An imbalance in the autonomic control of cardiovascular function leads to a significant increase in mortality and morbidity from cardiovascular disease. Two major signals, one mechanical (baroreceptor) and the other chemical (chemoreceptor), are integrated to maintain a tight reflex balance of the neurohumoral control of the circulation. The molecular sensors that initiate these reflexes are largely unknown. Acid Sensing Ion Channels - ASICs (a subfamily of the DEG/ENaC family), have important mechano and acid sensing properties. Our overall hypothesis is that ASIC2 is an important component of mechanosensory signaling in arterial baroreceptors whereas ASIC1 and ASICS are predominantly proton sensing channels that contribute to activation of chemoreceptors. The reciprocal expression of these channels may account, at least in part, for the suppressed baroreflex and enhanced chemoreflex in pathological states such as heart failure, hypertension and atherosclerosis. We propose 3 experimental models linking molecular events to integrative function: i) nodose ganglia baroreceptor neurons and carotid body chemoreceptor glomus cells for quantitative PCR, immunohistochemistry and electrophysiology; ii) anesthetized rodents for recording aortic depressor and carotid sinus nerve activities as well as arterial pressure, sympathetic and phrenic nerve activities, in response to activation of baro and chemoreceptor reflexes; and iii) awake rodents using ventilatory responses and telemetric recordings of blood pressure and heart rate variabilities to assess autonomic response. Each of these models allows pharmacologic and/or genetic manipulation of molecular sensors to address three specific aims.
Aim 1 is to determine the contribution of ASICs to baroreceptor and chemoreceptor activation (Hypothesis: ASIC2 is a component of the mechanosensitive complex in baroreceptor neurons and ASIC 1 and 3 mediate chemoreceptor signaling in glomus cells).
Aim 2 is to define a role for ASICs as endogenous modulators of electrical properties through an interaction with the large conductance Ca2+ sensitive K+ channel (BK) (Hypothesis: ASIC's inhibition ofBK alters the excitability and depolarization potential of baroreceptor neurons and glomus cells respectively).
Aim 3 is to discover molecular determinants of impaired baroreceptor sensitivity and enhanced chemoreceptor sensitivity in the spontaneously hypertensive rat (SHR) model of hypertension (Hypothesis: The reciprocal dysautonomia (suppressed baro/increased chemoreflex) in SHR is caused in part by suppressed ASIC2 activity in baroreceptor neurons and enhanced ASIC1 and 3 activity in glomus cells). We plan to identify mechanisms of malfunctions of cardiovascular sensory signaling that have disastrous clinical outcomes. Preservation or restoration of normal autonomic regulation would reduce the high risk of cardiovascular mortality and morbidity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL014388-40
Application #
8376393
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
40
Fiscal Year
2012
Total Cost
$600,245
Indirect Cost
$200,082
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Li, You; Shen, Xiao Z; Li, Liang et al. (2017) Brain Transforming Growth Factor-? Resists Hypertension Via Regulating Microglial Activation. Stroke 48:2557-2564
Pierce, Gary L; Kalil, Graziela Z; Ajibewa, Tiwaloluwa et al. (2017) Anxiety independently contributes to elevated inflammation in humans with obesity. Obesity (Silver Spring) 25:286-289
DuBose, Lyndsey E; Voss, Michelle W; Weng, Timothy B et al. (2017) Carotid ?-stiffness index is associated with slower processing speed but not working memory or white matter integrity in healthy middle-aged/older adults. J Appl Physiol (1985) 122:868-876
Shaffer Jr, Joseph J; Johnson, Casey P; Fiedorowicz, Jess G et al. (2017) Impaired sensory processing measured by functional MRI in Bipolar disorder manic and depressed mood states. Brain Imaging Behav :
Singh, Madhu V (2017) Toll-Like Receptors, Hypertension, and an Antimalarial Drug. Am J Hypertens 30:118-119
Konstam, Marvin A; Abboud, Fran├žois M (2017) Ejection Fraction: Misunderstood and Overrated (Changing the Paradigm in Categorizing Heart Failure). Circulation 135:717-719
Xue, Baojian; Yin, Haifeng; Guo, Fang et al. (2017) Maternal Gestational Hypertension-Induced Sensitization of Angiotensin II Hypertension Is Reversed by Renal Denervation or Angiotensin-Converting Enzyme Inhibition in Rat Offspring. Hypertension 69:669-677
Singh, Madhu V; Cicha, Michael Z; Kumar, Santosh et al. (2017) Abnormal CD161+ immune cells and retinoic acid receptor-related orphan receptor ?t-mediate enhanced IL-17F expression in the setting of genetic hypertension. J Allergy Clin Immunol 140:809-821.e3
Wang, Runping; Lu, Yongjun; Gunasekar, Susheel et al. (2017) The volume-regulated anion channel (LRRC8) in nodose neurons is sensitive to acidic pH. JCI Insight 2:e90632
Pierce, Gary L (2017) Mechanisms and Subclinical Consequences of Aortic Stiffness. Hypertension 70:848-853

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