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
Xue, Baojian; Thunhorst, Robert L; Yu, Yang et al. (2016) Central Renin-Angiotensin System Activation and Inflammation Induced by High-Fat Diet Sensitize Angiotensin II-Elicited Hypertension. Hypertension 67:163-70
Pierce, Gary L; Kalil, Graziela Z; Ajibewa, Tiwaloluwa et al. (2016) Anxiety independently contributes to elevated inflammation in humans with obesity. Obesity (Silver Spring) :
Chu, Yi; Lund, Donald D; Doshi, Hardik et al. (2016) Fibrotic Aortic Valve Stenosis in Hypercholesterolemic/Hypertensive Mice. Arterioscler Thromb Vasc Biol 36:466-74
Littlejohn, Nicole K; Keen, Henry L; Weidemann, Benjamin J et al. (2016) Suppression of Resting Metabolism by the Angiotensin AT2 Receptor. Cell Rep 16:1548-60
Pierce, G L; Harris, S A; Seals, D R et al. (2016) Estimated aortic stiffness is independently associated with cardiac baroreflex sensitivity in humans: role of ageing and habitual endurance exercise. J Hum Hypertens 30:513-20
Harwani, Sailesh C; Ratcliff, Jason; Sutterwala, Fayyaz S et al. (2016) Nicotine Mediates CD161a+ Renal Macrophage Infiltration and Premature Hypertension in the Spontaneously Hypertensive Rat. Circ Res 119:1101-1115
Chapleau, Mark W; Rotella, Diane L; Reho, John J et al. (2016) Chronic vagal nerve stimulation prevents high-salt diet-induced endothelial dysfunction and aortic stiffening in stroke-prone spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 311:H276-85
Fiedorowicz, Jess G; Dantz, Bezalel; Blazek, Mary C (2016) Attitudes and Confidence in the Integration of Psychiatry Scale. Acad Psychiatry 40:218-23
Sabharwal, Rasna; Rasmussen, Lynn; Sluka, Kathleen A et al. (2016) Exercise prevents development of autonomic dysregulation and hyperalgesia in a mouse model of chronic muscle pain. Pain 157:387-98
Xue, Baojian; Yu, Yang; Zhang, Zhongming et al. (2016) Leptin Mediates High-Fat Diet Sensitization of Angiotensin II-Elicited Hypertension by Upregulating the Brain Renin-Angiotensin System and Inflammation. Hypertension 67:970-6

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