling pathway as a mechanism by which many of these mediators increase sympathetic nerve activity, and we have found that inhibiting brain ERK1/2 signaling substantially reduces sympathetic activity in our rat model of systolic heart failure. The proposed studies will explore the molecular mechanisms by which ERK1/2 signaling in the hypothalamic paraventricular nucleus (PVN), a forebrain region that contains presympathetic neurons, increases sympathetic nerve activity in heart failure, and will test a novel pharmaceutical approach to the treatment of brain ERK1/2 signaling in heart failure that may have important translational implications.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tjurmina, Olga A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
United States
Zip Code
Yu, Yang; Wei, Shun-Guang; Weiss, Robert M et al. (2018) Sex Differences in the Central and Peripheral Manifestations of Ischemia-induced Heart Failure in Rats. Am J Physiol Heart Circ Physiol :